US 2016O220537A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0220537 A1 GARNER et al. (43) Pub. Date: Aug. 4, 2016

(54) COMPOSITIONS TO IMPROVE THE (86). PCT No.: PCT/US1.4/48135 THERAPEUTIC BENEFIT OF BISANTRENE S371 (c)(1) AND ANALOGS AND DERVATIVES (2) Date: Jan. 26, 2016 THEREOF Publication Classification (71) Applicants: William J. GARNER, San Francisco, (51) Int. Cl. CA (US); Amie FRANKLIN, Mountain A613 L/478 (2006.01) View, CA (US); John ROTHMAN, A647/48 (2006.01) Lebanon, NJ (US); UPDATE PHARMA (52) U.S. Cl. INC., Lebanon, NJ (US) CPC ...... A6 IK3I/4178 (2013.01); A61K 47/48 (2013.01) (72) Inventors: William GARNER, San Francisco, CA (57) ABSTRACT (US); Amie FRANKLIN, Mountain The present invention describes methods and compositions View, CA (US); John ROTHMAN, for improving the therapeutic efficacy of therapeutic agents Lebanon, NJ (US) previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side (21) Appl. No.: 14/907,728 effects. Such methods and compositions are particularly applicable to bisantrene or derivatives, analogs, or prodrugs (22) PCT Filed: Jul. 25, 2014 thereof. US 2016/0220537 A1 Aug. 4, 2016

COMPOSITIONS TO IMPROVE THE biological Screening systems that have been Successfully THERAPEUTIC BENEFIT OF BISANTRENE used. However, from the tens of billions of dollars spent over AND ANALOGS AND DERVATIVES the past thirty years Supporting these programs both preclini THEREOF cally and clinically, only a small number of compounds have been identified or discovered that have resulted in the suc CROSS-REFERENCE TO RELATED cessful development of useful therapeutic products. Never APPLICATION theless, the biological systems both in vitro and in vivo and the “decision trees’ used to warrant further animal studies 0001. This application claims the benefit of U.S. Provi leading to clinical studies have been validated. These pro sional Patent Application Ser. No. 61/858,729 by W. A. Gar grams, biological models, clinical trial protocols, and other ner et al., filed on Jul. 26, 2013 and entitled “Compositions information developed by this work remain critical for the and Methods to Improve the Therapeutic Benefit of Bisant discovery and development of any new therapeutic agent. rene and Analogs and Derivatives Thereof.” the contents of which are hereby incorporated in their entirety by this refer 0006 Unfortunately many of the compounds that have CCC. Successfully met the preclinical testing and federal regulatory requirements for clinical evaluation were either unsuccessful FIELD OF THE INVENTION or disappointing in human clinical trials. Many compounds were found to have untoward or idiosyncratic side-effects that 0002 The present invention is directed to methods and were discovered during human clinical Phase I dose-escala compositions to improve the therapeutic benefit of bisantrene tion studies used to determine the maximum tolerated dose and analogs and derivatives thereof, particularly in the treat (MTD) and side-effect profile. In some cases, these toxicities ment of malignancies. or the magnitude of their toxicity were not identified or pre dicted in preclinical toxicology studies. In other cases, chemi BACKGROUND OF THE INVENTION cal agents where in vitro and in vivo studies Suggested a 0003. The search for and identification of cures for many potentially unique activity against a particular tumor type, life-threatening diseases that plague humans still remains an molecular target or biological pathway were not successful in empirical and sometimes Serendipitous process. While many human Phase II clinical trials where specific examination of advances have been made from basic Scientific research to particular cancer indications/types were evaluated in govern improvements in practical patient management, there still ment sanctioned (e.g., U.S. FDA), IRB approved clinical remains tremendous frustration in the rational and Successful trials. In addition, there are those cases where potential new discovery of useful therapies particularly for life-threatening agents were evaluated in randomized Phase III clinical trials diseases such as cancer, inflammatory conditions, infection, where a significant clinical benefit could not be demon and other conditions. strated; Such cases have also been the cause of great frustra 0004 Since the “Waron Cancer” began in the early 1970's tion and disappointment. Finally, a number of compounds by the United States National Cancer Institute (NCI) of the have reached commercialization but their ultimate clinical National Institutes of Health (NIH), a wide variety of strate utility has been limited by poor efficacy as monotherapy gies and programs have been created and implemented to (<25% response rates) and untoward dose-limiting side-ef prevent, diagnose, treat and cure cancer. One of the oldestand fects (Grade III and IV) (e.g., myelosuppression, neurotoxic arguably most Successful programs has been the synthesis ity, cardiotoxicity, gastrointestinal toxicities, or other signifi and screening of small chemical entities (<1500 MW) for cant side effects). biological activity against cancer. This program was orga 0007. In many cases, after the great time and expense of nized to improve and streamline the progression of events developing and moving an investigational compound into from chemical synthesis and biological Screening to preclini human clinical trials and where clinical failure has occurred, cal studies for the logical progression into human clinical the tendency has been to return to the laboratory to create a trials with the hope of finding cures for the many types of better analog, look for agents with different structures but life-threatening malignant tumors. The synthesis and screen potentially related mechanisms of action, or try other modi ing of hundreds of thousands of chemical compounds from fications of the drug. In some cases, efforts have been made to academic and industrial sources, in addition to the screening try additional Phase I or II clinical trials in an attempt to make of natural products and extracts from prokaryotes, inverte some improvement with the side-effect profile or therapeutic brate animals, plant collections, and other sources from all effect in selected patients or cancer indications. In many of over the world has been and continues to be a major approach those cases, the results did not realize a significant enough for the identification of novel lead structures as potential new improvement to warrant further clinical development toward and useful medicines. This is in addition to other programs product registration. Even for commercialized products, their including biotherapeutics designed to stimulate the human ultimate use is still limited by suboptimal performance. immune system with vaccines, therapeutic antibodies, cytok 0008. With so few therapeutics approved for cancer ines, lymphokines, inhibitors of tumor blood vessel develop patients and the realization that cancer is a collection of ment (angiogenesis) or gene and antisense therapies to alter diseases with a multitude of etiologies and that a patients the genetic make-up of cancer cells, and other biological response and Survival from therapeutic intervention is com response modifiers. plex with many factors playing a role in the Success or failure 0005. The work supported by the NCI, other governmental of treatment including disease indication, stage of invasion agencies both domestic and foreign in academic or industrial and metastatic spread, patient gender, age, health conditions, research and development laboratories has resulted in an previous therapies or other illnesses, genetic markers that can extraordinary body of biological, chemical and clinical infor either promote or retard therapeutic efficacy, and other fac mation. In addition, large chemical libraries have been cre tors, the opportunity for cures in the near term remains elu ated, as well as highly characterized in vitro and in vivo sive. Moreover, the incidence of cancer continues to rise with US 2016/0220537 A1 Aug. 4, 2016 an approximate 4% increase predicted for 2003 in the United approval by government agencies for commercialization or States by the American Cancer Society such that over 1.3 commercialized agents whose clinical performance (i.e. million new cancer cases are estimated. In addition, with response rates) as a monotherapy are less than 25%, or whose advances in diagnosis such as mammography for breast can cer and PSA tests for prostate cancer, more patients are being side-effects are severe enough to limit wide utility. More diagnosed at a younger age. For difficult to treat cancers, a specifically, the inventive methods and compositions also patient’s treatment options are often exhausted quickly focus on improvements for bisantrene and derivatives orana resulting in a desperate need for additional treatment regi logs thereof, including, but not limited to, the derivatives and mens. Even for the most limited of patient populations, any analogs described below. additional treatment opportunities would be of considerable value. This invention focuses on inventive compositions and 0013. One aspect of the present invention is a method to methods for improving the therapeutic benefit of sub-opti improve the efficacy and/or reduce the side effects of subop mally administered chemical compounds including Substi timally administered drug therapy comprising the steps of: tuted hexitols such as dianhydrogalactitol. 0.014 (1) identifying at least one factor or parameter 0009 Relevant literature includes Foye, W. O., “Cancer associated with the efficacy and/or occurrence of side Chemotherapeutic Agents. American Chemical Society, effects of the drug therapy; and 1995, and Dorr, R.T., and Von Hoff, D.D., “Cancer Chemo 0.015 (2) modifying the factor or parameter to improve therapy Handbook. Appleton and Lange, 1994. the efficacy and/or reduce the side effects of the drug 0010. Therefore, there is a need for compositions and therapy; wherein the drug therapy comprises adminis methods including bisantrene or analogs or derivatives tration of bisantrene or a derivative or analog thereof. thereof that improve the therapeutic benefit of these com pounds, particularly for the treatment of malignancies. There 0016. In one alternative, the drug therapy comprises is a particular need for combinatorial methods to improve the administration of bisantrene. In another alternative, the drug therapeutic benefit of these compounds. therapy comprises a derivative or analog of bisantrene. 0017. The derivative or analog of bisantrene can be SUMMARY OF THE INVENTION selected from the group consisting of: 0011. This invention relates to novel compositions and 0.018 (a) the bisantrene analog of Formula (II) methods to improve the utility of chemical agents with sub optimal performance in patients suffering with immunologi (II) cal disease, metabolic disease, infection, or hyperprolifera H tive diseases including cancer. The invention describes novel N improvements, pharmaceutical ingredients, dosage forms, NH { D excipients, solvents, diluents, drug delivery systems, preser N N Vatives, more accurate drug administration, improved dose n •2HCl; determination and schedules, toxicity monitoring and ame lioration, techniques or agents to circumvent or reduce tox icity, techniques and tools to identify/predict those patients who might have a better outcome with a therapeutic agent by the use of phenotype or genotype determination through the use of diagnostic kits or pharmacokinetic or metabolism monitoring approaches. The invention also relates to the use 0.019 (b) the bisantrene analog of Formula (III) of drug delivery systems, novel prodrugs, polymer conju gates, novel routes of administration, other agents to poten (III) tiate the activity of the compounds or inhibit the repair of H suboptimal cellular effects or sublethal damage or to “push' N the cell into more destructive cellular phases Such as apopto NH { D sis. In some case, the use of these Suboptimal therapeutics in N N conjunction with radiation or other conventional chemothera n •2HCl; peutic agents or biotherapeutic agents such as antibodies, vaccines, cytokines, lymphokines, gene and antisense thera pies, or other biotherapeutic agents, would provide novel approaches and significant improvement. 0012. In the inventive compositions and methods, the term Suboptimal therapy includes agents where Phase I toxicity N precluded further human clinical evaluation. It also includes those agents from Phase II trials where limited or no signifi HNN cant tumor responses were identified. Also, Suboptimal therapy includes those agents, the subject of Phase III clinical trials the outcome of which was either medically or statisti cally not significant to warrant regulatory Submission or US 2016/0220537 A1 Aug. 4, 2016

0020 (c) the bisantrene analog of Formula (IV) 0024 (g) the bisantrene analog of Formula (VIII)

(IV)

HN N

(VIII)

0021 (d) the bisantrene analog of Formula (V) 0.025 (h) the bisantrene analog anthracen-9-ylmethyl (V) ene-2-methoxyethoxymethylsulfanyl-5-pyridin-3-yl 1.2.4 triazol-4-amine;

NHNN 0026 (i) the bisantrene analog of Formula (X)

(X) 0022 (e) the bisantrene analog of Formula (VI) ) (VI) s 2 N N. HN N HNS

0027 () the bisantrene analog of Formula (XI)

0023 (f) the bisantrene analog of Formula (VII)

(VII) (XI)

HN O)N 2 N

2 N US 2016/0220537 A1 Aug. 4, 2016

0028 (k) the bisantrene analog of Formula (XII) ent can be ortho, meta, or para and is fluoro, nitro, C-C alkyl, C-C alkoxy, or cyano), pentafluorophenyl, naphthyl, fura nyl, (XII) CH3 t -CHNHCOOC(CH3)3, -CHNH2, -CH2CHCOOH, -OC(CH3)3, -CHOCH, COOH

-(CH2)3COOH, -(CH2)2SOH or

O O -CHNsGE) (CH3)3CI));e, -P(OH), -P(OCH3), --( ) )2, --( )—cil O

SOH; wherein only one of R and R may be hydrogen or 0029 (1) the bisantrene analog of Formula (XIII) C-C alkyl; R and Ra are the same or different and are: hydrogen, C-C alkyl or—C(O)—R, where R is hydrogen, C-C alkyl, phenyl, mono-Substituted phenyl (wherein the (XIII) Substituent may be in the ortho, meta, or para position and is fluoro, nitro, C-C alkyl, C-C alkoxy, or cyano), pentafluo rophenyl, naphthyl, furanyl, or —CHOCH. The com pounds can have the schematic structure B(O), wherein B is the residue formed by removal of a hydrogen atom from one or more basic nitrogen atoms of an amine, amidine, guani dine, isourea, isothiourea, or biguanide-containing pharma ceutically active compound, and Q is hydrogen or A, wherein A is

RO 9 V

such that RandR" are the same or different and are R (where R is C-C alkyl, aryl, aralkyl, heteroalkyl, NC CHCH . 0030 (m) bisantrene analogs of Formula (XIV)

R D-CH R2 N ClC CH , or R.OCHCH , where R, is hydrogen or C-C alkyl, hydrogen, or a pharmaceutically acceptable cat ---K ion or R' and R" are linked to form a —CHCH group or a R3 N CHEN-N R4 KN wherein RandR are the same or different and are hydrogen, group, and n is an integer representing the number of primary C-C alkyl, —C(O)—Rs, wherein Rs is hydrogen, C-C, or secondary basic nitrogenatoms in the compound such that alkyl, phenyl, mono-substituted phenyl (wherein the substitu at least one Q is A: US 2016/0220537 A1 Aug. 4, 2016

0031 (n) the bisantrene analog 9,10-bis(2-hydroxy 0078 (36) use to inhibit telomerase or induce telomere ethyl)iminomethylanthracene; dysfunction; 0032 (o) the bisantrene analog 9,10-bis(2-(-2-hy 0079 (37) use to activate macrophages or innate immu droxyethylamino)ethyliminomethyl)anthracene; nity; 0033 (p) the bisantrene analog 9,10-bis(2-(-2-hy droxyethylamino)ethyliminomethyl)anthracene; 0080 (38) use to inhibit expression of survivin or with 0034 (q) the bisantrene analog 9,10-bis(2-(morpho survivin inhibitors or modulators; lin-4-yl)ethyliminomethyl)anthracene; 0081 (39) use with multidrug resistance reversal 0035 (r) the bisantrene analog 9,10-bis(2-hydroxy agents; ethyl)aminomethylanthracene; 0082 (40) use in combinatorial regimes: 0036 (s) the bisantrene analog 9,10-bis(2-(2-hy 0.083 (41) use with directed antibody conjugates; and droxyethylamino)ethylaminomethyl)anthracene tet 0084 (42) use with adjuvants. rahydrochloride: I0085. Another aspect of the invention is a composition to 0037 (t) the bisantrene analog 9,10-bis(2-(piperazin improve the efficacy and/or reduce the side effects of subop 1-yl)ethylaminomethyl)anthracene hexahydrochlo timally administered drug therapy comprising an alternative ride; selected from the group consisting of: 0038 (u) the bisantrene analog 9,10-bis(2-(morpho I0086 (a) a therapeutically effective quantity of a modi lin-4-yl)ethylaminomethyl)anthracene tetrahydro fied therapeutic agent or a derivative, analog, or prodrug chloride; of a therapeutic agent or modified therapeutic agent, 0039 (v) N,N'-bis(2-(dimethylamino)ethyl-9,10-an wherein the modified therapeutic agent or the derivative, thracene-bis(methylamine); analog or prodrug of the therapeutic agent or modified 0040 (w) N,N'-bis(1-ethyl-3-piperidinyl)-9,10-an therapeutic agent possesses increased therapeutic effi thracene-bis(methylamine); and cacy or reduced side effects as compared with an 0041 (x) derivatives and salt forms of the compounds of unmodified therapeutic agent; (a)-(u). 0042 Typically, the factor or parameter is selected from 0087 (b) a composition comprising: the group consisting of I0088 (i) a therapeutically effective quantity of a 0043 (1) dose modification; therapeutic agent, a modified therapeutic agent or a 0044 (2) route of administration; derivative, analog, or prodrug. ofatherapeutic agent or 0045 (3) schedule of administration; modified therapeutic agent; and 0046 (4) indications for use: I0089 (ii) at least one additional therapeutic agent, 0047 (5) selection of disease stage; therapeutic agent Subject to chemosensitization, 0048 (6) other indications; therapeutic agent Subject to chemopotentiation, dilu 0049 (7) patient selection: ent, excipient, solvent system, drug delivery system, 0050 (8) patient/disease phenotype: or agent for enhancing the activity or efficacy of the 0051 (9) patient/disease genotype: therapeutic agent, the modified therapeutic agent or 0.052 (10) prefpost-treatment preparation; the derivative, analog, or prodrug of a therapeutic 0053 (11) toxicity management; agent or modified therapeutic agent of (a), wherein the 0054 (12) pharmacokinetic/pharmacodynamic moni composition possesses increased therapeutic efficacy toring: or reduced side effects as compared with an unmodi 0055 (13) drug combinations: fied therapeutic agent; 0090 (c) a therapeutically effective quantity of a thera 0056 (14) chemosensitization; peutic agent, a modified therapeutic agent, or a deriva 0057 (15) chemopotentiation: tive, analog, or prodrug of a therapeutic agent or modi 0.058 (16) post-treatment patient management; fied therapeutic agent that is incorporated into a dosage 0059 (17) alternative medicine/therapeutic support; form, wherein the therapeutic agent, the modified thera 0060 (18) bulk drug product improvements; peutic agent, or the derivative, analog, or prodrug of a 0061 (19) diluent systems; therapeutic agent or modified therapeutic agent incorpo 0062 (20) solvent systems: rated into the dosage form possesses increased therapeu 0063 (21) excipients: tic efficacy or reduced side effects as compared with an 0064 (22) dosage forms: unmodified therapeutic agent; 0065 (23) dosage kits and packaging: 0.091 (d) a therapeutically effective quantity of a thera 0.066 (24) drug delivery systems; peutic agent, a modified therapeutic agent, or a deriva 0067 (25) drug conjugate forms; tive, analog, or prodrug of a therapeutic agent or modi 0068 (26) compound analogs; fied therapeutic agent that is incorporated into a dosage 0069 (27) prodrugs: kit and packaging, wherein the therapeutic agent, the 0070 (28) multiple drug systems; modified therapeutic agent, or the derivative, analog, or 0071 (29) biotherapeutic enhancement; prodrug of a therapeutic agent or modified therapeutic 0072 (30) biotherapeutic resistance modulation; agent incorporated into the dosage kit and packaging 0073 (31) radiation therapy enhancement; possesses increased therapeutic efficacy or reduced side 0074 (32) novel mechanisms of action; effects as compared with an unmodified therapeutic 0075 (33) selective target cell population therapeutics; agent, 0076 (34) use with an agent enhancing its activity; 0092 (e) a therapeutically effective quantity of a thera (0077 (35) use to modulate DNA methylation: peutic agent, a modified therapeutic agent, or a deriva US 2016/0220537 A1 Aug. 4, 2016

tive, analog, or prodrug of a therapeutic agent or modi 0106 (c) is formulated for use in a program of alteration fied therapeutic agent that is Subjected to a bulk drug or modification of schedule of administration; product improvement; 0.107 (d) is formulated for use in a program of selecting 0093 (f) a therapeutically effective quantity of a thera appropriate indications for use: peutic agent or a derivative, analog, or prodrug of a 0.108 (e) is formulated for use in a program of selecting therapeutic agent, wherein the therapeutic agent or the appropriate disease stages for use: derivative, analog, or prodrug of the therapeutic agent is 0.109 (f) is formulated for use in a program of selecting optimized for increasing an immunologic response; and appropriate additional indications for use: 0094 (g) a composition comprising: 0110 (g) is formulated for use in a program of selecting 0.095 (i) a therapeutically effective quantity of a appropriate patients for use of the composition; therapeutic agent or a derivative, analog, or prodrug of 0.111 (h) is formulated for use in a program of selecting a therapeutic agent; and appropriate patient or disease phenotypes for use of the 0096 (ii) at least one immune adjuvant for stimulat composition; ing an immune response; 0112 (i) is formulated for use in a program of selecting wherein the therapeutic agent, the modified therapeutic agent, appropriate patient or disease genotypes for use of the or the derivative, analog, or prodrug of a therapeutic agent or composition; modified therapeutic agent Subject to the bulk drug product 0113 () is formulated for use in a program of toxicity improvement possesses increased therapeutic efficacy or management; reduced side effects as compared with an unmodified thera 0114 (k) is formulated for use in a program of pre?post peutic agent; wherein the unmodified therapeutic agent is treatment management; bisantrene or a derivative or analog of bisantrene, the modi 0115 (1) is formulated for use in a program of post fied therapeutic agent is a modification of bisantrene or a treatment management; derivative or analog of bisantrene, and the derivative, analog, 0116 (m) is formulated for use in a program of alterna or prodrug is a derivative, analog, or prodrug of bisantrene or tive medicine/therapeutic Support; of a derivative or analog of bisantrene. 0.117 (n) is formulated for use in a program of biothera 0097. Accordingly, as described in further detail below, peutic enhancement; one aspect of the present invention is a composition to 0118 (o) is formulated for use in a program of biothera improve the efficacy and/or reduce the side effects of subop peutic resistance modulation; timally administered drug therapy comprising a therapeuti 0119 (p) is formulated for use in a program of radiation cally effective quantity of a therapeutic agent or modified therapy enhancement; therapeutic agent or a derivative, analog, or prodrug of a 0120 (q) is formulated for use to employ novel mecha therapeutic agent or modified therapeutic agent, wherein the nisms of action in its therapeutic activity; therapeutic agent or modified therapeutic agent or the deriva 0121 (r) is formulated for use in a program of selective tive, analog or prodrug of the therapeutic agent or modified target cell population therapeutics; therapeutic agent possesses increased therapeutic efficacy or 0.122 (s) is formulated for use in a program of modu reduced side effects, wherein the composition: lating DNA methylation; 0.098 (a) includes at least one bulk drug product 0123 (t) is formulated for use in a program of inhibiting improvement; telomerase or inducing telomere dysfunction; 0099 (b) is produced in a specified dosage form: 0.124 (u) is formulated for use in a program of activat 0100 (c) includes a drug conjugate form; ing macrophages and/or inducing innate and/or adaptive 0101 (d) includes a compound analog; or immunity; 0102 (e) includes a prodrug; 0.125 (v) is formulated for use in a program of inhibit wherein the therapeutic agent, the modified therapeutic agent, ing Survivin; or the derivative, analog, or prodrug of a therapeutic agent or 0.126 (w) further comprises a diluent; modified therapeutic agent Subject to the bulk drug product 0.127 (x) further comprises a solvent system; improvement possesses increased therapeutic efficacy or 0.128 (y) further comprises an excipient; reduced side effects as compared with an unmodified thera 0.129 (Z) is incorporated into a dosage kit and packag peutic agent; wherein the unmodified therapeutic agent is 1ng bisantrene or a derivative or analog of bisantrene, the modi 0.130 (aa) comprises a drug delivery system; or fied therapeutic agent is a modification of bisantrene or a 0131 (ab) is formulated to optimize an immunological derivative or analog of bisantrene, and the derivative, analog, response; or prodrug is a derivative, analog, or prodrug of bisantrene or wherein the therapeutic agent or the modified therapeutic of a derivative or analog of bisantrene. agent in the composition possesses increased therapeutic effi 0103) As described in further detail below, another aspect cacy or reduced side effects as compared with the therapeutic of the present invention is a composition to improve the agent or unmodified therapeutic agent as administered indi efficacy and/or reduce the side effects of suboptimally admin vidually and not in the composition, wherein the unmodified istered drug therapy comprising a therapeutically effective therapeutic agent is bisantrene or a derivative or analog of quantity of a therapeutic agent or modified therapeutic agent, bisantrene, and the modified therapeutic agent is a modifica wherein the composition: tion of bisantrene or a derivative or analog of bisantrene. 0104 (a) is formulated for use in a program of dose 0.132. As described in further detail below, yet another modification; aspect of the present invention is a composition to improve 0105 (b) is formulated for use in a program of alteration the efficacy and/or reduce the side effects of suboptimally or modification of route of administration; administered drug therapy comprising a therapeutically US 2016/0220537 A1 Aug. 4, 2016

effective quantity of a therapeutic agent or modified thera site necrosis, enterocolitis, muscle degeneration, and pulmo peutic agent, wherein the composition further comprises: nary edema were observed. Although anthracyclines, despite 0.133 (a) an additional therapeutic agent; their clinical utility, are known to be cardiotoxic, the toxicity 0.134 (b) a therapeutic agent subject to chemosensitiza of bisantrene was observed to be less than that of the anthra tion; cycline doxorubicin. 0.135 (c) a therapeutic agent subject to chemopotentia 0145 Because of its lack of aqueous solubility at physi tion; ologic pH bisantrene precipitates in the body have been 0.136 (d) a second therapeutic agent that forms a mul observed in studies of rabbits and calves. Deposition of drug tiple drug system; into the tissues has been associated with phlebitis, and depo 0.137 (e)anagent that enhances the activity of the thera sition has also been explored as a mechanism for the delivery peutic agent or modified therapeutic agent; of high tissue concentrations of the drug. 0.138 (f) at least one survivin modulator or inhibitor; 0146 Bisantrene may have immunologic and/or genomic 0.139 (g) at least one multidrug resistance reversal properties that might be responsible for some of its activities, agent, and which may make this agent a useful tool in the combina 0140 (h) at least one directed antibody conjugate; torial treatment of cancer in conjunction with newer immu 0141 (i) at least one adjuvant; or notherapeutic agents. Subsequent to treatment with bisant 0.142 () an additional therapeutic agent suitable for use rene, treated with bisantrene, and for 4 weeks thereafter, with the therapeutic agent in a combinatorial regime, macrophages could be isolated from peritoneal exudate that wherein the quantities of the therapeutic agent and the had cytostatic anti-proliferative functionality in cultures of additional therapeutic agent are chosen to provide effec P815 (mastocytoma) tumor cells. Moreover, the supernatants tive activity of both the therapeutic agent and the addi from bisantrene activated macrophages also had a protective tional therapeutic agent, wherein the therapeutic agent cytostatic effect in the tumor cell cultures. Further work or the modified therapeutic agent in the composition revealed that macrophages activated with bisantrene and possesses increased therapeutic efficacy or reduced side adoptively transferred to mice with EL-4 lymphomas more effects as compared with the therapeutic agent or than doubled their median survival time, with 7 of 10 mice in unmodified therapeutic agent as administered individu the group being cured. Multiple administrations of activated ally and not in the composition, wherein the unmodified macrophages were more effective than a single administra therapeutic agent is bisantrene or a derivative or analog tion. of bisantrene, and the modified therapeutic agent is a 10147 There is also evidence that the survivin inhibitors modification of bisantrene or a derivative or analog of research that looked at the effect of bisantrene on survivin bisantrene. reported an interaction; one paper did find that the Survivin inhibitors NSC80467 and YM155 acted in a manner that DETAILED DESCRIPTION OF THE INVENTION correlated with the known mechanism of DNA expression 0143 Bisantrene is an unusual agent with direct cytotoxic inhibition of bisantrene. action as well as genomic and immunologic methods of 0.148 Bisantrene has also been found to have non-immu action. The chemical name forbisantrene is 9, 10-anthracene nologic telomeric effects. Bisantrene binds to DNA at a site dicarboxaldehyde-bis(4, 5-dihydro-1H-imidazole-2-yl) called a G-quadraplex, in which 4 guanines are associated by hydrazinedihydrochloride, and it was originally classed as folding. Stabilization of the G-quadraplex can interfere with an anthracycline chemotherapeutic agent. These are drugs telomere-telomerase interaction and thus inhibit the activity with planar structures based around a resonant aromatic ring of telomerase in various ways, including the displacement of structure that intercalates within the helices of DNA and telomerase binding proteins. Since the level oftopoisomerase disrupt various functions, including replication, presumably II inhibition does not always correlate with cytotoxic efficacy, due to a strong inhibitory effect on the enzyme topoisomerase alternative mechanisms may play a role in the actions of II. It was found that, like other anthracyclines, it could kill bisantrene. Analogs of bisantrene have been made in an tumor cells in clonogenic assays and intercalate with DNA, attempt to improve upon the anti-telomerase activity; these where it inhibits both DNA and RNA synthesis. The primary analogs are described further below. Human melanoma (SK chemo-therapeutic mechanism for bisantrene is its preferen Mel5) and colon cancer (LoVo) tumor cells were observed to tial binding to A-T rich regions where it effects changes to lose their proliferative ability in the presence of these agents. Supercoiling and initiates Strand breaks in association with Apoptosis was not observed, however a loss of immortality DNA associated proteins. This results from the inhibition of was seen, with treated cells reacquiring the ability to become the enzyme topoisomerase II, which relaxes DNA coiling Senescent, age, and die. during replication. It was found that while inactive orally, 0149 Several clinical trials have investigated the pharma intravenously (i.v.), intraperitoneally (i.p.), or Subcutane cokinetics of bisantrene in humans. In one trial of patients ously (s.c.), the drug was effective in cancer models using given a 90 mininfusion at 260 mg/m a biphasic elimination colon 26, Lewis lung, Ridgway osteosarcoma, B16, Lieber with an initial half-life of 65+15 min, a terminal half-life of man plasma cell, P388 or L1210 cancer cells. Activity in 1142+226 min, and a steady state volume of distribution clonogenic assays from 684 patients was seen in breast, Small (Vdss) of 1845 L/m. Plasma clearance in this trial was 735 cell lung, large cell lung, Squamous cell lung, ovarian, pan ml/min/m, with 11.3% of the administered dose excreted creatic, renal, adrenal, head and neck, sarcoma, gastric, lym unchanged in the urine in 24 hr. In another trial, doses of phoma and melanoma tumor cells, but not in colorectal can 80-250 mg/m were assessed, and the initial and terminal cer. Importantly, a lack of cross resistance with adriamycin half-lives were 0.6 hr and 24.7 hr, respectively, with a clear and mitoxantrone was found. ance of 1045.5+51.0 ml/kg/hr and a calculated volume of 0144. Toxicity studies in in dogs and monkeys revealed distribution of 42.1+5.9 L/kg. In this study only 3.4+1.1% of that at high doses leukopenia, anorexia, diarrhea, injection the administered dose was found in the urine over 96 hr. In US 2016/0220537 A1 Aug. 4, 2016

three other single dose studies triphasic elimination was tolerated dose (MTD) model. That is, since the drug is a toxin reported, one with t'//a, (3, and Y of 3.44 min, 1.33 hr and and the objective is to kill cells (hopefully more cancer cells 26.13 hr, respectively, another was 3 min, 1 hr., and 8 hr than healthy normal cells) that the way to determine the most respectively, and the last revealed clearances of 0.1 hr, 1.9 hr effective dose was to see how much drug could be given and 43.9 hr, respectively. In one report a large volume of before doing irreparable damage to the patient. In this model, distribution (687 L/m) was interpreted as tissue sequestra deaths due to drug overdose were an unfortunate but accepted tion of the drug with a subsequent depot effect. In a 72-hr aspect of treatment. Immunotherapy was in its infancy, and infusion study, a plasma concentration of 12-6 ng/ml was immunologic efficacy was not a consideration in the devel observed at a dose of 56 mg/m, while a dose of 260 mg/m opment of anti-cancer agents of the day. Today we know that resulted in a plasma concentration of 55+8 ng/ml. In this trial a maximum tolerated dose is not necessarily the maximum plasma clearance was 1306+179 ml/min/m with urinary immune-efficient dose, and that immune efficacy results from excretion of 4.6% of the dose in 24 hr. Finally, in another the Summation of many disparate events which may be under study, a 5 day schedule of 60 min infusions revealed a t/2 C. stimulated or over-stimulated at any given time. Further, and B of 0.9 and 9.7 hr, respectively with 7.1% of the dose many of the bisantrene studies reported in the 1980's used a excreted in the urine. classical RECIST reporting schema that quantified objective 0150. In phase 1 trials toxicity consisting of myelosup responses, but did not look at overall survival (OS). It is now pression, phlebitis, erythema and edema was observed in known that different therapies can increase Survival signifi patients with melanoma, hypernephroma, renal cell, cantly, even in the absence of objective responses. Therefore, hepatoma, bladder, or lung adenoma. A phase I pediatric the clinical models and reporting structures used at the time of study at doses between 10-120 mg/m2/dx5 q3W observed bisantrene development were not sufficient to understand the leukopenia, neutropenia, minor LFT elevations, transient BP potential mechanisms of action of the drug or to capture all of fluctuation during infusion, transient edema at injection site, the important clinical outcomes. and phlebitis. A phase I study found the MTD to be 300 0153. The development of an agent that has both cytotoxic mg/m2 over 72 h with doses over 156 mg/m2 requiring a and anti-tumor immune stimulating properties is a novel para central line due to phlebitis. Allergic reactions, fever, dysp digm for which no clinical models exist. However, at a time in nea, and chest pain were observed. Another study found IA which a considerable effort is being given to understanding infusions to be of no benefit over IV administration. In how to integrate the newer immunotherapies with the existing another study, with phase I doses between 190-430 mg/m2 battery of effective chemotherapeutic agents, bisantrene may q3w, neutropenia was found to be the DLT, and phlebitis was be poised to become a useful tool to develop methods for observed. In phase II trials, the trials included patients with integrating these two disparate therapeutic modalities. breast, colon, gastric, head and neck, hepatoma, NSCLC, 0154 The structure of bisantrene hydrochloride is shown SCLC, melanoma, leukemia, Hodgkin’s and NHL lym in Formula (I) phoma, multiple myeloma, ovarian, pancreas, prostate, renal, bladder, sarcoma, and a variety of pediatric cancers. Most patients had been previously treated. Adverse events (AE) (I) were similar to that observed in phase I. In a phase III trial, it was found that bisantrene was less cardiotoxic than mitox antrone or doxorubicin. Also, it is worth noting that in a number of clinical trials in which central venous administra tion was used that toxicity was noted to be considerably less than with peripheral venous administration. 0151. Prior trials, concerned with a toxic chemotherapeu N tic mechanism of action in which the clinical dose was defined by tolerance, a model not suitable for the develop ment of immunotherapies. The maximum tolerated dose id=N-NH-(N D model for the development of bisantrene was attended by H toxicities that prompted investigators to co-administer hydro cortisone to limit potential acute inflammatory and allergic 0155 Bisantrene is a tricyclic aromatic compound with reactions which may have negatively impacted the then the chemical name, 9,10-anthracenedicarboxaldehyde bis(4, unrecognized immunologic aspects of the drug. These prior 5-dihydro-1H-imidazol-2-yl)hydrazinedihydrochloride. trials typically reported objective response rates, usually The molecular formula is CHNs.2HCl and the molecular predicated on the RECIST scale (Response Evaluation Cri weight, 471.4. The alkylimidazole side chains are very basic teria In Solid Tumors), but not survival, performance status, and, at physiologic pH, are positively charged. This is or other measures of response. The methodology of Such believed to facilitate electrostatic attractions to negatively trials was derived from agents having a chemotherapeutic charged ribose phosphate groups in DNA. mechanism of action exclusively, not best Suited for agents 0156 Bisantrene has shown antitumor activity in murine with immunological or genomic effects Such as bisantrene, as tumor models including P-388 leukemia and B-16 melanoma it is now known that immune therapies can have salutary (R. V. Citarella et al., “Anti-Tumor Activity of CL-216942: effects on Survival independent of tumor responses, and that 9,10-Anthracenedicarboxaldehyde bis(4,5-dihydro-1H-imi even minor responses of the type not reported in the older dazol-2-yl)hydrazone) dihydrochloride (Abstract #23) in studies can be attended by a favorable overall outcome in Abstracts of the 20' Interscience Conference on Antimicro terms of performance status and Survival. bial Agents and Chemotherapy (Bethesda, Md., American 0152 Cancer drug development in the 1980s, especially Society for Microbiology 1980)). Human tumor cells that anthracycline development, was predicated upon a maximum were sensitive to bisantrene as assessed by in vitro colony US 2016/0220537 A1 Aug. 4, 2016

forming assays include breast cancer, ovarian cancer, renal 0159. In one alternative, bisantrene vials have been recon cancer, Small cell and non-Small cell lung cancer, lymphoma, stituted with 2 to 5 mL of Sterile Waterfor Injection, USP, and acute myelogenous leukemia, melanoma, gastric cancer, then diluted with approximately 0.1 to 0.5 mg/mL in D5W adrenal cancer, and head and neck cancer (D. D. Von Hoffet (5% dextrose in water). Bisantrene is incompatible with al, “Activity of 9,10-Anthracenedicarboxaldehyde bis(4,5- saline and unstable in light (G. Powis et al., “Pharmacokinetic dihydro-1H-imidazol-2-yl)hydrazinedihydrochloride Study of ADAH in Humans and Sensitivity of ADAH to (CL216,942) in a human tumor cloning system. Cancer Light” (Abstract #C-74).” ASCO Proc. 1: 19 (1982). Chemother: Pharmacol. 6: 141-144 (1981) (“Von Hoffet al. 0160 Because of severe local venous toxicity, bisantrene (1981a)”). In phase I clinical trials bisantrene showed activity doses have been infused via central venous access devices in hepatocellular cancer and hypernephroma (one patient over 1 hour (Van Hoff et al., 1981b). Bisantrene has been each) (D.D. Von Hoffet al., Phase I Clinical Investigation of infused through peripheral veins over 2 hours, and has been 10-Anthracenedicarboxaldehyde bis(4,5-dihydro-1H-imi "piggybacked' into a running dextrose infusion in an attempt dazol-2-yl)hydrazinedihydrochloride (CL216,942). Can to lessen delayed Swelling in the arm used for infusion. cer Res. 31 18-3121 (1981) (“Von Hoffetal. (1981b)') and in 0.161 To reduce venous irritation, hyperpigmentation, lymphoma, myeloma, melanoma, renal cancer, and tumors of drug extravasation, and anaphylactoid reactions, patients the bladder and lung (D. S. Alberts et al., “Phase I Clinical have been given hydrocortisone (50 mg IV) and the antihis Investigation of 9,10-Anthracenedicarboxaldehyde bis(4,5- tamine diphenhydramine (50 mg 1M) immediately prior to dihydro-1H-imidazol-2-yl)hydrazone Dihydrochloride with bisantrene (Alberts et al. (1982)), supra). Bisantrene is known Correlative in Vitro Human Tumor Clonogenic Assay. Can to stain the skin orange. cer Res. 42: 1170-1175 (1982)). Phase I activity was also 0162 Maximally tolerated doses in several bisantrene observed in two other hypernephroma patients (R. J. Spiegel phase I schedules include: (1) 200 mg/m weeklyx3 (150 et al., “Phase I Clinical Trial of 9,10-Anthracene Dicarbox mg/mg for patients with poor bone marrow reserve (e.g., aldehyde (Bisantrene) Administered in a Five-Day Sched those patients who have received radiotherapy or extensive ule. Cancer Res. 42: 354-358 (1982)). Bisantrene was inac chemotherapy regimens) (Alberts et al. (1982), supra); (2) tive in human colon cancer tested in vitro or in vivo (M. C. 150 mg/m weeklyx3 (repeat every 4-5 week) (B.-S. Yap et Perry et al. “Phase II trial of bisantrene inadvanced colorectal al., “Phase I Clinical Evaluation of 9,10-Anthracenedicar cancer: A cancer and leukemia group B study. Cancer Treat. boxaldehydebis(4,5-dihydro-1H-imidazol-2-yl)hydrazone Rep. 66: 1997-1998 (1982); Von Hoffetal. (1981a); Von Hoff dihydrochloride (Bisantrene). Cancer Treat. Rep. 66: 1517 et al. (1981 b). It was also inactive in refractory malignant 1520 (1982)) (3) 260 mg/m monthly (every 3-4 week) (240 melanoma (D. S. Alberts et al., “Phase II Evaluation of mg/mg for patients with poor bone marrow reserve (e.g., Bisantrene Hydrochloride in Refractory Malignant Mela those patients who have received radiotherapy or extensive noma.” Invest. New Drugs 5: 289-292 (1987)). chemotherapy regimens) (Von Hoffet al., 1981 b); and (4) 80 O157. In Phase II clinical trials, bisantrene was active in mg/m dailyx5 (repeat every 4 week) (R. J. Spiegel et al. patients with metastatic breast cancer (H.-Y. Yap et al., (1982), supra). “Bisantrene, an Active New Drug in the Treatment of Meta 0163 More than 95% of bisantrene is bound to plasma static Breast Cancer.” Cancer Res. 43: 1402-1404 (1983)). proteins and the drug has a long terminal plasma half-life. Partial response rates were observed in heavily pretreated There appeared to be three phases of elimination: an initial patients with metastatic breast cancer. However, the study distributive phase of 6 minutes, a betaphase of approximately was terminated because of significant local toxicity observed. 1.5 hours, and a final gamma elimination phase of 23 to 54 0158. The mechanism of action for bisantrene has been hours (Alberts et al. (1983), supra). Typical areas under the studied. Bisantrene has been shown to induce altered DNA plasma concentrationxtime curve are 4.4 to 5.7 mgh/mL supercoiling indicative of DNA intercalation (G. T. Bowden following intravenous doses of 260 to 340 mg/m, respec et al., “Comparative Molecular Pharmacology in Leukemic tively (Alberts et al. 1983, supra). Less than 7% of a bisant L1210 cells of the Anthracene Anticancer Drugs Mitox rene dose is excreted in the urine and the majority of the drug antrone and Bisantrene, Cancer Res. 45: 4915-4920 (1985)). is eliminated by the hepatobiliary route. The drug may be In L-1210 leukemia cells bisantrene was also shownto induce metabolized to some extent in vivo. In vitro bisantrene is a protein-associated DNA strand breaks typical of drug-in Substrate for hepatic microsomal enzymes but specific duced inhibition of DNA topoisomerase II enzymes (Bowden metabolites have not been identified. Preclinical drug distri et al., 1985). Both cytotoxicity and the DNA strand breaks bution studies showed that the tissues with the highest con appear to be reduced in hypoxic conditions (C. U. Ludwig et centration (in descending order) are kidney, liver, gallbladder, al., “Reduced Bisantrene-Induced Cytotoxicity and Protein spleen, lung, and heart. Brain levels were extremely low. The Associated DNA Strand Breaks Under Hypoxic Condition.” drug did distribute to lymph nodes and bone marrow (W. H. Cancer Treat. Rep. 68: 367-372 (1984)). The noncovalent Wu & G. Nicolau, “Disposition and Metabolic Profile of a binding of bisantrene to DNA appears to comprise two types New Antitumor Agent, CL 216,942 (Bisantrene) in Labora of interactions: (1) intercalation of the planaranthracene moi tory Animals.” Cancer Treat Rep. 66: 1173-1185 (1982)). ety between DNA base pairs, and (2) electrostatic binding 0164. The major dose-limiting toxic effect of bisantrene is between negatively charged ribose phosphates of DNA and leukopenia (Von Hoffetal. 1981b: Alberts et al. 1982, supra; positively charged basic nitrogens on the alkyl side chains of Spiegel et al. 1982, supra; Yap et al 1982, supra)). On a the drug. This is reflected in the biphasic DNA dissociation schedule of every 3 to 4 weeks, the nadir for myelosuppres curves for bisantrene in calfthymus DNA in vitro (W.O. Foye sion was 9 days with recovery by 19 days (Von Hoff et al. et al., “DNA-Binding Abilities of Bisguanylhydrazones of 1981 b). Thrombocytopenia was mild although bisantrene anthracene-9,10-dicarboxaldehyde. Anti-Cancer Drug can also inhibit platelet aggregation (M. E. Rybak et al., “The Design 1:65-71 (1986)). Effects of Bisantrene on Human Platelets.” Invest. New Drugs US 2016/0220537 A1 Aug. 4, 2016

4: 119-125 (1986)). Anemia and cumulative myelosuppres is substantially free of butylated hydroxyanisole (BHA) or sive toxic effects were not encountered with this drug. butylated hydroxytoluene (BHT); (iii) a co-surfactant or 0.165. In addition to myelosuppression, bisantrene pro emulsifier; (iv) a co-surfactant or auxiliary emulsifier, and (v) duced severe phlebitis along peripheral veins used for drug benzyl alcohol as a co-solvent. U.S. Pat. No. 4,816.247 by infusion (Von Hoffetal. 1981 b: Alberts et al. 1982). This may Desai et al., incorporated herein by this reference, discloses a have been caused by drug precipitation in veins which has composition of matter for delivery by intravenous, intramus been documented in experimental models (G. Powis & J. S. cular, or intraarticular routes of hydrophobic drugs (such as Kovach 1983). The drug is a potent vesicant and produces bisantrene or a derivative or analog thereof) comprising: (i) severe local tissue necrosis if inadvertently extravasated (Von the hydrophobic drug; (ii) a pharmaceutically acceptable ole Hoff et al 1981b). Severe arm swelling, hyperpigmented aginous vehicle or oil selected from the group consisting of veins, and punctate perivenous orange discolorations have (a) naturally occurring vegetable oils and (b) semisynthetic been occasionally observed following bisantrene infusions mono-, di-, and triglycerides, wherein the oleaginous vehicle given through peripheral veins. The arm Swelling appeared to or oil is free of BHT or BHA; (iii) a surfactant or emulsifier; be the result of a localized capillary leak syndrome in the arm (iv) a co-surfactant or emulsifier, (v) an ion-pair former used for infusion. In an experimental mouse skin model, selected from C-C Saturated or unsaturated aliphatic acids extravasation necrosis was blocked with a local injection of when the hydrophobic drug is basic and a pharmaceutically Sodium bicarbonate which physically decomposes bisantrene acceptable aromatic amine when the hydrophobic drug is (R. T. Dorr et al., “Bisantrene Solubility and Skin Toxicity acidic; and (vi) water. U.S. Pat. No. 5,000,886 to Lawteretal. Studies: Effect of Sodium Bicarbonate as a Local Ulceration and U.S. Pat. No. 5,143,661 to Lawter et al., both incorpo Antidote.” Invest. New Drugs 2: 351-357 (1984)). rated herein by this reference, disclose compositions for 0166 Up to 10% of patients experienced anaphylactoid delivery of pharmaceutical agents such as bisantrene or a reactions following a bisantrene infusion (J. W. Myers et al., derivative or analog thereof comprising a microcapsule, Anaphylactoid Reactions Associated with Bisantrene Infu wherein the microcapsule includes a hardening agent that is a sions.” Invest. New Drugs 1: 85-88 (1983)). Symptoms volatile silicone fluid. U.S. Pat. No. 5,070,082 to Murdocket included chills, chest pain, shortness of breath, flushing, and al., U.S. Pat. No. 5,077,282 to Murdock et al., and U.S. Pat. pruritus. These effects may be caused by drug-induced hista No. 5,077.283 to Murdock et al., all incorporated herein by mine release. Hypotension is also reported with bisantrene, this reference, disclose prodrug forms of poorly soluble and prolongation of the infusion was recommended to reduce hydrophobic drugs, including bisantrene and derivatives and this complication (Von Hoffet al., 1981b). In addition, a few analogs, that are salts of a phosphoramidic acid. U.S. Pat. No. patients experienced diaphoresis and palpitations, usually 5,116,827 to Murdock et al. and U.S. Pat. No. 5,212.291 to near the end of a bisantrene infusion (Von Hoffet al., 1981b). Murdock et al., both incorporated herein by this reference, The drug was not cardiotoxic in animals and use in the clinic disclose prodrug forms of poorly soluble hydrophobic drugs, has confirmed less cardiotoxicity than other agents in its including bisantrene and derivatives and analogs, that are class. No patients experienced electrocardiographic changes quinolinecarboxylic acid derivatives. U.S. Pat. No. 5,378.456 while receiving the drug and radioangiocardiographic moni to Tsoul, incorporated herein by this reference, includes com toring demonstrated no decrease in ejection fraction or any positions containing an anthracene antitumor agent, such as other significant change in cardiac function (J. W. Myers et bisantrene or a derivative or analog thereof, in which the al., “Radioangiocardiographic Monitoring in Patients bisantrene or derivative or analog thereof is conjugated to or Receiving Bisantrene. Am. J. Clin. Oncol. 7: 129-130 admixed with a divinyl ether-maleic acid (MVE) copolymer. (1984), incorporated herein by this reference). U.S. Pat. No. 5,609,867 to Tsou, incorporated herein by this 0167 Bisantrene has been reported to produce very little reference, discloses polymeric 1,4-bis derivatives of bisant nausea or Vomiting. Alopecia (hair loss) is also less intense rene and copolymers of bisantrene and another monomer, with bisantrene compared with doxorubicin (J. D. Cowan et Such as a dianhydride. al., “Randomized Trial of Doxorubicin, Bisantrene, and 0170 The present application, therefore, provides Mitoxantrone in Advanced Breast Cancer: A Southwest improved methods and compositions for the use of bisantrene Oncology Group Study,” J. Nat'l Cancer Inst. 83: 1077-1084 and analogs or derivatives thereof for the treatment of malig (1991)). However, bisantrene can produce a mild fever in nancies while avoiding the side effects described above and Some patients and malaise may be particularly common. This improving the therapeutic efficacy of the drug. was reported by up to one-half of patients studied (Yap et al. 0171 As detailed above, in addition to directantineoplas (1982), supra). tic effects related to the activity of bisantrene as a DNA 0168 Therefore, because of the range and severity of intercalator, bisantrene also possesses other mechanisms of potential side effects, particularly the existence of local action, including immunopotentiation. These mechanisms venous reactions and anaphylactoid reactions, development are described in: (i) N. R. West et al., “Tumor-Infiltrating of bisantrene had been halted. However, the results suggest a Lymphocytes Predict Response to Anthracycline-Based Che reevaluation of the use of bisantrene for antineoplastic use motherapy in Estrogen-Resistant Breast Cancer. Breast and for other indications, despite the prior halt of develop Canc. Res. 13: R126 (2011), which concludes that the level of ment. tumor-infiltrating lymphocytes is correlated with a response 0169. Various formulations suitable for use in the admin istration of bisantrene or derivatives or analogs thereof are to the administration of anthracycline-based agents; the known in the art. U.S. Pat. No. 4,784,845 to Desai et al., markers associated with tumor-infiltrating lymphocytes incorporated herein by this reference, discloses a composi (TIL) include CD19, CD3D, CD48, GZMB, LCK, MS4A1, tion of matter for delivery of a hydrophobic drug (i.e., bisant PRF1, and SELL; (ii) L. Zitvogel et al., “Immunological rene or a derivative or analog thereof) comprising: (i) the Aspects of Cancer Chemotherapy.” Nature Rev. Immunol. 8: hydrophobic drug; (ii) an oleaginous vehicle or oil phase that 59-73 (2008), which states that DNA damage, such as that US 2016/0220537 A1 Aug. 4, 2016 produced by intercalating agents such as bisantrene, induces dipeptide, pl.:pC copolymer, pyran copolymer, lymphokines, the expression of NKG2D ligands on tumor cells in an ATM Adriamycin, cyclophosphamide, and mitomycin C. The effi dependent and CHK1-dependent (but p53-independent) cacy of bisantrene in allogeneic macrophage transplants and manner; NKG2D is an activating receptor that is involved in with Supernatants of macrophages activated by bisantrene has tumor immunosurveillance by NK cells, NKT cells, Yö T cells been shown in B. S. Wang et al., “Immunotherapy of a Murine and resting (in mice) and/or activated (in humans) CD8" T Lymphoma by Adoptive Transfer of Syngeneic Macrophages cells, and also states that anthracycline-based agents may act Activated by Bisantrene.” Cancer Res. 46: 503-506 (1986), as immunostimulators, particularly in combination with incorporated herein by this reference. Specifically, the active IL-12; such agents also promote HMGB1 release and activate cells were obtained from peritoneal exudate. Bisantrene-ac T cells; (iii) D.V. Krysko et al., “TLR2 and TLR9 Are Sensors tivated macrophages were shown to be highly cytostatic to of Apoptosis in a Mouse Model of Doxorubicin-Induced tumor cells. Repeated treatments with activated macrophages Acute Inflammation.” Cell Death Different. 18: 1316-1325 (2011), which states that anthracycline-based antibiotics were shown to be more effective in protecting animals inocu induce an immunogenic form of apoptosis that has immuno lated with tumors. This represents immunotherapy by adop stimulatory properties mediated by MyD88, TLR2, and tive transfer of immunocompetent cells. Culture Supernatants TLR9; (iv) C. Ferraro et al., “Anthracyclines Trigger Apop of activated macrophages were also found to have antiprolif tosis of Both GO-G1 and Cycling Peripheral Blood Lympho erative effects on tumor cells, indicating that a cytostatic cytes and Induce Massive Deletion of Mature T and B Cells.” factor or factors were produced by these macrophages. (B.S. Cancer Res. 60: 1901-1907 (2000), which stated that anthra Wang et al., “Activation of Tumor-Cytostatic Macrophages cyclines induce apoptosis and ceramide production, as well as with the Antitumor Agent 9,10-Anthracenedicarboxaldehyde activate caspase-3 in resting and cycling cells; the apoptosis Bis(4,5-dihydro-1H-imidazole-2-yl)hydrazine Dihydro induced is independent from CD95-L/CD95 and TNF/TNF chloride (Bisantrene).” Cancer Res. 44: 2363-2367 (1984)). R; and (v) K. Lee et al., “Anthracycline Chemotherapy Inhib 0.174 Bisantrene and analogs thereof have been reported its HIF-1 Transcriptional Activity and Tumor-Induced Mobi as inhibiting telomerase activity, especially by stabilizing lization of Circulating Angiogenic Cells. Proc. Natl. Acad. G-quadruplex DNA structures as disclosed in M. Folini et al., Sci USA 106: 2353-2358 (2009), which provides another “Remarkable Interference with Telomeric Function by a antineoplastic mechanism for anthracycline-based antibiot G-Quadruplex Selective Bisantrene Regioisomer. Biochem. ics, namely inhibition of HIF-1 mediated gene transcription, Pharmacol. 79: 1781-1790 (2010). The bisantrene analogs which, in turn, inhibits transcription of VEGF required for used are those of Formulas (II), (III), (IV), (V), (VI), (VII), angiogenesis; HIF-1 also activates transcription of genes and (VIII): encoding glucose transporter GLUT1 and hexokinases HK1 and HK2, which are required for the high level of glucose uptake and phosphorylation that is observed in metastatic (II) H cancer cells, and pyruvate dehydrogenase kinase 1 (PDK1), N which shunts pyruvate away from the mitochondria, thereby increasing lactate production; patients with HIF-1C. overex pression based on immunohistochemical results were Sug N i-ON gested to be good candidates for treatment with anthracy n cline-based antibiotics. 0172 Among the types of cancer for which a response to bisantrene has been seen are bladder carcinoma, multiple myeloma, lung adenocarcinoma, melanoma, and renal cell carcinoma (Alberts et al. (1982), supra), as well as breast cancer (Bowden et al. (1985), Supra) and acute myelogenous leukemia, especially relapsed or refractory acute myeloid leukemia (A. Spadea et al., “Bisantrene in Relapsed and Refractory Myelogenous Leukemia. Leukemia Lymphoma 9:217-220 (1993). 0173 Bisantrene has been reported as activating tumor cytostatic macrophages (B. S. Wang et al., “Activation of Tumor-Cytostatic Macrophages with the Antitumor Agent 9,10-Anthracenedicarboxaldehyde Bis(4,5-dihydro-1H imidazole-2-yl)hydrazine Dihydrochloride (Bisantrene).” Cancer Res. 44: 2363-2367 (1984)), incorporated herein by this reference. The minimal effective in vivo dose of bisant rene appeared to be 25 mg/kg, with peak activation being achieved at doses of 50 to 100 mg/kg. A number of macroph age activators are known, including Bacillus Calmette Guerin, Corynebacterium parvum, endotoxins, muramyl US 2016/0220537 A1 Aug. 4, 2016 12

-continued cancer agents, including nucleotide analogs such as 7-deaza (IV) 2'-deoxyguanosine, BIBR1532, antisense oligonucleotides, GRN163L, and other agents. For such agents, a number of HN different pathways are involved in inhibition of telomerase H activity. Generally, inhibition of telomerase activity results in Y N cellular senescence or apoptosis in a time-dependent manner that correlates with the initial telomere length in the cells in N NH NH-4N D which telomerase is inhibited. When telomere architecture N collapses or is disrupted, a signaling cascade comparable to n •2HCl; that produced by DNA damage is activated and cell cycle arrest (accelerated Senescence) or cell death through apopto sis is induced. (0176 Telomerase substrates are the telomeres, double stranded DNA portions with a 3' protruding overhang (100 (V) 200 bases long), formed by a repeating noncoding sequence (TTAGGG (SEQ ID NO: 1) in humans). In analogy to other G-rich sequences, the single-stranded portion can fold into a structure called G-quadruplex. These folding results of over N lapping planar regions were identified by four Hoogsteen HN •2HCl; paired guanines. Hoogsteen base-pairing is between the N7 position of the purine base as a hydrogen-bond acceptor and the C6 amino group of the pyrimidine base as a donor. By recognizing and stabilizing this abnormal DNA base-pairing arrangement, selected ligands impair telomere-telomerase interaction thus interfering with the telomere elongation step (VI) catalyzed by the enzyme. Additionally, they can displace the telomere binding proteins (i.e., TRF2 and hPOT1) involved in telomere capping, thereby allowing recognition of the free terminal sequence as a DNA damage region. Several com f \ NHN pounds able to interact with and stabilize G-quadruplex struc HNNeN NN tures formed by G-rich single-stranded overhangs of telom Y •2HCl; eres have been identified, including anthraquinones, fluorenones, acridines, triazine, cationic porphyrins, and I perylenes, as well as other compounds. These compounds NS share ageneral consensus structural motif based on a large flat (VII) aromatic surface linked to protonatable side chains. DNA binding occurs mainly through stacking on a terminal G-tet rad, whereas side chains contribute to the stability of the N complex by hydrophobic/ionic interactions into the DNA H N grooves. N1 NH-6M D HN NN 0177 Since similar basic features characterize intercala N 2HCl; and tion and base stacking, the scaffolds of classical intercalating agents are commonly used as starting structures to produce G-quadruplex recognition. Literature data have proven that, by working on the number, the length and the position of the charged side chains bound to a “classical intercalator, it is (VIII) H possible to preferentially direct drug binding towards G-qua N druplex forms. Indeed, such an approach has led to the iden tification of effective G-quadruplex binders such as the tri substituted acridine BRACO 19 and the 2.6 or 2.7 bis 2N i-O Substituted amido-anthraquinones. These binders are characterized by poor cytotoxicity and are able to induce a reduction in telomere length upon long-term drug exposure. Bisantrene shares the structural “consensus motif character istic of effective G-quadruplex binders. 0.178 At least two side chains with amine groups proto natable at physiological pH are required for G-quadruplex binding. This includes bisantrene. Bisantrene is believed to 0175 Telomerase is a ribonucleoprotein reverse tran intercalate between adjacent base pairs of double-stranded Scriptase responsible for maintenance of telomere length. Its DNA through L-L stacking, with side chains located in either expression is associated with cell immortalization and tum groove (threading mode), which grants affinity constants well origenesis since it is expressed in most human tumor cells but above 10 M' under physiological conditions. For the ana is not active in most normal Somatic cells. Telomerase logs described above, the fact that the most efficient G-qua machinery inhibitors have been evaluated as potential anti druplex binders are substituted on two distinct aromatic rings US 2016/0220537 A1 Aug. 4, 2016

with side chains pointing in opposite directions with refer hybrid. Still other bisantrene analogs and derivatives are dis ence to the long axis of the aromatic system likely suggests closed in G. Zagotto et al., “Synthesis, DNA-Damaging and formation of additional specific interactions between the 4.5- Cytotoxic Properties of Novel Topoisomerase II-Directed dihydro-1H-imidazol-2-yl hydrazone groups and the G-qua druplex structure. Bisantrene Analogues. Bioorg. Med. Chem. Lett. 20: 121 0179 At least one of the bisantrene analogs. Formula (III), 126 (1998).T. L. Fields et al., “The Synthesis of Heterocyclic has the ability to act both at the telomerase level, by interfer Analogs of Bisantrene.” J. Heterocyclic Chem. 25: 1917 ing with Substrate recognition (hence Suppressing its catalytic 1918 (1988) discloses bisguanylhydrazones of anthracene-9, activity), and at the telomere level, by modifying its structural 10-dicarboxaldehyde as bisantrene analogs. Bisantrene organization. This compound affects telomere function not amsacrine hybrids are also disclosed in G. Capranico et al., only in telomerase-expressing cells but also in ALT-positive "Mapping Drug Interactions at the Covalent Topoisomerase cell lines, since it consistently provokes a DNA damage II-DNA Complex by Bisantrene/Amsacrine Congeners. J. response, as evidenced by the formation of YH2AX foci that Biol. Chem. 273: 12732-12739 (1998). These compounds are partially co-localize at the telomere, in agreement with results depicted below as Formulas (X), (XI), (XII), and (XIII): reported for telomestatin. For this compound, such a DNA damage response, together with the absence of apoptosis and the induction of cell cycle impairment (mainly G2M phase arrest), Suggest a drug-mediated activation of a senescence (X) pathway. 0180 Additional bisantrene analogs have been described in T. P. Wunz et al., “New Antitumor Agents Containing the O Anthracene Nucleus,” J. Med. Chem. 30: 1313-1321 (1987), I N including N,N'-bis(2-(dimethylamino)ethyl-9,10-an thracene-bis(methylamine) and N,N'-bis(1-ethyl-3-piperidi 2N nyl)-9,10-anthracene-bis(methylamine). 0181 Another bisantrene analog is the compound known as HL-37 and described in S. Q. Xie et al., “Anti-Tumour Effects of HL-37, a Novel Anthracene Derivative, In-Vivo and In-Vitro. J. Pharm. Pharmacol. 60:213-219 (2008), incorporated herein by this reference. HL-37 is anthracen-9- ylmethylene-2-methoxyethoxymethylsulfanyl-5-pyridin (XI) 3-yl-1,2,4-triazol-4-amine and has the structure shown below as Formula (IX): I O)N 2N (IX) N

2 N s

(XII)

0182. Other bisantrene analogs and derivatives are known in the art, including the bisantrene analogs disclosed in J. A. Elliott et al., “Interaction of Bisantrene Anti-Cancer Agents with DNA: Footprinting, Structural Requirements for DNA Unwinding, Kinetics and Mechanism of Binding and Corre lation of Structural and Kinetic Parameters with Anti-Cancer Activity.” Anticancer Drug Dis. 3: 271-282 (1989). In C. Sissi et al., “DNA-Binding Preferences of Bisantrene Analogs: Relevance to the Sequence Specificity of Drug-Mediated s Topoisomerase II Poisoning. Mol. Pharmacol. 54: 1036 K. ; and 1045 (1998) discloses additional analogs, including an aza bioisostere that can be considered a bisantrene-amsacrine US 2016/0220537 A1 Aug. 4, 2016 14

-continued -continued O (XIII) | -P(OH)2, O | -P(OCH3)2, O --(| ) )2, --( )—cil O 0183. Additional derivatives and analogs of bisantrene —SOH; wherein only one of R and R may be hydrogen or include the diphosphoramidic and monophosphoramidic C-C alkyl; R and Ra are the same or different and are: derivatives of bisantrene, disclosed in U.S. Pat. No. 4,900,838 hydrogen, C-C alkyl or—C(O)—R, where R is hydrogen, to Murdock and U.S. Pat. No. 5,212,191 to Murdock et al., C-C alkyl, phenyl, mono-Substituted phenyl (wherein the both of which are incorporated herein by this reference. These Substituent may be in the ortho, meta, or para position and is compounds are compounds of Formula (XIV): fluoro, nitro, C-C alkyl, C-C alkoxy, or cyano), pentafluo rophenyl, naphthyl, furanyl, or —CHOCH. The com pounds can have the schematic structure B(O), wherein B is (XIV) the residue formed by removal of a hydrogen atom from one R or more basic nitrogen atoms of an amine, amidine, guani dine, isourea, isothiourea, or biguanide-containing pharma CHEN-N ceutically active compound, and Q is hydrogen or A, wherein –K A is R3 N CHEN-N R, KN such that RandR" are the same or different and are R (where R is C-C alkyl, aryl, aralkyl, heteroalkyl, NC CHCH . wherein RandR are the same or different and are hydrogen, C-C alkyl, —C(O)—Rs, wherein Rs is hydrogen, C-C, alkyl, phenyl, mono-substituted phenyl (wherein the substitu ent can be ortho, meta, or para and is fluoro, nitro, C-C alkyl, D-CH C-C alkoxy, or cyano), pentafluorophenyl, naphthyl, fura nyl, ClC CH , or R.OCHCH , where R is hydrogen or C-C alkyl, hydrogen, or a pharmaceutically acceptable cat CH3 ion or Rand R" are linked to forma —CH-CH group or a -CHNHCOOC(CH3)3, CH3 -CHNH2, -CH2CH2COOH,

group, and n is an integer representing the number of primary or secondary basic nitrogenatoms in the compound such that COOH at least one Q is A. 0184. Additional bisantrene analogs are disclosed in M. Kozurkova et al., “DNA Binding Properties and Evaluation of s Cytotoxic Activity of 9,10-Bis-N-Substituted (Aminomethy l)anthracenes.” Int. J. Biol. Macromol. 41: 415-422 (2007). These compounds include 9,10-bis(2-hydroxyethyl)imi nomethyl)anthracene: 9,10-bis(2-(-2-hydroxyethylamino) -CH2NG)-(CH) Cle)); ethyliminomethyl)anthracene: 9,10-bis(2-(morpholin-4- yl)ethyliminomethyl)anthracene; 9,10-bis(2- US 2016/0220537 A1 Aug. 4, 2016

hydroxyethyl)aminomethylanthracene; 9,10-bis(2-(2- aromatic nucleus but has one or more Substituents as hydroxyethylamino)ethylaminomethyl)anthracene described below that replace at least one hydrogen present in tetrahydrochloride; 9,10-bis(2-(piperazin-1-yl)ethyl bisantrene with another moiety. As used herein, the term aminomethyl)anthracene hexahydrochloride; and 9,10-bis: “analog as applied to bisantrene applies to a compound 2-(morpholin-4-yl)ethylaminomethyl)anthracene tetrahy related structurally to bisantrene but alters one or more of the drochloride. tricyclic aromatic nucleus or one or more of the side chains, 0185. Other analogs and derivatives are known in the art, for example, by replacing one or more carbons in the tricyclic including derivatives and salt forms of the compounds aromatic nucleus with nitrogens or by removing or moving described above. one or both of the side chains. Some analogs are described 0186 This invention relates to novel compositions and above; others are known to one of skill in the art. methods to improve the utility of chemical agents including 0191 In summary, bisantrene and its derivatives or ana bisantrene and derivatives and analogs thereof, as described logs can be expected to have antineoplastic activity against above, with Suboptimal performance for patients with cancer the following cancers: acute myelogenous leukemia (AML, and with other diseases and conditions, including metabolic also called acute non-lymphocytic leukemia, ANLL), lym diseases, immunological diseases, and infectious diseases. phoma, ovarian cancer, and breast cancer, especially refrac The invention describes the novel development of improved tory AML or breast cancer. pharmaceutical ingredients, dosage forms, excipients, Sol 0.192 Derivatives of bisantrene include, but are not limited vents, diluents, drug delivery systems, preservatives, more to: (1) derivatives of bisantrene in which at least one of the accurate drug administrations, improved dose determination hydrogen atoms bound to the carbon atoms that are directly and schedules, toxicity monitoring and ameliorization, tech bound to the tricyclic aromatic nucleus is replaced with lower niques or agents to circumvent or reduce toxicity, techniques alkyl; (2) derivatives of bisantrene in which at least one of the and tools to identify/predict those patients who might have a hydrogen atoms in the N=NH moiety is replaced with lower better outcome with a therapeutic agent by the use of pheno alkyl; or (3) derivatives of bisantrene in which at least one of type or genotype determination through the use of diagnostic the hydrogen atoms bound to the nitrogens of the five-mem kits or pharmacokinetic or metabolism monitoring bered rings are replaced with lower alkyl. Other derivatives of approaches, the use of drug delivery systems, novel prodrugs, bisantrene are described below. polymer conjugates, novel routes of administration, other 0193 Analogs of bisantrene include, but are not limited to agents to potentiate the activity of the compounds or inhibit compounds described above as Formulas (II)-(XIV), as well the repair of suboptimal cellular effects or sub-lethal damage as additional compounds described above and their deriva or to “push the cell into more destructive cellular phases tives. Such as apoptosis. In some cases, the inventive examples 0194 As described above, and as detailed more generally include the use of these sub-optimal therapeutics in conjunc below, derivatives and analogs of bisantrene can be optionally tion with radiation or other conventional chemotherapeutic Substituted with one or more groups that do not substantially agents or biotherapeutic agents such as antibodies, vaccines, affect the pharmacological activity of the derivative or ana cytokines, lymphokines, gene and antisense therapies, or log. These groups are generally known in the art. Definitions other biotherapeutic agents. for a number of common groups that can be used as optional 0187. By definition, the term “suboptimal therapy” substituents are provided below; however, the omission of includes agents where Phase I toxicity precluded further any group from these definitions cannot be taken to mean that human clinical evaluation. It also includes those agents from Such a group cannot be used as an optional Substituent as long Phase II trials where inadequate tumor responses were iden as the chemical and pharmacological requirements for an tified. In addition, it also includes those agents, the Subject of optional Substituent are satisfied. Phase III clinical trials, whose outcome was either medically (0195 As used herein, the term “alkyl refers to an or statistically not sufficiently significant to warrant Submis unbranched, branched, or cyclic Saturated hydrocarbyl resi sion or approval by regulatory agencies for commercializa due, or a combination thereof, of from 1 to 12 carbon atoms tion or commercialized agents whose response rates as a that can be optionally substituted; the alkyl residues contain monotherapy are inadequate or whose side-effects are severe only C and H when unsubstituted. Typically, the unbranched enough to limit wider utility. Agents with Suboptimal activity or branched saturated hydrocarbyl residue is from 1 to 6 include but are not limited to the following: bisantrene and carbon atoms, which is referred to herein as “lower alkyl.” analogs and derivatives thereof. More specifically, the inven When the alkyl residue is cyclic and includes a ring, it is tive methods and compositions also focus on improvements understood that the hydrocarbyl residue includes at least three for bisantrene or analogs or derivatives thereof, as described carbon atoms, which is the minimum number to form a ring. above. As used herein, the term “alkenyl refers to an unbranched, 0188 The activity of bisantrene has been described above. branched or cyclic hydrocarbyl residue having one or more 0189 Bisantrene and its analogs and derivatives possess carbon-carbon double bonds. As used herein, the term “alky antineoplastic activity through several mechanisms, includ nyl refers to an unbranched, branched, or cyclic hydrocarbyl ing, but not necessarily limited to, intercalation in DNA, residue having one or more carbon-carbon triple bonds; the inhibition of the enzyme topoisomerase II, immune stimula residue can also include one or more double bonds. With tion, and inhibition of telomerase. These activities are respect to the use of “alkenyl' or “alkynyl.” the presence of described above. Also, as described above, bisantrene and its multiple double bonds cannot produce an aromatic ring. As analogs and derivatives also can activate macrophages. used herein, the terms “hydroxyalkyl,” “hydroxyalkenyl. 0190. As used herein, the term "derivative' as applied to and “hydroxyalkynyl respectively, refer to an alkyl, alkenyl, bisantrene refers to a compound that has the same carbon or alkynyl group including one or more hydroxyl groups as skeleton as bisantrene, including the tricyclic aromatic substituents; as detailed below, further substituents can be nucleus and the two side chains attached to the tricyclic optionally included. As used herein, the term “aryl' refers to US 2016/0220537 A1 Aug. 4, 2016

a monocyclic or fused bicyclic moiety having the well-known hydrogen Substituents consistent with the chemistry and characteristics of aromaticity; examples include phenyl and pharmacological activity of the resulting molecule. If not naphthyl, which can be optionally Substituted. As used herein, otherwise specified, the total number of such substituents that the term "hydroxyaryl” refers to an aryl group including one may be present is equal to the total number of hydrogenatoms or more hydroxyl groups as Substituents; as further detailed present on the unsubstituted form of the group being below, further substituents can be optionally included. As described; fewer than the maximum number of such substitu used herein, the term "heteroaryl refers to monocyclic or ents may be present. Where an optional substituent is attached fused bicyclic ring systems that have the characteristics of via a double bond, Such as a carbonyl oxygen (C=O), the aromaticity and include one or more heteroatoms selected group takes up two available Valences on the carbon atom to from O, S, and N. The inclusion of a heteroatom permits which the optional substituent is attached, so the total number aromaticity in 5-membered rings as well as in 6-membered of Substituents that may be included is reduced according to rings. Typical heteroaromatic systems include monocyclic the number of available valences. As used herein, the term Cs-C heteroaromatic groups such as pyridyl, pyrimidyl, “substituted, whether used as part of “optionally substituted pyrazinyl, thienyl, furanyl, pyrrolyl pyrazolyl, thiazolyl, or otherwise, when used to modify a specific group, moiety, oxazolyl, triazolyl, triazinyl, tetrazolyl, tetrazinyl, and imida or radical, means that one or more hydrogenatoms are, each, Zolyl, as well as the fused bicyclic moieties formed by fusing independently of each other, replaced with the same or dif one of these monocyclic heteroaromatic groups with a phenyl ferent substituent or substituents. ring or with any of the heteroaromatic monocyclic groups to 0.197 Substituent groups useful for substituting saturated form a Cs-Co. bicyclic group Such as indolyl, benzimida carbon atoms in the specified group, moiety, or radical Zolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, ben include, but are not limited to, -Z", =O, OZ’, SZ, Zothiazolyl, benzofuranyl, pyrazolylpyridyl, quinazolinyl, =S, NZZ, =NZ", =N-OZ’, trihalomethyl, -CF, quinoxalinyl, cinnolinyl, and other ring systems known in the ON, OCN, SCN, NO, NO =N - N - S(O) art. Any monocyclic or fused ring bicyclic system that has the Z”, -S(O)NZ, -S(O)O S(O)OZ’, OS(O)OZ’, characteristics of aromaticity interms of delocalized electron OS(O)O, OS(O)OZ, -P(O)(O), -P(O)(OZ) distribution throughout the ring system is included in this (O), P(O)(OZ)(OZ), C(O)Z, C(S)Z, C(NZ)Z, definition. This definition also includes bicyclic groups where C(O)C, C(O)CZ, C(S)OZ, C(O)NZZ, at least the ring that is directly attached to the remainder of the C(NZ)NZZ, OC(O)Z, OC(S)Z, OC(O)O, molecule has the characteristics of aromaticity, including the OC(O)OZ, OC(S)OZ’, NZ'C(O)Z, NZ'C(S)Z, delocalized electron distribution that is characteristic of aro NZPC(O)O, NZ'C(O)OZ’, NZC(S)OZ’, NZ'C maticity. Typically the ring systems contain 5 to 12 ring (O)NZZ, NZ'C(NZ)Z, NZ'C(NZ)NZZ, wherein member atoms and up to four heteroatoms, wherein the het Z' is selected from the group consisting of alkyl, cycloalkyl, eroatoms are selected from the group consisting of N, O, and heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryland S. Frequently, the monocyclic heteroaryls contain 5 to 6 ring heteroarylalkyl; each Z” is independently hydrogen or Z", and members and up to three heteroatoms selected from the group each Z is independently Z” or, alternatively, the two Z's may consisting of N, O, and S; frequently, the bicyclic heteroaryls be taken together with the nitrogen atom to which they are contain 8 to 10 ring members and up to four heteroatoms bonded to form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl selected from the group consisting of N, O, and S. The num ring structure which may optionally include from 1 to 4 of the ber and placement of heteroatoms in heteroaryl ring struc same or different heteroatoms selected from the group con tures is in accordance with the well-known limitations of sisting of N, O, and S. As specific examples, —NZZ is aromaticity and stability, where stability requires the het meant to include - NH, -NH-alkyl, - N-pyrrolidinyl, and eroaromatic group to be stable enough to be exposed to water —N-morpholinyl, but is not limited to those specific alterna at physiological temperatures without rapid degradation. As tives and includes other alternatives known in the art. Simi used herein, the term “hydroxheteroaryl refers to a het larly, as another specific example, a Substituted alkyl is meant eroaryl group including one or more hydroxyl groups as to include -alkylene-O-alkyl, -alkylene-heteroaryl, -alky substituents; as further detailed below, further substituents lene-cycloheteroaryl, -alkylene-C(O)OZ, -alkylene-C(O) can be optionally included. As used herein, the terms NZZ”, and CH, CH, C(O) CH, but is not limited to “haloaryl' and “haloheteroaryl refer to aryl and heteroaryl those specific alternatives and includes other alternatives groups, respectively, Substituted with at least one halo group, known in the art. The one or more Substituent groups, together where “halo' refers to a halogen selected from the group with the atoms to which they are bonded, may form a cyclic consisting of fluorine, chlorine, bromine, and iodine, typi ring, including, but not limited to, cycloalkyl and cyclohet cally, the halogen is selected from the group consisting of eroalkyl. chlorine, bromine, and iodine; as detailed below, further sub stituents can be optionally included. As used herein, the terms 0198 Similarly, substituent groups useful for substituting “haloalkyl,” “haloalkenyl, and “haloalkynyl refer to alkyl, unsaturated carbon atoms in the specified group, moiety, or alkenyl, and alkynyl groups, respectively, Substituted with at radical include, but are not limited to, —Z', halo, —OT, least one halo group, where "halo' refers to a halogen —OZ, -SZ, -S, NZZ, trihalomethyl, -CF, CN, selected from the group consisting of fluorine, chlorine, bro mine, and iodine, typically, the halogen is selected from the group consisting of chlorine, bromine, and iodine; as detailed below, further substituents can be optionally included. 0196. As used herein, the term “optionally substituted indicates that the particular group or groups referred to as optionally Substituted may have no non-hydrogen Substitu ents, or the group or groups may have one or more non US 2016/0220537 A1 Aug. 4, 2016

0199 Similarly, substituent groups useful for substituting pound or through natural absorption of moisture by the anhy nitrogen atoms in heteroalkyl and cycloheteroalkyl groups drous compound of the present invention. include, but are not limited to, -Z", halo, O, OZ’, 0203 As used herein, the term “ester” means any ester of —SZ, -S, NZZ, trihalomethyl, -CF, CN, a present compound in which any of the —COOH functions OCN, -SCN, NO, NO, -S(O)Z, -S(O)O, of the molecule is replaced by a —COOR function, in which —S(O)OZ, OS(O)OZ, -OS(O)O, -P(O)(O), the R moiety of the ester is any carbon-containing group - P(O)(OZ)(O), P(O)(OZ)(OZ), C(O)Z, C(S)Z, which forms a stable ester moiety, including but not limited to C(NZ)Z, C(O)OZ, C(S)OZ, C(O)NZZ, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, ary C(NZ)NZZ, OC(O)Z, OC(S)Z, OC(O)OZ’, lalkyl, heterocyclyl, heterocyclylalkyl and substituted deriva OC(S)OZ, NZ'C(O)Z, NZ'C(S)Z, NZ'C(O) tives thereof. The hydrolyzable esters of the present com OZ, NZPC(S)OZ, NZPC(O)NZZ, NZPC(NZ)Z, pounds are the compounds whose carboxyls are present in the and - NZ'C(NZ)NZZ, wherein Z, Z”, and Z are as form of hydrolyzable ester groups. That is, these esters are defined above. pharmaceutically acceptable and can be hydrolyzed to the 0200. The compounds described herein may contain one corresponding carboxyl acid in vivo. or more chiral centers and/or double bonds and therefore, 0204. In addition to the substituents described above, may exist as stereoisomers, such as double-bond isomers alkyl, alkenyl and alkynyl groups can alternatively or in addi (i.e., geometric isomers such as E and Z), enantiomers or tion be substituted by C-Cs acyl, C-Cs heteroacyl, Co-Co diastereomers. The invention includes each of the isolated aryl, C-C cycloalkyl, C-C heterocyclyl, or Cs-Co het Stereoisomeric forms (such as the enantiomerically pure iso eroaryl, each of which can be optionally substituted. Also, in mers, the E and Z isomers, and other stereoisomeric forms) as addition, when two groups capable of forming a ring having well as mixtures of stereoisomers in varying degrees of chiral 5 to 8 ring members are present on the same or adjacent purity or percentage of E and Z, including racemic mixtures, atoms, the two groups can optionally be taken together with mixtures of diastereomers, and mixtures of E and Z isomers. Accordingly, the chemical structures depicted herein encom the atom or atoms in the Substituent groups to which they are pass all possible enantiomers and stereoisomers of the illus attached to form Such a ring. trated compounds including the stereoisomerically pure form (0205. “Heteroalkyl,” “heteroalkenyl,” and “heteroalky (e.g., geometrically pure, enantiomerically pure or diastereo nyl' and the like are defined similarly to the corresponding merically pure) and enantiomeric and stereoisomeric mix hydrocarbyl(alkyl, alkenyl and alkynyl) groups, but the het tures. Enantiomeric and stereoisomeric mixtures can be ero terms refer to groups that contain 1-3 O.S or N heteroa resolved into their component enantiomers or stereoisomers toms or combinations thereof within the backbone residue; using separation techniques or chiral synthesis techniques thus at least one carbon atom of a corresponding alkyl, alk well known to the skilled artisan. The invention includes each enyl, or alkynyl group is replaced by one of the specified of the isolated stereoisomeric forms as well as mixtures of heteroatoms to form, respectively, a heteroalkyl, heteroalk Stereoisomers in varying degrees of chiral purity, including enyl, or heteroalkynyl group. For reasons of chemical stabil racemic mixtures. It also encompasses the various diastere ity, it is also understood that, unless otherwise specified. Such omers. Other structures may appear to depict a specific iso groups do not include more than two contiguous heteroatoms mer, but that is merely for convenience, and is not intended to except where an oxo group is present on NorSas in a nitro or limit the invention to the depicted isomer. When the chemical Sulfonyl group. name does not specify the isomeric form of the compound, it 0206 While “alkyl as used herein includes cycloalkyl denotes any one of the possible isomeric forms or mixtures of and cycloalkylalkyl groups, the term "cycloalkyl may be those isomeric forms of the compound. used hereinto describe a carbocyclic non-aromatic group that 0201 The compounds may also exist in several tautomeric is connected via a ring carbon atom, and “cycloalkylalkyl forms, and the depiction herein of one tautomer is for conve may be used to describe a carbocyclic non-aromatic group nience only, and is also understood to encompass other tau that is connected to the molecule through an alkyl linker. tomers of the form shown. Accordingly, the chemical struc 0207 Similarly, "heterocyclyl may be used to describe a tures depicted herein encompass all possible tautomeric non-aromatic cyclic group that contains at least one heteroa forms of the illustrated compounds. The term “tautomer as tom (typically selected from N, O and S) as a ring member and used herein refers to isomers that change into one another that is connected to the molecule via a ring atom, which may with great ease so that they can exist together in equilibrium. be C (carbon-linked) or N (nitrogen-linked); and "heterocy For example, ketone and enol are two tautomeric forms of one clylalkyl may be used to describe Such a group that is con compound. nected to another molecule through a linker. The heterocyclyl 0202 As used herein, the term “solvate” means a com can be fully saturated or partially saturated, but non-aromatic. pound formed by solvation (the combination of solvent mol The sizes and substituents that are suitable for the cycloalkyl, ecules with molecules or ions of the Solute), or an aggregate cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl groups that consists of a solute ion or molecule, i.e., a compound of are the same as those described above for alkyl groups. The the invention, with one or more solvent molecules. When heterocyclyl groups typically contain 1, 2 or 3 heteroatoms, water is the solvent, the corresponding solvate is a “hydrate.” selected from N, O and S as ring members; and the Nor S can Examples of hydrates include, but are not limited to, hemi be substituted with the groups commonly found on these hydrate, monohydrate, dihydrate, trihydrate, hexahydrate, atoms in heterocyclic systems. As used herein, these terms and other hydrated forms. It should be understood by one of also include rings that contain a double bond or two double ordinary skill in the art that the pharmaceutically acceptable bonds, as long as the ring that is attached is not aromatic. The salt and/or prodrug of the present compound may also exist in Substituted cycloalkyl and heterocyclyl groups also include a solvate form. The solvate is typically formed via hydration cycloalkyl or heterocyclic rings fused to an aromatic ring or which is either part of the preparation of the present com heteroaromatic ring, provided the point of attachment of the US 2016/0220537 A1 Aug. 4, 2016 group is to the cycloalkyl or heterocyclyl ring rather than to linked through a hydrocarbyl linker Such as an alkylene; and the aromatic/heteroaromatic ring. heteroaryl groups linked through a heteroalkyl linker. Thus, 0208. As used herein, “acyl encompasses groups com for example, C7-heteroarylalkyl would include pyridylm prising an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical ethyl, phenoxy, and N-pyrrolylmethoxy. attached at one of the two available valence positions of a 0214 Alkylene' as used herein refers to a divalent hydro carbonyl carbon atom, and heteroacyl refers to the corre carbyl group; because it is divalent, it can link two other sponding groups wherein at least one carbon other than the groups together. Typically it refers to —(CH), where n is carbonyl carbon has been replaced by a heteroatom chosen 1-8 and preferably n is 1-4, though where specified, an alky from N, O and S. lene can also be substituted by other groups, and can be of 0209 Acyl and heteroacyl groups are bonded to any group other lengths, and the open Valences need not be at opposite or molecule to which they are attached through the open ends of a chain. The general term “alkylene' encompasses valence of the carbonyl carbon atom. Typically, they are more specific examples Such as “ethylene wherein n is 2. C-Cs acyl groups, which include formyl, acetyl, pivaloyl, “propylene, wherein n is 3, and “butylene, wherein n is 4. and benzoyl, and C-C heteroacyl groups, which include The hydrocarbyl groups of the alkylene can be optionally methoxyacetyl, ethoxycarbonyl, and 4-pyridinoyl. substituted as described above. 0210. Similarly, “arylalkyl and “heteroarylalkyl refer to 0215. In general, any alkyl, alkenyl, alkynyl, acyl, or aryl aromatic and heteroaromatic ring systems which are bonded orarylalkyl group that is contained in a Substituent may itself to their attachment point through a linking group Such as an optionally be substituted by additional substituents. The alkylene, including Substituted or unsubstituted, Saturated or nature of these substituents is similar to those recited with unsaturated, cyclic or acyclic linkers. Typically the linker is regard to the primary substituents themselves if the substitu C-Cs alkyl. These linkers may also include a carbonyl group, ents are not otherwise described. thus making them able to provide Substituents as an acyl or 0216 “Amino” as used herein refers to —NH, but where heteroacyl moiety. An aryl or heteroaryl ring in an arylalkyl or an amino is described as “substituted' or “optionally substi heteroarylalkyl group may be substituted with the same sub tuted’, the term includes NR'R'" wherein each R' and R" is stituents described above for aryl groups. Preferably, an ary independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or lalkyl group includes a phenyl ring optionally Substituted arylalkyl group, and each of the alkyl, alkenyl, alkynyl, acyl, with the groups defined above for aryl groups and a C-C, aryl, or arylalkyl groups is optionally substituted with the alkylene that is unsubstituted or is substituted with one or two substituents described herein as suitable for the correspond C-C alkyl groups or heteroalkyl groups, where the alkyl or ing group; the R' and R" groups and the nitrogen atom to heteroalkyl groups can optionally cyclize to form a ring Such which they are attached can optionally form a 3- to 8-mem as cyclopropane, dioxolane, or oxacyclopentane. Similarly, a bered ring which may be saturated, unsaturated or aromatic heteroarylalkyl group preferably includes a C-C monocy and which contains 1-3 heteroatoms independently selected clic heteroaryl group that is optionally substituted with the from N, O and S as ring members, and which is optionally groups described above as Substituents typical on aryl groups substituted with the substituents described as suitable for and a C-C alkylene that is unsubstituted or is Substituted with one or two C-C alkyl groups or heteroalkyl groups, or alkyl groups or, if NR'R" is an aromatic group, it is optionally it includes an optionally substituted phenyl ring or Cs-C substituted with the substituents described as typical for het monocyclic heteroaryl and a C-C heteroalkylene that is eroaryl groups. unsubstituted or is substituted with one or two C-C alkyl or 0217. As used herein, the term “carbocycle “carbocy heteroalkyl groups, where the alkyl or heteroalkyl groups can clyl or “carbocyclic” refers to a cyclic ring containing only optionally cyclize to form a ring Such as cyclopropane, diox carbon atoms in the ring, whereas the term "heterocycle' or olane, or oxacyclopentane. "heterocyclic” refers to a ring comprising a heteroatom. The 0211 Where an arylalkyl or heteroarylalkyl group is carbocyclyl can be fully saturated or partially saturated, but described as optionally substituted, the substituents may be non-aromatic. For example, the general term "carbocyclyl on either the alkyl or heteroalkyl portion or on the aryl or encompasses cycloalkyl. The carbocyclic and heterocyclic heteroaryl portion of the group. The substituents optionally structures encompass compounds having monocyclic, bicy present on the alkyl or heteroalkyl portion are the same as clic or multiple ring systems; and Such systems may mix those described above for alkyl groups generally; the Sub aromatic, heterocyclic, and carbocyclic rings. Mixed ring stituents optionally present on the aryl or heteroaryl portion systems are described according to the ring that is attached to are the same as those described above for aryl groups gener the rest of the compound being described. ally. 0218. As used herein, the term "heteroatom” refers to any 0212 "Arylalkyl groups as used herein are hydrocarbyl atom that is not carbon or hydrogen, Such as nitrogen, oxygen groups if they are unsubstituted, and are described by the total or Sulfur, although, in Some contexts, "heteroatom' can refer number of carbon atoms in the ring and alkylene or similar to phosphorus, selenium, or other atoms other than carbon or linker. Thus a benzyl group is a C7-arylalkyl group, and hydrogen. When it is part of the backbone or skeleton of a phenylethyl is a C8-arylalkyl. chain or ring, a heteroatom must be at least divalent, and will 0213 “Heteroarylalkyl as described above refers to a typically be selected from N, O, P, and S. moiety comprising an aryl group that is attached through a 0219. As used herein, the term "alkanoyl refers to an linking group, and differs from “arylalkyl in that at least one alkyl group covalently linked to a carbonyl (C=O) group. ring atom of the aryl moiety or one atom in the linking group The term “lower alkanoyl refers to an alkanoyl group in is a heteroatom selected from N, O and S. The heteroarylalkyl which the alkyl portion of the alkanoyl group is C-C. The groups are described herein according to the total number of alkyl portion of the alkanoyl group can be optionally Substi atoms in the ring and linker combined, and they include aryl tuted as described above. The term “alkylcarbonyl can alter groups linked through a heteroalkyl linker; heteroaryl groups natively be used. Similarly, the terms “alkenylcarbonyl and US 2016/0220537 A1 Aug. 4, 2016

“alkynylcarbonyl refer to an alkenyl or alkynyl group, 0229. Accordingly, methods and compositions according respectively, linked to a carbonyl group. to the present invention encompass bisantrene derivatives and 0220. As used herein, the term “alkoxy' refers to an alkyl analogs including one or more optional Substituents as group covalently linked to an oxygen atom; the alkyl group defined above, provided that the optionally substituted bisant can be considered as replacing the hydrogen atom of a rene derivative or analog possesses Substantially equivalent hydroxyl group. The term “lower alkoxy” refers to an alkoxy pharmacological activity to amonafide as defined in terms of group in which the alkyl portion of the alkoxy group is C-C. either or both topoisomerase II inhibition and DNA interca The alkyl portion of the alkoxy group can be optionally Sub lation. Methods for determination of topoisomerase II inhi stituted as described above. As used herein, the term bition are known in the art and are described, for example, in “haloalkoxy' refers to an alkoxy group in which the alkyl A. Constantinou et al., “Novobiocin- and Phorbol-12 portion is Substituted with one or more halo groups. Myristate-13-Acetate-Induced Differentiation of Human 0221. As used herein, the term "sulfo’ refers to a sulfonic Leukemia Cells Associates with a Reduction in Topoi acid ( -SOH) substituent. somerase II Activity.” Cancer Res. 49: 1110-1117 (1989), 0222. As used herein, the term "sulfamoyl refers to a incorporated herein by this reference. Methods for determi substituent with the structure—S(O)NH2, wherein the nitro nation of DNA intercalation are known in the art and are gen of the NH portion of the group can be optionally substi described, for example, in H. Zipper et al., “Investigations on tuted as described above. DNA Intercalation and Surface Binding by SYBR Green I. Its 0223) As used herein, the term “carboxyl refers to a group Structure Determination and Methodological Implications.” of the structure —C(O)H. Nucl. Acids. Res. 32(12): e103 (2004), incorporated herein by 0224. As used herein, the term “carbamyl refers to a this reference. group of the structure —C(O)NH, wherein the nitrogen of 0230. Accordingly, as described in further detail below, the NH portion of the group can be optionally substituted as one aspect of the present invention is a composition to described above. improve the efficacy and/or reduce the side effects of subop 0225. As used herein, the terms “monoalkylaminoalkyl timally administered drug therapy comprising a therapeuti and “dialkylaminoalkyl refer to groups of the structure cally effective quantity of a therapeutic agent or modified -Alk-NH-Alk, and -Alk-N(Alk)(Alk3), wherein Alk, therapeutic agent or a derivative, analog, or prodrug of a Alk, and Alks refer to alkyl groups as described above. therapeutic agent or modified therapeutic agent, wherein the 0226. As used herein, the term “alkylsulfonyl refers to a therapeutic agent or modified therapeutic agent or the deriva group of the structure —S(O)-Alk wherein Alk refers to an tive, analog or prodrug of the therapeutic agent or modified alkyl group as described above. The terms “alkenylsulfonyl therapeutic agent possesses increased therapeutic efficacy or and “alkynylsulfonyl refer analogously to Sulfonyl groups reduced side effects, wherein the composition: covalently bound to alkenyl and alkynyl groups, respectively. 0231 (a) includes at least one bulk drug product The term “arylsulfonyl refers to a group of the structure improvement; —S(O), Ar wherein Ar refers to an aryl group as described 0232 (b) is produced in a specified dosage form; above. The term “aryloxyalkylsulfonyl refers to a group of 0233 (c) includes a drug conjugate form; the structure —S(O)-Alk-O Ar, where Alk is an alkyl 0234 (d) includes a compound analog; or group as described above and Aris an aryl group as described 0235 (e) includes a prodrug; above. The term “arylalkylsulfonyl refers to a group of the wherein the therapeutic agent, the modified therapeutic agent, structure —S(O)-AlkAr, where Alk is an alkyl group as or the derivative, analog, or prodrug of a therapeutic agent or described above and Ar is an aryl group as described above. modified therapeutic agent Subject to the bulk drug product 0227. As used herein, the term “alkyloxycarbonyl refers improvement possesses increased therapeutic efficacy or to an ester Substituent including an alkyl group wherein the reduced side effects as compared with an unmodified thera carbonyl carbon is the point of attachment to the molecule. An peutic agent; wherein the unmodified therapeutic agent is example is ethoxycarbonyl, which is CHCHOC(O)—. bisantrene or a derivative or analog of bisantrene, the modi Similarly, the terms “alkenyloxycarbonyl.” “alkynyloxycar fied therapeutic agent is a modification of bisantrene or a bonyl, and “cycloalkylcarbonyl refer to similar ester sub derivative or analog of bisantrene, and the derivative, analog, stituents including an alkenyl group, alkenyl group, or or prodrug is a derivative, analog, or prodrug of bisantrene or cycloalkyl group respectively. Similarly, the term “aryloxy of a derivative or analog of bisantrene. carbonyl refers to an ester Substituent including an aryl 0236. As described in further detail below, another aspect group wherein the carbonyl carbon is the point of attachment of the present invention is a composition to improve the to the molecule. Similarly, the term “aryloxyalkylcarbonyl efficacy and/or reduce the side effects of suboptimally admin refers to an ester Substituent including an alkyl group wherein istered drug therapy comprising a therapeutically effective the alkyl group is itself substituted by an aryloxy group. quantity of a therapeutic agent or modified therapeutic agent, 0228. Other combinations of substituents are known in the wherein the composition: art and, are described, for example, in U.S. Pat. No. 8,344,162 0237 (a) is formulated for use in a program of dose to Jung et al., incorporated herein by this reference. For modification; example, the term “thiocarbonyl and combinations of sub 0238 (b) is formulated for use in a program of alteration stituents including “thiocarbonyl include a carbonyl group or modification of route of administration; in which a double-bonded sulfur replaces the normal double 0239 (c) is formulated for use in a program of alteration bonded oxygen in the group. The term “alkylidene' and simi or modification of schedule of administration; lar terminology refer to an alkyl group, alkenyl group, alkynyl 0240 (d) is formulated for use in a program of selecting group, or cycloalkyl group, as specified, that has two hydro appropriate indications for use: gen atoms removed from a single carbon atom so that the 0241 (e) is formulated for use in a program of selecting group is double-bonded to the remainder of the structure. appropriate disease stages for use: US 2016/0220537 A1 Aug. 4, 2016 20

0242 (f) is formulated for use in a program of selecting 0269 (d) a second therapeutic agent that forms a mul appropriate additional indications for use; tiple drug system; 0243 (g) is formulated for use in a program of selecting 0270 (e) an agent that enhances the activity of the thera appropriate patients for use of the composition; peutic agent or modified therapeutic agent; 0244 (h) is formulated for use in a program of selecting 0271 (f) at least one survivin modulator or inhibitor; appropriate patient or disease phenotypes for use of the 0272 (g) at least one multidrug resistance reversal composition; agent, 0245 (i) is formulated for use in a program of selecting 0273 (h) at least one directed antibody conjugate; appropriate patient or disease genotypes for use of the 0274 (i) at least one adjuvant; or composition; 0275 () an additional therapeutic agent suitable for use 0246 () is formulated for use in a program of toxicity with the therapeutic agent in a combinatorial regime, management; wherein the quantities of the therapeutic agent and the 0247 (k) is formulated for use in a program of pre?post additional therapeutic agent are chosen to provide effec treatment management; tive activity of both the therapeutic agent and the addi 0248 (1) is formulated for use in a program of post tional therapeutic agent, wherein the therapeutic agent treatment management; or the modified therapeutic agent in the composition 0249 (m) is formulated for use in a program of alterna possesses increased therapeutic efficacy or reduced side tive medicine/therapeutic Support; effects as compared with the therapeutic agent or 0250 (n) is formulated for use in a program of biothera unmodified therapeutic agent as administered individu peutic enhancement; ally and not in the composition, wherein the unmodified 0251 (o) is formulated for use in a program of biothera therapeutic agent is bisantrene or a derivative or analog peutic resistance modulation; of bisantrene, and the modified therapeutic agent is a 0252 (p) is formulated for use in a program of radiation modification of bisantrene or a derivative or analog of therapy enhancement; bisantrene. 0253 (q) is formulated for use to employ novel mecha nisms of action in its therapeutic activity; 0276 (I) Suboptimal Therapeutics 0254 (r) is formulated for use in a program of selective 0277. In general, examples of compounds with subopti target cell population therapeutics; mal therapeutic activity may include antimetabolites, DNA/ 0255 (s) is formulated for use in a program of modu nucleic acid binding/reactive agents, topoisomerase inibitors, lating DNA methylation: anti-tubulin agents, signal transduction inhibitors, protein 0256 (t) is formulated for use in a program of inhibiting synthesis inhibitors, inhibitors of DNA transcribing enzymes, telomerase or inducing telomere dysfunction; DNA/RNA intercalating agents, DNA minor groove binders, 0257 (u) is formulated for use in a program of activat drugs that block steroid hormone action, photochemically ing macrophages and/or inducing innate and/or adaptive active agents, immune modifying agents, hypoxia selective immunity; cytotoxins, chemical radiation sensitizers and protectors, antisense nucleic acids, oligonucleotide and polynucleotide 0258 (v) is formulated for use in a program of inhibit therapeutic agents, immune modifying agents, antitumor ing Survivin; antibiotics, and other classes of therapeutic agents having 0259 (w) further comprises a diluent; antineoplastic, antiproliferative, or immune-system-modu 0260 (x) further comprises a solvent system; lating activity. Specific examples include: fluoropyrimidines, 0261 (y) further comprises an excipient; thiopurines, inhibitors of nucleoside diphosphate reductase, 0262 (Z) is incorporated into a dosage kit and packag 2'-deoxyribonucleoside analogs, nucleosides, folic acid ana 1ng logs, methotrexate, 6-diazo-5-oxo-norleucine, L-asparagi 0263 (aa) comprises a drug delivery system; or nase, N-(phosphoacetyl)-L-aspartic acid, nitrogen mustard, 0264 (ab) is formulated to optimize an immunological mechlorethamine, chlorambucil, melphalan, cyclophospha response; mide, estramustine, platinum complexes, nitrosoureas, wherein the therapeutic agent or the modified therapeutic BCNU, CCNU, streptozotocin, alkyl sulfonates, busulfan, agent in the composition possesses increased therapeutic effi clomesone, triaZenylimidazoles and related triaZenes, mito cacy or reduced side effects as compared with the therapeutic Zolomide, temozolomide, aziridines, tris(1-aziridinyl)phos agent or unmodified therapeutic agent as administered indi phine sulfide, aziridinylphosphines, 3.6,-diaziridinyl-2,5-bis vidually and not in the composition, wherein the unmodified (carboethoxyamino)-1,4-benzoquinone (diaziquone) (AZQ). therapeutic agent is bisantrene or a derivative or analog of AZQ analogs, procarbazine, hexamethylamine, topoi bisantrene, and the modified therapeutic agent is a modifica Somerase I inhibitors, camptothecin, camptothecin analogs, tion of bisantrene or a derivative or analog of bisantrene. topoisomerase II inhibitors, anthracyclines, doxorubicin, epi 0265. As described in further detail below, yet another rubicin, etoposide, DNA intercalating agents, amsacrine, aspect of the present invention is a composition to improve CI-921, 1'-carbamate analogs of amsacrine, 9-aminoacri the efficacy and/or reduce the side effects of suboptimally dine-4-carboxamides, acridine carboxamide, tricyclic car administered drug therapy comprising a therapeutically boxamides, 1-nitroacridine, acridine derivatives, diacridines, effective quantity of a therapeutic agent or modified thera triacridines, podophyllotoxins, ellipticine, merbarone, ben peutic agent, wherein the composition further comprises: Zisoquinolinediones, etoposide, teniposide, aminoan 0266 (a) an additional therapeutic agent; thraquinones, inhibitors of DNA-transcribing enzymes, tran 0267 (b) a therapeutic agent subject to chemosensitiza scription inhibitors, replication inhibitors, RNA replication tion; inhibitors, polymerase inhibitors, rifamycins, actinomycins, 0268 (c) a therapeutic agent subject to chemopotentia DNA minor groove binding compounds, Hoechst 33258, tion; mitomycins, CC-1065, mithramycins, chloromycins, olivo US 2016/0220537 A1 Aug. 4, 2016 mycins, phthalanilides, anthramycins, antimitotic agents, DHAC, didemnin B, dideoxy-B-fluorouracil, dideoxyad Vinca alkaloids, vinblastine and analogs, Vincristine and ana enosine, dideoxyinosine, dihydrotriazine benzene Sulfonyl logs, navelbine, colchicine and analogs, bleomycin and ana fluoride, dolastatin 10, ecteinascidin 743, etanidazole, ethio logs, estramustine, aromatase inhibitors, tamoxifen, LHRH fos (WR-2721), fazarabine, flavopiridol, fludarabine phos antagonists and analogs, porfimer, hematoporphyrins, elec phate, fostriecin, gallium nitrate, genistein, hepsulfam, tron-affinic oxygen mimetics, nitoaromatics, nitroheterocy HMBA, hydrazine sulfate, iododeoxyuridine, ipomeanol, clics, nitroimidizaoles, tirapazamine, mitomycins, menadi KNI-272, leucovorin calcium, levamisole, melphalan, one and analogs, napthoguinones, aziridoquinones, amine menogaril, merbarone, methotrexate, misonidazole, mitoguaZone, mitoxantrone HCl, mitoZolomide, N-methyl oxides, N-oxides, bioreductive agents, bioreductive alkylat formamide, 06-benzylguanine, PALA, pancratistatin, pen ing agents, metal complexes, radiation sensitizers, radiation clomedine, pentamethylmelamine HCl, pentamidine protectors, antisense agents, antigene agents, transcription isethionate, pentostatin, perillyl alcohol, phyllanthoside, factor inhibitors, ODN complexes, ribozymes, double pibenZimole HCl, piroXantrone, pyrazine diaZohydroxide, Stranded RNA, antitumor antibiotics, acivicin, aclararubicin, pyrazoloacridine, quinocarmycins, rebeccamycins, rhizoxin, acodazole, acronycine, adoZelesin, alanosine, allopurinol, semustine (methyl CCNU), Taxol, terephthalamidine, terox altretamine, aminoglutethimide, amonafide, amsacrine, irone, thioguanine, thymidine, tiazofurin, TMCA, 5-fluorou androgens, anguidine, aphidicolin glycinate, asaley, 5-azac racil, methotrexate, cyclophosphamide, ras inhibitors, farne itidine, azathioprine, Baker's Antifol, B-2'-deoxythiogua Sylation inhibitors, bromodeoxyuridine, tetracycline nosine, bisantrene HCl, bleomycin sulfate, busulfan, buthion compounds, arsenic trioxide, combretastatins, 2-methox ine sulfoximine (BSO), BWA 773U82, BW 502U83 HCl, yestradiol, thalidomide and analogs, cephalotaxine deriva BW 7U85 mesylate, caracemide, carbetimer, carboplatin, tives, gleevec, stributyrin, triciribine phosphate, trimetrexate, carmustine, chlorambucil, chloroquinoxaline Sulfonamide, UCN-01, 7-hydroxystaurosporine, uridine, lycurium, ritro chlorozotocin, chromomycin A3, cisplatin, cladribine, carbo Sulfan, artemisinin, artesunate, lonidamine, mesna, bromo platin, oxaliplatin, rhodamine compounds, corticosteroids, mannitol, hydrazine Sulfate, pipobroman, phenesterin, pyra CPT-11, cristanol cyclocytidine, cyclophosphamide, cytara Zine diaZohydroxide, cytemberna, Spirogermanium, bine, cytemberna, dabis maleate, dacarbazine, dactinomycin, terephthalamidine, bufalin, dibromodulcitol, gemcitabine, daunorubicin HCl, deazauridine, dexraZOxane, dianhydroga FMDC, colchicine, thiocolchicine, colchicine analogs, lactitol (DAG), dibromodulcitol, didemnin B, diethyldithio LHRH analogs, paclitaxel, MGBG, meisoindigo, indarubin carbamate, diglycoaldehyde, dihydro-5-azacytidine, doxoru analogs, metformin, phlorizin, and other compounds, includ bicin, echinomycin, edatrexate, edelfosine, efornithine, ing homoharringtonine (HHT). elsamitrucin, epirubicin, esorubicin, estramustine phosphate, estrogens, etanidazole, ethiofos, etoposide, fadrazole, faZara 0278. In particular, this invention is directed to bisantrene bine, fenretinide, finasteride, flavone acetic acid, floxuridine, and derivatives and analogs thereofas described above. fludarabine phosphate, 5-fluorouracil, flutamide, gallium (0279 (II) Dose Modification nitrate, gemcitabine, goserelinacetate, hepsulfam, hexameth 0280 Improvements for suboptimal chemotherapeutics ylene bisacetamide, amonafide, hydrazine Sulfate, 4-hy including bisantrene and analogs and derivatives thereof are droxyandrostenedione, hydroxyurea, idarubicin HCl, ifosfa made by alterations to the time that the compound is admin mide, 4-ipomeanol, iproplatin, isotretinoin, leuproloide istered, the use of dose-modifying agents that control the rate acetate, levamisole, liposomal daunorubicin, liposomal of metabolism of the compound, normal tissue protective doxorubicin, lomustine, lonidamine, maytansine, mechloet agents, and other alterations. General examples include: hamine hydrochloride, melphalan, menogaril, 6-mercaptopu variations of infusion schedules (e.g., bolus i.V. Versus con rine, mesna, methotrexate, N-methylformamide, mifepris tinuous infusion), the use of lymphokines (e.g., G-CSF, tone, mitoguaZone, mitomycin C, mitotane, mitoxantrone M-CSF, GM-CSF, EPO) to increase leukocyte count for hydrochloride, nabilone, nafoxidine, neocarzinostatin, oct improved immune response or for preventing anemia caused reotide acetate, ormaplatin, oxaliplatin, paclitaxel, pala, pen by myelosuppressive agents, or the use of rescue agents such to statin, piperazinedione, pipobroman, pirarubicin, piritr as leucovorin for 5-FU or thiosulfate for cisplatin treatment. exim, piroXantrone hydrochloride, plicamycin, porfimer Specific inventive examples for bisantrene and analogs and Sodium, predimustine, procarbazine, progestins, pyrazofurin, derivatives thereof include: continuous i.v. infusion for hours razoxane, Sargramostim, semustine, Spirogermanium, Strep to days; biweekly administration; doses greater than 5 tonigrin, streptozocin, Sulofenur, Suramin Sodium, tamox mg/m/day; progressive escalation of dosing from 1 mg/m/ ifen, taxotere, tegafur, teniposide, terephthalamidine, teroX day based on patient tolerance; doses less than 1 mg/m for irone, thioguanine, thiotepa, thymidine, tiazofurin, greater than 14 days; use of caffeine to modulate metabolism; topotecan, tormifene, treinoin, trifluoroperazine hydrochlo use ofisoniazid to modulate metabolism; selected and inter ride, trifluridine, trimetrexate, uracil mustard, vinblastine sul mittent boost dose administrations; bolus single and multiple fate, Vincristine sulfate, vindesine, vinorelbine, Vinzolidine, doses of 1-5 mg/m, oral dosing including multiple daily Yoshi 864, Zorubicin, 2-CI-2'-deoxyadenosine, 3-deazauri dosing; micro dosing, immediate release dosing: slow release dine, 4-nitroestrone, 6-methylmercaptopurine riboside, dosing; or controlled release dosing. 9-aminocamptothecin, nitrocamptothecin, irinotecan, CPT 0281 (III) Route of Administration 11, acivicin, acodazole HCl, ADR-529, ICRF-187, amasa 0282 Improvements for suboptimal chemotherapeutics crine, aminothiadiazole, ADTA, antibiotic FR901228, including bisantrene and analogs and derivatives thereof are aphidicolin glycinate, azacytidine, AZT, bizelesin, brefel made by alterations in the route by which the compound is dins, wortmannins, canthardins, bromodeoxyuridines, bry administered. General examples include: changing route ostatin, BSO, CAI, caracemide, carboplatin, chlorosulfaqui from oral to intravenous administration and vice versa; or the noxaline, Sulfonamide, cisplatin, clomesone, cyclocytidine use of specialized routes Such as Subcutaneous, intramuscu HCl, cyclodisone, cyclopentenylcytosine, deoxyspergualin, lar, intra-arterial, intraperitoneal, intra-lesional, intralym US 2016/0220537 A1 Aug. 4, 2016 22 phatic, intratumoral, intrathecal, intravesicular, intracranial. that is resistant to one or both of the following therapeutic Specific inventive examples for bisantrene and analogs and agents: temozolomide (Temodar) or bevacizumab (Avastin), derivatives thereof include: central venous administration; or is characterized by EGFR variant III, either alone or in intraperitoneal administration; intravenous administration; combination with other therapeutic agents; use for treatment intravesicular administration for bladder cancer; intrathecal of malignancies characterized by overexpressed topoi administration; intra-arterial administration; continuous Somerase II; or use for treatment of malignancies character infusion; or intermittent infusion. Particularly significant ized by overexpressed and/or mutated EGFR. Particularly routes of administration for bisantrene and analogs and significant indications for use for bisantrene and analogs and derivatives thereof include central venous administration, derivatives thereof include refractory breast cancer, triple intraperitoneal administration, and intravenous administra negative breast cancer, acute myelocytic leukemia, and acute tion. leukemias of childhood, including ALL and AML. (0283 (IV) Schedule of Administration (0287 (VI) Disease Stages 0284. Improvements for suboptimal chemotherapeutics 0288. Improvements for suboptimal chemotherapeutics including bisantrene and analogs and derivatives thereof are including bisantrene and analogs and derivatives thereof are made by alterations to the time that the compound is admin made by alterations in the stage of disease at diagnosis/pro istered. General examples include: changing from a monthly gression that the compound is administered. General administration to a weekly or daily dosing or variations of the examples include: the use of chemotherapy for non-resect schedule. Specific inventive examples forbisantrene and ana able local disease, prophylactic use to prevent metastatic logs and derivatives thereof include: administration to avoid spread or inhibit disease progression or conversion to more anaphylaxis; daily administration; weekly administration for malignant stages. Specific inventive examples for bisantrene three weeks; weekly administration for two weeks; biweekly and analogs and derivatives thereof include: use for the treat administration; biweekly administration for three weeks with ment of localized polyp stage colon cancer, use for the treat a 1-2 week rest period; intermittent boost dose administra ment of leukoplakia in the oral cavity; use to induce angio tion; or administration daily for one week then once per week genesis inhibition to prevent or limit metastatic spread; or use for multiple weeks. Particularly significant schedules of against HIV with AZT, DDI, or reverse transcriptase inhibi administration for bisantrene and analogs and derivatives tOrS. thereof include a schedule of administration to avoid anaphy (0289 (VII) Other Indications laxis. 0290 Improvements for suboptimal chemotherapeutics 0285 (V) Indications for Use including bisantrene and analogs and derivatives thereofare 0286 Improvements for suboptimal chemotherapeutics made by using the compound for non-malignant diseases and including bisantrene and analogs and derivatives thereof are conditions. General examples include: premalignant condi made by alterations in the types of disease or the clinical stage tions, benign hyperproliferative conditions, treatment of of disease for which the compound is administered. General infections, treatment of parasitic infections, usage to relieve examples include: the use of solid tumor agents for leukemias pain, use for control of pleural effusions. Specific inventive and vice versa, the use of antitumor agents for the treatment of examples for bisantrene and analogs and derivatives thereof benign hyperproliferative disease Such as psoriasis or benign include: use as an anti-infective agent; use as an antiviral prostate hypertrophy, metabolic diseases, immunological dis agent; use as an antibacterial agent; use for control of pleural eases or infection. Specific inventive examples for bisantrene effusions; use as an antifungal agent; use as an antiparasitic and analogs and derivatives thereof include: use for the treat agent; use for treatment of eczema, use for treatment of ment of refractory breast cancer; use for the treatment of shingles; use for treatment of condylomata; use for treatment triple-negative breast cancer, use for the treatment of acute of human papilloma virus (HPV); or use for treatment of leukemias, including, but not limited to, acute myelocytic herpes simplex virus (HSV). leukemia (AML); use for treatment of acute leukemias of 0291 (VIII) Patient Selection childhood, including acute myelocytic leukemia (AML) and 0292 Improvements for suboptimal chemotherapeutics acute lymphocytic leukemia (ALL); use for treatment of including bisantrene and analogs and derivatives thereof are myelodysplastic syndrome; use for treatment of chronic made by alterations to the type of patient that would best myelocytic leukemia (CML), either Subsequent to or in com tolerate or benefit from the use of the compound. General bination with the administration of tyrosine kinase inhibitors examples include: use of pediatric doses for elderly patients, or homoharringtonine; use for treatment of chronic lympho altered doses for obese patients; exploitation of co-morbid cytic leukemia; use for treatment of ovarian cancer, use for disease conditions such as diabetes, cirrhosis, or other con treatment of lymphoma including Hodgkin’s lymphoma and ditions that may uniquely exploit a feature of the compound. non-Hodgkin’s lymphoma; use for treatment of mycosis fun Specific inventive examples for bisantrene and analogs and goides; use for treatment of prostate cancer, especially andro derivatives thereof include: patients with disease conditions gen-resistant prostate cancer, use for treatment of lung Small with high levels of metabolic enzymes such as histone cell carcinoma, either Subsequent to or in combination with deacetylase, protein kinases, ornithine decarboxylase; the administration of EGFR inhibitors such as erlotinib patients with disease conditions with low levels of metabolic (Tarceva) or gefitinib (Iressa), wherein the lung small cell enzymes Such as histone deacetylase, protein kinases, or orni carcinoma is characterized by either wild-type or mutated thine decarboxylase; patients with low or high susceptibility EGFR: use for treatment of lung non-small cell carcinoma, to thrombocytopenia or neutropenia; patients intolerant of GI subsequent to or in combination with EGFR inhibitors such toxicities; patients characterized by over- or under-expres as erlotinib or gefitinib, wherein the lung non-Small cell car sion of jun, GPCRs, signal transduction proteins, VEGF, cinoma is characterized by either wild-type or mutated prostate specific genes, protein kinases, or telomerase; EGFR: use for treatment of breast cancer characterized by patients selected by immune Screening; patients selected by overexpressed Her-2-neu; use for treatment of glioblastoma DNA methylation screening. US 2016/0220537 A1 Aug. 4, 2016

0293 (IX) Patient/Disease Phenotype rs72552784 associated with sensitivity to bisantrene; or 0294 Improvements for suboptimal chemotherapeutics genetic abnormalities associated with acute myeloid leuke including Substituted naphthalimides such as bisantrene and mia. Particularly significant examples of patient/disease analogs and derivatives thereof are made by more precise genotypes for bisantrene and analogs and derivatives thereof identification of a patient’s ability to tolerate, metabolize and include the absence or nonfunctionality of ABCG2; the pres exploit the use of the compound. General examples include: ence or functionality of FABP7; the presence of single nucle use of diagnostic tools and kits to better characterize a otide polymorphisms rs229109 and rs72552784 associated patient’s ability to process/metabolize a chemotherapeutic with sensitivity to bisantrene; or genetic abnormalities asso agent or the patient’s Susceptibility to toxicity caused by ciated with acute myeloid leukemia. Genetic abnormalities potential specialized cellular, metabolic, or organ system associated with acute myeloid leukemia are disclosed in C. C. phenotypes. Specific inventive examples for bisantrene and Kumar, “Genetic Abnormalities and Challenges in the Treat analogs and derivatives thereof include: use of a diagnostic ment of Acute Myeloid Leukemia. Genes & Cancer 2: tool, a diagnostic technique, a diagnostic kit, or a diagnostic 95-107 (2011), incorporated herein by this reference, and assay to confirm a patient’s particular phenotype; use of a include, but are not limited to, the following genomic abnor method for measurement of a marker selected from the group malities: (i) t8:21); (ii) to 15,17); (iii) inv(16); (iv) der consisting of histone deacetylase, ornithine decarboxylase, (11q23); (v) t9:22); (vi) to:9); (vii) to 1:22); (viii) t8,16); VEGF, a protein that is a gene product of a prostate specific (ix) to 7:11); (x) to 12.22); (xi) inv(3); and (xii) to 16.21), lead gene, a protein that is a gene product of jun, and a protein ing to the following oncofusion proteins: (i) AML 1-ETO; (ii) kinase; Surrogate compound dosing; low dose pre-testing for PML-RARC.; (iii) CBFB-MYH11; (iv) MLL fusions; (v) enzymatic status; determination of the multi-drug resistance BCR-ABL1; (vi) DEK-CAN: (vii) OTT-MAL: (viii) MOZ activity of cells; determining expression or activation of a CPA; (ix) NUP98-HOXA9;(x) MN1-TEL; (xi) RPN1-EVI1; signaling or metabolic protein, where an alteration in the level and (xii) FUS-ERG. Additionally, gene mutations have been of expression or activation of the signaling or metabolic pro found to occur in AML, including, but not limited to, muta tein indicates the therapeutic potential of a chemotherapeutic tions in KIT, FLT3, NRAS, KRAS, MML, BAAL, WT-1, agent; detection or assay of expression of biomarkers indi CEBPO, NPM1, DNMT3A, and IDH1. cating sensitivity to apoptosis-inducing agents; use of an in 0297 (XI) Pre-/Post-Treatment Preparation vitro human tumor clonal assay to determine patients with 0298 Improvements for suboptimal chemotherapeutics enhanced responses; or use of an immunohistochemical assay including bisantrene and analogs and derivatives thereof are to determine overexpression of HIF-1C. Particularly signifi made by specialized preparation of a patient prior to or after cant patient/disease phenotypes for bisantrene and analogs the use of a chemotherapeutic agent. General examples and derivatives thereof include patients with an enhanced include: induction or inhibition of metabolizing enzymes, response in an in vitro human tumor clonal assay and the specific protection of sensitive normal tissues or organ sys quantity or activity of topoisomerase 2B present in cardiac tems. Specific inventive examples forbisantrene and analogs cells. and derivatives thereof include: the use of colchicine or an 0295) (X) Patient/Disease Genotype analog thereof; the use of auricoSuric; the use of uricase; the 0296 Improvements for suboptimal chemotherapeutics non-oral use of nicotinamide; the use of a Sustained-release including bisantrene and analogs and derivatives thereof are form of nicotinamide; the use of an inhibitor of poly-ADP made by testing and analyzingapatient’s genotype for unique ribose polymerase; the use of caffeine; the use of leucovorin features that may be of value to predict efficacy, toxicity, rescue; infection control; or the use of an anti-hypertensive metabolism, or other parameters relevant to therapeutic use of agent. the Suboptimal therapeutic. General examples include: 0299 (XII) Toxicity Management biopsy samples of tumors or normal tissues (e.g., white blood 0300 Improvements for suboptimal chemotherapeutics cells) may be taken and analyzed to specifically tailor or including bisantrene and analogs and derivatives thereof are monitor the use of a particular drug against a gene target; made by use of additional drugs or procedures to prevent or analysis of unique tumor gene expression pattern, SNPs reduce potential side-effects or toxicities. General examples (single nucleotide polymorphisms), to enhance efficacy or to include: the use of anti-emetics, anti-nausea agents, hemato avoid particular drug-sensitive normal tissue toxicities. Spe logical Support agents to limit or prevent neutropenia, ane cific inventive examples for bisantrene and analogs and mia, thrombocytopenia, Vitamins, antidepressants, treat derivatives thereof include: genetic tests to determine the ments for sexual dysfunction, or use of other agents or absence or nonfunctionality of ABCG2; genetic tests to deter methods to reduce potential side effects or toxicities. Specific mine the presence or functionality of FABP7; diagnostic inventive examples forbisantrene and analogs and derivatives tools, techniques, kits and assays to confirm a patient’s par thereof include: the use of colchicine or analogs; the use of ticular genotype; gene/protein expression chips and analysis; uricoSurics such as probenecid; the use of diuretics; the use of Single Nucleotide Polymorphisms (SNPs) assessment; uricase; non-oral use of nicotinamide; use of Sustained SNPs for histone deacetylase, ornithine decarboxylase, release forms of nicotinamide; use of inhibitors of poly-ADP GPCRs, protein kinases, telomerase, jun: identification and ribose polymerase; the use of caffeine; leucovorin rescue; the measurement of metabolism enzymes and metabolites; deter use of Sustained release allopurinol; non-oral use of allopu mination of the presence of one or more specific genetic rinol; administration of bone marrow transplant stimulants, variants of the MDR1 gene associated with increased efficacy blood, platelet infusions, Neupogen, G-CSF; or GM-CSF: of an antineoplastic drug transported by MDR1 protein; iden pain management; infection control; administration of anti tification of one or more biomarkers associated with sensitiv inflammatories; administration of fluids; administration of ity or resistance to bisantrene, derivatives or analogs thereof, corticosteroids; administration of insulin control medica or other intercalating agents or topoisomerase II inhibitors; tions; administration of antipyretics; administration of anti presence of single nucleotide polymorphisms rs229109 and nausea treatments; administration of anti-diarrhea treat US 2016/0220537 A1 Aug. 4, 2016 24 ments; administration of antihistamines as pre-treatment to binding to a tumor-associated antigen; use with bispecific prevent anaphylaxis; administration of agents for reduction of antibodies that have a cell-penetrating determinant and an gastric toxicity; administration of steroids as pre-treatment to intracellular target-binding determinant; use with multido prevent anaphylaxis; administration of sympathetomimetics main molecules that comprise a cell binding ligand that binds as pre-treatment to prevent anaphylaxis; and administration to cells in the tumor stroma such as endothelial cells, fibro of an agent to control or prevent chemotherapy-induced blasts, or immune cells and an oligonucleotide that inhibits thrombocytopenia. the nonsense-mediated decay pathway; use with tumor-spe 0301 (XIII) Pharmacokinetic/Pharmacodynamic Moni cific antibodies binding to a portion of the CD44 protein or a toring binding protein derived from the light-chain or heavy-chain 0302 Improvements for suboptimal chemotherapeutics complementary-determining regions of Such antibodies; use including bisantrene and analogs and derivatives thereof are with inhibitors of CXCR4: use with pyruvate dehydrogenase made by the use of monitoring drug levels after dosing in an kinase (PDK1) inhibitors; use with epherin receptor targeting effort to maximize a patient's drug plasma level, to monitor agents; use with binding proteins for Axl; use with Wnt path the generation of toxic metabolites, or to monitor of ancillary way inhibitors together with MAPK pathway inhibitors; use medicines that could be beneficial or harmful in terms of with TEC family kinase inhibitors; use with substituted mac drug-drug interactions. General examples include: the moni rocyclic compounds with proteasome activity; use with pep toring of drug plasma protein binding, the monitoring of tide-based PACE4 inhibitors; use with azaindole derivatives specific metabolites or breakdown products, or other products as JAK3 inhibitors; use with inhibitors of Myc; use with of biotransformation. Specific inventive examples for bisant inhibitors of furin and other pro-protein convertases; use with rene and analogs and derivatives thereof include: multiple GPBP-1 inhibitors, optionally together with a p21 inhibitor; determinations of drug plasma levels; multiple determina or use with PGE inhibitors. Particularly significant examples tions of metabolites in the blood or urine; monitoring of of drug combinations for bisantrene and analogs and deriva immune function; use of ELISPOT to measure immune tives thereof include the use with cytarabine in acute leuke responses; determination of Surface marker upregulation; or mias of childhood (AML and ALL); use with survivin inhibi monitoring of checkpoint inhibition. tors or modulators, described below; use with PGE 0303 (XIV) Drug Combinations inhibitors; or use with activatable antibodies targeting tumor 0304 Improvements for suboptimal chemotherapeutics specific markers. including bisantrene and analogs and derivatives thereof are (0305 (XV) Chemosensitization made by exploiting unique drug combinations that may pro 0306 Improvements for suboptimal chemotherapeutics vide a more than additive or synergistic improvement in effi including bisantrene and analogs and derivatives thereof are cacy or side-effect management. General examples include: made by exploiting them as chemosensitizers where no mea alkylating agents with anti-metabolites, topoisomerase sureable activity is observed when used alone but in combi inhibitors with antitubulin agents. Specific inventive nation with other therapeutics a more than additive or syner examples for bisantrene and analogs and derivatives thereof gistic improvement in efficacy is observed. General examples include: use with fraudulent nucleosides; use with fraudulent include: misonidazole with alkylating agents, tirapazamine nucleotides; use with thymidylate synthetase inhibitors; use with cisplatin. Specific inventive examples for bisantrene and with signal transduction inhibitors; use with cisplatin or plati analogs and derivatives thereof include: as a chemosensitizer numanalogs; use with alkylating agents; use with anti-tubulin in combination with topoisomerase inhibitors; as a agents; use with antimetabolites; use with berberine; use with chemosensitizer in combination with fraudulent nucleosides; apigenin; use with colchicine and analogs; use with genistein; as a chemosensitizer in combination with fraudulent nucle use with etoposide; use with cytarabine; use with camptoth otides; as a chemosensitizer in combination with thymidylate ecins; use with Vinca alkaloids, including vinblastine; use synthetase inhibitors; as a chemosensitizer in combination with topoisomerase inhibitors; use with 5-fluorouracil; use with signal transduction inhibitors; as a chemosensitizer in with curcumin; use with roSmarinic acid; use with mitogua combination with cisplatin or platinum analogs; as a Zone; use with meisoindigo; use withimatinib; use with dasa chemosensitizer in combination with alkylating agents; as a tinib, use with nilotinib, use with epigenetic modulators; use chemosensitizer in combination with anti-tubulin agents; as a with transcription factor inhibitors; use with taxol; use with chemosensitizer in combination with antimetabolites; as a homoharringtonine; use with pyridoxal; use with spirogerma chemosensitizer in combination with berberine; as a nium; use with caffeine; use with nicotinamide; use with chemosensitizer in combination with apigenin; as a methylglyoxalbisguanylhydraZone; use with epidermal chemosensitizer in combination with colchicine or analogs of growth factor receptor (EGFR) inhibitors; use with poly colchicine; as a chemosensitizer in combination with ADP ribose polymerase (PARP) inhibitors; use with Bruton's genistein; as a chemosensitizer in combination with etopo tyrosine kinase (BTK) inhibitors; use with bis-thio-hy side; as a chemosensitizer in combination with cytarabine; as drazideamides; use with Succinimide or maleimide deriva a chemosensitizer in combination with camptothecins; as a tives as inhibitors oftopoisomerase II; use with HDAC inhibi chemosensitizer in combination with Vinca alkaloids; as a tors; use with immunostimulants; use with inhibitors of chemosensitizer in combination with 5-fluorouracil; as a telomerase; use with agents that inhibit the expression or chemosensitizer in combination with curcumin; as a activity of Her2: use with agents that inhibit the expression or chemosensitizer in combination with roSmarinic acid; or as a activity of estrogen receptors; use with agents that inhibit the chemosensitizer in combination with mitoguaZone. expression or activity of antigens associated with specific (0307 (XVI) Chemopotentiation tumor targets, such as CT antigens; use with G-quadruplex 0308 Improvements for suboptimal chemotherapeutics ligands; use with polycyclic lysophosphatidic receptor including bisantrene and analogs and derivatives thereof are antagonists; use with anti-CTGF agents; use with myeloid made by exploiting them as chemopotentiators where mini differentiation inducing agents; use with covalent diabodies mal therapeutic activity is observed alone but in combination US 2016/0220537 A1 Aug. 4, 2016

with other therapeutics a more than additive or synergistic examples for bisantrene and analogs and derivatives thereof improvement in efficacy is observed. General examples include: free base form; salt formation; homogeneous crys include: dibromodulcitol with fraudulent nucleosides or talline structure; amorphous structure; pure isomers; fraudulent nucleotides. Specific inventive examples for increased purity; or lower residual solvents and heavy metals. bisantrene and analogs and derivatives thereof include: as a 0315 (XX) Diluent Systems chemopotentiator in combination with fraudulent nucleo 0316 Improvements for suboptimal chemotherapeutics sides; as a chemopotentiator in combination with fraudulent including bisantrene and analogs and derivatives thereof are nucleotides; as a chemopotentiator in combination with made by alterations in the diluents used to solubilize and thymidylate synthetase inhibitors; as a chemopotentiator in deliver/present the compound for administration. General combination with signal transduction inhibitors; as a chemo examples include: Cremophor-EL, cyclodextrins for poorly potentiator in combination with cisplatin or platinum ana water soluble compounds. Specific inventive examples for logs; as a chemopotentiator in combination with alkylating bisantrene and analogs and derivatives thereof include: use of agents; as a chemopotentiator in combination with anti-tubu emulsions: dimethylsulfoxide (DMSO); N-methylforma lin agents; as a chemopotentiator in combination with anti mide (NMF); dimethylformamide (DMF); dimethylaceta metabolites; as a chemopotentiator in combination with ber mide (DMA): ethanol; benzyl alcohol; dextrose-containing berine; as a chemopotentiator in combination with apigenin: water for injection; Cremophor; cyclodextrins; or PEG. as a chemopotentiator in combination with colchicine orana 0317 (XXI) Solvent Systems logs of colchicine; as a chemopotentiator in combination with 0318. Improvements for suboptimal chemotherapeutics genistein; as a chemopotentiator in combination with etopo including bisantrene and analogs and derivatives thereof are side; as a chemopotentiator in combination with cytarabine; made by alterations in the solvents used or required to solu as a chemopotentiator in combination with camptothecins; as bilize a compound for administration or for further dilution. a chemopotentiator in combination with Vinca alkaloids; as a General examples include: ethanol, dimethylacetamide chemopotentiator in combination with topoisomerase inhibi (DMA). Specific inventive examples for bisantrene and ana tors; as a chemopotentiator in combination with 5-fluorou logs and derivatives thereof include: the use of emulsions; racil; as a chemopotentiator in combination with curcumin; as DMSO; NMF: DMF, DMA; ethanol; benzyl alcohol; dex a chemopotentiator in combination with rosmarinic acid; or trose-containing water for injection; Cremophor; PEG, or salt as a chemopotentiator in combination with mitoguaZone. systems. 0309 (XVII) Post-Treatment Patient Management 0319 (XXII) Excipients 0310 Improvements for suboptimal chemotherapeutics 0320 Improvements for suboptimal chemotherapeutics including bisantrene and analogs and derivatives thereof are including bisantrene and analogs and derivatives thereof are made by drugs, treatments and or diagnostics to allow for the made by alterations in the materials/excipients, buffering maximum benefit to patients treated with a compound. Gen agents, or preservatives required to stabilize and present a eral examples include: pain management, nutritional Support, chemical compound for proper administration. General anti-emetics, anti-nausea therapies, anti-anemia therapy, examples include: mannitol, albumin, EDTA, Sodium anti-inflammatories, growth factors. Specific inventive bisulfite, benzyl alcohol. Specific inventive examples for examples for bisantrene and analogs and derivatives thereof bisantrene and analogs and derivatives thereof include: the include: use with therapies associated with pain management; use of mannitol; the use of albumin; the use of EDTA; the use nutritional Support; anti-emetics; anti-nausea therapies; anti of sodium bisulfite; the use of benzyl alcohol; the use of anemia therapy; anti-inflammatories: antipyretics; immune carbonate buffers; the use of phosphate buffers; the use of stimulants; or growth factors. polyethylene glycol (PEG); the use of vitamin A; the use of 0311 (XVIII) Alternative Medicine/Therapeutic Support vitamin D; the use of vitamin E: the use of esterase inhibitors; 0312 Improvements for suboptimal chemotherapeutics the use of cytochrome P450 inhibitors; the use of multi-drug including bisantrene and analogs and derivatives thereof are resistance (MDR) inhibitors; the use of organic resins; or the made by the use of unapproved/non-conventional therapeu use of detergents. tics or methods to enhance effectiveness or reduce side 0321 (Mall) Dosage Forms effects. General examples include: hypnosis, acupuncture, 0322 Improvements for suboptimal chemotherapeutics meditation, herbal medications and extracts, applied kinesi are made by alterations in the potential dosage forms of the ology. Specific inventive examples forbisantrene and analogs compound dependent on the route of administration, duration and derivatives thereof include: hypnosis; acupuncture; of effect, plasma levels required, exposure to normal tissues meditation; herbal medications created either synthetically or potentially resulting in side effects, and exposure to metabo through extraction including natural anti-inflammatories (in lizing enzymes. General examples include: tablets, capsules, cluding rhein or parthenolide); immunostimulants (such as topical gels, creams, patches, suppositories. Specific inven those found in Echinacea); antimicrobials (such as ber tive examples for bisantrene or derivatives or analogs thereof berine); flavonoids, isoflavones, and flavones (such as api include: the use of tablets; the use of capsules; the use of genenin, genistein, genistin, 6"-O-malonylgenistin, 6"-O- topical gels; the use of topical creams; the use of patches; the acetylgenistin, daidzein, daidzin, 6"-O-malonyldaidzin, use of Suppositories; the use of lyophilized dosage fills; the 6"-O-acetylgenistin, glycitein, glycitin, 6"-O-malonylgly use of immediate-release formulations; the use of slow-re citin, and 6-O-acetylglycitin); or applied kinesiology. lease formulations; the use of controlled-release formula 0313 (XIX) Bulk Drug Product Improvements tions; the use of liquid in capsules; or the use of liposomal 0314 Improvements for suboptimal chemotherapeutics formulations. including bisantrene and analogs and derivatives thereof are 0323 (XXIV) Dosage Kits and Packaging made by alterations in the pharmaceutical bulk Substance. 0324 Improvements for suboptimal chemotherapeutics General examples include: Salt formation, homogeneous including bisantrene and analogs and derivatives thereof are crystalline structure, pure isomers. Specific inventive made by alterations in the dosage forms, container/closure US 2016/0220537 A1 Aug. 4, 2016 26 systems, accuracy of mixing and dosage preparation and pre vetoxins, gambierols, and gambieric acids; the use of conju sentation. General examples include: amber vials to protect gates to antibodies having one or more non-natural amino from light, or stoppers with specialized coatings. Specific acid residues at specific positions in the heavy or light chains; inventive examples forbisantrene and analogs and derivatives the use of conjugates to a sialoadhesin binding moiety; the use thereof include: the use of amber vials to protect from light; of pheophorbide-C conjugates to bisantrene or a derivative or and stoppers with specialized coatings to improve shelf-life analog thereof; the use of conjugates to multi-component stability. Other forms of dosage kits and packaging are also nanochains; the use of conjugates to activatable antibodies known in the art and can include, for example, vials, ampules, that include a masking moiety, a cleavable moiety, and an jars, intravenous bags, or other containers. antibody binding specifically to interleukin-6; the use of con 0325 (XXV) Drug Delivery Systems jugates including hydrophilic linkers; the use of conjugates to 0326 Improvements for suboptimal chemotherapeutics antibodies specific for p97; the use of conjugates including a including bisantrene and analogs and derivatives thereof are modified amino acid incorporating an azido group; the use of made by the use of delivery systems to improve the potential albumin conjugates; or the use of conjugates to folate. attributes of a pharmaceutical product Such as convenience, 0329 (XXVII) Compound Analogs duration of effect, or reduction of toxicities. General 0330 Improvements for suboptimal chemotherapeutics examples include: nanocrystals, bioerodible polymers, lipo including bisantrene and analogs and derivatives thereof are Somes, slow release injectable gels, microspheres. Specific made by alterations to the parent structure of a molecule with inventive examples forbisantrene and analogs and derivatives additional chemical functionalities that may alter efficacy, thereof include: the use of oral dosage forms; the use of reduce toxicity, improve pharmacological performance, be nanocrystals; the use of nanoparticles; the use of cosolvents; compatible with a particular route of administration, or alter the use of slurries; the use of syrups; the use of bioerodible the metabolism of the therapeutic agent. General examples polymers; the use of liposomes; the use of slow release inject include: alteration of side chains to increase or decrease lipo able gels; the use of microspheres; the use of amphiphilic philicity; additional chemical functionalities to alter reactiv block copolymer systems; the use of emulsion vehicles com ity, electron affinity, or binding capacity; Salt forms; conju prising an emulsion of C-tocopherol stabilized by biocompat gates to albumin. Specific inventive examples for bisantrene ible Surfactants; the use of biodegradable polymer composi and analogs and derivatives thereof include: alteration of side tions containing phosphorus and desaminotyrosyl L-tyrosine chains to increase or decrease lipophilicity; additional chemi linkages in the polymer backbone; the use of Substantially cal functionalities to alter reactivity, electron affinity, or bind anhydrous injectable semi-solid compositions comprising a ing capacity; salt forms; conjugates to albumin. water immiscible fatty acid matrix and a cytostatic agent; the 0331 (XXVIII) Prodrugs use of lipophilic vehicles; the use of pH-dependent carriers 0332 Improvements for suboptimal chemotherapeutics that include a compound that includes at least one ionizable including bisantrene and analogs and derivatives thereof are group; the use of pH-dependent carriers that include a mono made by alterations to the molecule Such that improved phar carboxylic acid having at least 8 carbons and less than about maceutical performance is gained with a variant of the active 10% by weight of Zwitterionic phospholipids; the use of molecule in that after introduction into the body a portion of liposomes comprising the bisantrene or the derivative orana the molecule is cleaved to reveal the preferred active mol log thereof followed by administration of a lipid nanoparticle ecule. General examples include: enzyme sensitive esters, comprising a triggering agent, or the use of nonpegylated dimers, Schiff bases. Specific inventive examples for bisant liposomes. rene and analogs and derivatives thereof include: the use of 0327 (XXVI) Drug Conjugate Forms enzyme sensitive esters; the use of dimers; the use of Schiff 0328. Improvements for suboptimal chemotherapeutics bases; the use of pyridoxal complexes; the use of caffeine including bisantrene and analogs and derivatives thereof are complexes; the use of plasmin-activated prodrugs; the use of made by alterations to the parent molecule with covalent, a drug targeting complex comprising a targeting carrier mol ionic, or hydrogen bonded moieties to alter the efficacy, tox ecule that is selectively distributed to a specific cell type or icity, pharmacokinetics, metabolism, or route of administra tissue containing the specific cell type, a linker which is acted tion. General examples include: polymer systems such as upon by a molecule that is present at an effective concentra polyethylene glycols, polylactides, polyglycolides, amino tion in the environs of the specific cell type, and a therapeu acids, peptides, multivalent linkers, albumin conjugates. Spe tically active agent to be delivered to the specific cell type; or cific inventive examples for bisantrene and analogs and the use of a prodrug molecule comprising a conjugate of derivatives thereof include: the use of polymer systems such bisantrene or a derivative or analog of bisantrene, a protease as polyethylene glycols; the use of polylactides; the use of specific cleavable peptide, and optionally, a targeting peptide, polyglycolides; the use of amino acids; the use of peptides; with the prodrug molecule being Substantially inactive prior the use of multivalent linkers; the use of conjugates to fatty to degradation of the protease-specific cleavable peptide by a acids; the use of conjugates to fatty alcohols; the use of proteolytic enzyme within or in close proximity to the cancer conjugates to elastin-like peptide; the use of conjugates with cell. polyclonal or monoclonal antibodies, proteins, or peptides; 0333 (XXIX) Multiple Drug Systems the use of conjugates with cell-binding agents through a 0334 Improvements for suboptimal chemotherapeutics charged or pro-charged cross-linker, the use of conjugates to including bisantrene and analogs and derivatives thereof are antibodies targeted to tumor markers; the use of biodegrad made by the use of additional compounds, such as therapeutic able polymer-bioactive moiety conjugates; the use of conju or biological agents that when administered in the proper gates with 2-nitroimidazole compounds with a secondary fashion, a unique and beneficial effect can be realized. Gen basic nitrogen atom and a linker, the use of conjugates with eral examples include: inhibitors of multi-drug resistance, ladder frame polyether compounds, including those derived specific drug resistance inhibitors, specific inhibitors of from brevenal, brevisin, tamulamide, brevetoxins, hemibre selective enzymes, signal transduction inhibitors, repair inhi US 2016/0220537 A1 Aug. 4, 2016 27 bition. Specific inventive examples for bisantrene and ana nuclides; use with radiolabeled antibodies; use with brachy logs and derivatives thereof include the use of bisantrene or therapy, or use with bioreductive alkylating agents. analogs and derivatives thereof with: the use of inhibitors of (0341 (XXXIII) Novel Mechanisms of Action multi-drug resistance; the use of specific drug resistance 0342 Improvements for suboptimal chemotherapeutics inhibitors; the use of specific inhibitors of selective enzymes: including bisantrene and analogs and derivatives thereof are the use of signal transduction inhibitors; the use of meisoin made by optimizing their utility by determining the various digo; the use of imatinib; the use of hydroxyurea; the use of mechanisms of actions or biological targets of a compound dasatinib; the use of capecitabine; the use of nilotinib; the use for greater understanding and precision to better exploit the of repair inhibition; the use of topoisomerase inhibitors with utility of the molecule. General examples include: imatinib non-overlapping side effects; PARP inhibitors; EGFR inhibi (Gleevec) for chronic myelocytic leukemia (CML), arsenic tors; or HDAC inhibitors. trioxide for acute promyelocytic leukemia (APL), retinoic 0335 (XXX) Biotherapeutic Enhancement acid for APL. Specific inventive examples for bisantrene and 0336 Improvements for suboptimal chemotherapeutics analogs and derivatives thereof include: use with inhibitors of including bisantrene and analogs and derivatives thereof are poly-ADP ribose polymerase; use with agents that affect made by its use in combination as sensitizers/potentiators vasculature; use with agents that promote vasodilation; use with biological response modifiers. General examples with oncogenic targeted agents; use with signal transduction include: use in combination as sensitizers/potentiators with inhibitors; use with agents inducing EGFR inhibition; use biological response modifiers, cytokines, lymphokines, with agents inducing Protein Kinase C inhibition; use with therapeutic antibodies, antisense therapies, gene therapies. agents inducing Phospholipase C down regulation; use with Specific inventive examples for bisantrene and analogs and agents includingjun down regulation; use with agents modu derivatives thereof include: use in combination as sensitizers/ lating expression of histone genes; use with agents modulat potentiators with biological response modifiers; use in com ing expression of VEGF; use with agents modulating expres bination as sensitizers/potentiators with cytokines; use in sion of ornithine decarboxylase; use with agents modulating combination as sensitizers/potentiators with lymphokines; expression of jun D; use with agents modulating expression use in combination as sensitizers/potentiators with therapeu of V-jun, use with agents modulating expression of GPCRs: tic antibodies; use in combination as sensitizers/potentiators use with agents modulating expression of protein kinase A: with antisense therapies; use in combination as sensitizers/ use with agents modulating expression of protein kinases potentiators with gene therapies; use in combination as sen other than protein kinase A, use with agents modulating sitizers/potentiators with ribozymes; use in combination as expression of telomerase; use with agents modulating expres sensitizers/potentiators with RNA interference; use in com sion of prostate specific genes; use with agents modulating bination with vaccines (cellular or non-cellular); or use in expression of histone deacetylase; or use with agents modu combination with stem cells. lating expression of CHK2 checkpoint kinase. (0343 (XXXIV) Selective Target Cell Population Thera 0337 (XXXI) Biotherapeutic Resistance Modulation peutics 0338. Improvements for suboptimal chemotherapeutics 0344 Improvements for suboptimal chemotherapeutics including bisantrene and analogs and derivatives thereof are including bisantrene and analogs and derivatives thereof are made by exploiting their selective use to overcome develop made by more precise identification and exposure of the ing or complete resistance to the efficient use of biotherapeu compound to those select cell populations where the com tics. General examples include: tumors resistant to the effects pounds effect can be maximally exploited. General examples of biological response modifiers, cytokines, lymphokines, include: tirapazamine and mitomycin c for hypoxic cells, therapeutic antibodies, antisense therapies, gene therapies. Vinca alkaloids for cells entering mitosis. Specific inventive Specific inventive examples for bisantrene and analogs and examples for bisantrene and analogs and derivatives thereof derivatives thereof include: use against tumors resistant to the include: use against radiation sensitive cells; use against effects of biological response modifiers; use against tumors radiation resistant cells; use against energy depleted cells; use resistant to the effects of cytokines; use against tumors resis against endothelial cells. tant to the effects of lymphokines; use against tumors resis (0345 (XXXV) Use with Agents to Enhance Activity tant to the effects of therapeutic antibodies; use against 0346 Improvements for suboptimal chemotherapeutics tumors resistant to the effects of antisense therapies; use including bisantrene and analogs and derivatives thereof are against tumors resistant to the effects of gene therapies; use made by use of agents to enhance activity of the amonafide or against tumors resistant to the effects of ribozymes; or use the derivative or analog of amonafide. General examples against tumors resistant to the effects of RNA interference. include: use with nicotinamide, caffeine, tetandrine, or ber 0339 (XXXII) Radiation Therapy Enhancement berine. Specific inventive examples for bisantrene and ana 0340 Improvements for suboptimal chemotherapeutics logs and derivatives thereof include: use with nicotinamide; including bisantrene and analogs and derivatives thereof are use with caffeine; use with tetandrine; or use with berberine. made by exploiting their use in combination with ionizing (0347 (XXXVI) Use to Modulate DNA Methylation radiation, phototherapies, heat therapies, radio-frequency 0348 Improvements for suboptimal chemotherapeutics generated therapies. General examples include: hypoxic cell including bisantrene and derivatives and analogs thereof are sensitizers, radiation sensitizers/protectors, photosensitizers, made by use of bisantrene or derivatives or analogs thereof to radiation repair inhibitors. Specific inventive examples for modulate DNA methylation. It is known that aberrant DNA bisantrene and analogs and derivatives thereof include: use methylation is associated with malignancy. Specific inventive with hypoxic cell sensitizers; use with radiation sensitizers/ examples for bisantrene and derivatives and analogs thereof protectors; use with photosensitizers; use with radiation include: use to promote gene silencing; or use with drugs that repair inhibitors; use with thiol depletion; use with vaso inhibit DNA methylation. The effect of demethylation is targeted agents; use with radioactive seeds; use with radio described in L. Suarez & S. D. Gore, “Demethylation Demys US 2016/0220537 A1 Aug. 4, 2016 28 tification.” Blood 121: 1488-1489 (2011), incorporated impair telomere-telomerase interaction, thus interfering with herein by this reference. Drugs that inhibit DNA methylation the catalysis of the telomere elongation step catalyzed by are described in PCT Patent Application Publication No. WO telomerase. Certain ligands also can displace the telomere 2009/106549 by Geroni et al., incorporated herein by this binding proteins such as TRF2 and hPOT1 normally involved reference. Drugs that inhibit DNA methylation include, but in telomere capping, thus allowing recognition of the free are not limited to, 5'-azacytidine, 5-aza-2'-deoxycytidine, terminal sequence as a region of DNA damage. Bisantrene Zebularine, L-methionine, apicidine, hydralazine, procaina and derivatives and analogs thereofshare a general consensus mide, and antisense oligonucleotides directed against mRNA structural motif of compounds either inhibiting telomerase for DNA methyltransferase. Additional drugs that inhibit activity or disrupting telomere structure. This structural motif DNA methylation include inhibitors of histone deacetylase includes a large flat aromatic Surface linked to protonatable (HDAC). These compounds include, but are not limited to, side chains. In compounds with this structural motif, DNA compounds disclosed in PCT Patent Application Publication binding occurs mainly through stacking on a terminal G-tet No. WO 02/22577 by Bair et al., incorporated herein by this rad, whereas side chains contribute to the stability of the reference, including, but not limited to, N-hydroxy-3-4-(2- complex by hydrophobic/ionic interactions into the DNA hydroxyethyl)2-(1H-indol-3-yl)ethyl-aminomethylphe grooves. The number and position of side chains affect nyl-2E-2-propenamide, Suberoylanilide hydroxamic acid, anthracene/G-quadruplex interaction. Such derivatives can 4-(2-amino-phenylcarbamoyl)-benzyl-carbamic acid pyri selectively stabilize G-quadruplex folding. Telomerase inhi dine-3-ylmethyl ester and derivatives thereof, butyric acid, bition correlates with G-quadruplex recognition for Such pyroxamide, trichostatin A, oxamflatin, apicidin, depsipep derivatives. At least some of these derivatives are capable of tide, depudecin, trapoxin, HC toxin, and Sodium phenylbu inducing antiproliferative effects and a DNA damage tyrate. response at the telomeric level in telomerase-positive and (0349 (XXXVII) Use to Inhibit Telomerase or Induce ALT-positive tumor cells. This result is associated with the Telomere Dysfunction expression of the cyclin-dependent kinase inhibitor p21", 0350 Improvements for suboptimal chemotherapeutics which is known to be involved in a senescence pathway including bisantrene and derivatives or analogs thereof are triggered by telomere dysfunction. There is also enhanced made by use of bisantrene or derivatives or analogs thereof to expression of trimethyl K9 histone H3, which is a marker inhibit telomerase or induce telomere dysfunction. It is Suggestive of cellular senescence-associated changes in chro known that the expression and activity of telomerase in main matin structure. The expression of senescence-associated taining telomere length is associated with cell immortaliza B-galactosidase is also enhanced. These responses are asso tion and carcinogenesis; telomerase is active in most human ciated with the occurrence of a DNA damage signal at the tumor cells but generally inactive in most human Somatic telomere level. The results with bisantrene analogs and cells. Specific inventive examples for bisantrene and deriva derivatives suggest formation of additional specific interac tives and analogs thereof include: use to inhibit telomerase; or tions between the 4,5-dihydro-1H-imidazol-2-yl hydrazone use to induce telomere dysfunction. groups and the G-quadruplex structure. These analogs and derivatives can act at both the telomerase level, by interfering 0351. The use of derivatives of bisantrene to interfere with with Substrate recognition and thus Suppressing its catalytic telomeric function is disclosed in M. Folini et al., “Remark activity, and at the telomere level, by Suppressing its organi able Interference with Telomeric Function by a G-Quadru Zation. These results suggest a drug-mediated activation of a plex Selective Bisantrene Regioisomer. Biochem. Pharma senescence pathway. col. 79: 1781-1790 (2010), incorporated herein by this reference. The enzyme telomerase is a ribonucleoprotein 0352. These results suggest that bisantrene analogs and reverse transcriptase responsible for telomere length mainte derivatives can be used with other telomerase inhibitors, nance. Its expression is associated with cell immortalization including BPPA (2,6-bis(3-piperidinopropionamido)an and tumorigenesis, as it is expressed in most human tumor thraquinone), (-)-epigallocatechingallate, H-7 (2,6-bis(3-pi cells but is not active in most human Somatic cells. Typically, peridinopropionamido)anthraquinone), 3-rubromycin, and inhibition of telomerase results in cellular senescence or apo BIBR1532 (2-(2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl 1 ptosis in a time-dependent manner correlating with initial ylaminobenzoic acid). telomere length. Alternatively, tumor cell crisis can be 0353 (XXXVIII) Use to Activate Macrophages or Innate induced rapidly by promoting telomere dysfunction; this Immunity must be distinguished from the inhibition of telomerase activ 0354) Improvements for suboptional chemotherapeutics ity. Many proteins are involved in preserving the complex including bisantrene and derivatives or analogs thereof are telomere architecture. When the complex telomere architec made by use of bisantrene or derivatives or analogs thereof to ture is disrupted or collapses, it activates a signaling cascade activate macrophages or induce innate immunity. Macroph comparable to that promoted by DNA damage and leads to ages bridge innate and adaptive immunity. The role of mac cell cycle arrest (accelerated senescence) or apoptosis. rophages is described in J. Rothman & Y. Patterson, “Live Telomerase substrates are telomeres in DNA. These are Attenuated Listeria-Based Immunotherapy.” Exp. Rev. 12: double-stranded DNA portions with a 3'-protruding overhang 493-504 (2013), incorporated herein by this reference, which 100-200 bases in length formed by a repeated noncoding shows the effectiveness of genetically engineered Listeria sequence, typically TTAGGG (SEQID NO: 1) in humans. In strains in promoting both innate and adaptive immune analogy to other guanine-rich structures, the single-stranded responses mediated by the activity of macrophages. Specific portion can fold into a structure called G-quadruplex, which inventive examples forbisantrene and derivatives and analogs includes four Hoogsten-paired guanine residues. Hoogsten thereof include: use to activate macrophages; use to induce base-pairing is an alternative for base-pairing in DNA to the innate immunity; or use to induce adaptive immunity. conventional Watson-Crick base pairs. Certain ligands stabi 0355 B. S. Wang et al., “Immunotherapy of a Murine lize this unconventional DNA base-pairing arrangement and Lymphoma by Adoptive Transfer of Syngeneic Macrophages US 2016/0220537 A1 Aug. 4, 2016 29

Activated with Bisantrene.” Cancer Res. 46:503-506 (1986), encodes eight IAP family members including X-linked and B. S. Wang et al., “Activation of Tumor-Cytostatic Mac inhibitor of apoptosis protein (X-IAP), cIAP1, cIAP2, ML rophages with the Antitumor Agent 9,10-Anthracenedicar IAP (Livin; K-IAP), Naip, ILP2 (TS-IAP), Apollon/Bruce boxaldehyde Bis4,5-dihydro-1H-imidazole-1-2yl)hydra and Survivin. The human Survivin gene spans 14.7 kb on the Zone Dihydrochloride (Bisantrene). Cancer Res. 44: 2363 telomeric position of chromosome 17 and is transcribed from 2367 (1984), both of which are incorporated herein by this a TATA-less, GC-rich promoter to generate the wild-type reference, disclose that macrophages can be activated with transcript and four different splice variant mRNA molecules. bisantrene and that such activated macrophages had an anti Wild-type human survivin is a 16.5 kD protein of 142 amino neoplastic effect in vivo. These effects appear to involve adaptive immunity via the activation of tumor killing T cells acids and is composed of a single baculovirus IAP repeat directly, as allogeneic transplants of activated macrophages domain and an extended C-terminal C-helical coiled-coil were shown to eliminate tumors in recipients, as well as domain; the Survivin protein molecule does not contain the through innate immunity, as the Supernatants of bisantrene RING-finger domain found in other IAPs. There is consider activated macrophages had a lesser, but still significant thera able evidence pointing to a functional role of survivin in both peutic effect on tumor bearing recipient mice. Additionally, apoptosis control and cell division. Survivin is a chromo there exist immune agents that have the effect of inducing Somal passenger protein that localizes to kinetochores at apoptosis in cancer cells, and the use of Such agents is metaphase, transfers to the central spindle mid-Zone at described further below. This approach is described in D. anaphase and accumulates in mid-bodies at telophase. Physi Tormo et al., “Targeted Activation of Innate Immunity for cal interactions with the inner centromere protein, Aurora B Therapeutic Induction of Autophagy and Apoptosis in Mela and Borealin/Dasra Bare required to target the complex to the noma Cells. Cancer Cell 16: 103-114 (2009), incorporated kinetochore, to properly form the bipolar spindle and to com herein by this reference. These agents include polyinosine plete cytokinesis. This function, involving preservation of polycytidylic acid, especially when complexed to polyethyl genome fidelity and regulation of microtubule dynamics, eneimine. requires close control of cell-cycle-dependent transcription of the Survivin gene during the mitotic phase, as well as 0356 (XXXIX) Use to Inhibit Expression of Survivin or post-translational modifications of the protein including with Survivin Inhibitors or Modulators phosphorylation by the p34* and Aurora B kinases and 0357 Bisantrene analogs and derivatives also selectively monoubiquitination through Lys48 and Lys63 linkages. This inhibit gene promoter activity for survivin (BIRC5) and to pathway may be dominant in normal, differentiated cells and down-regulate survivin in vitro, leading to apoptosis (T. G. may constitute the primary function of survivin in adult tis Glaros et al., “The Survivin Suppressants NSC80467 and sues. However, there is evidence that survivin is upregulated YM1155 Induce a DNA Damage Response.” Cancer in G/M cell compartments in a number of cancer lines. Other Chemother: Pharmacol. 70: 207-212 (2012), incorporated non-cell-cycle-dependent mechanisms driving Survivin gene herein by this reference). Survivin is encoded by the BIRC5 transcription independent of mitosis have been described, gene and is a member of the inhibitor of apoptosis (IAP) which involve tissue patterning circuits (Wnt/B-catenin), family. The Survivin protein functions to inhibit caspase acti cytokine activation signal-transducer-and-activator-of-tran Vation and thereby leads to negative regulation of apoptosis. Scription-3, costimulatory messages such as those of OX-40, The Survivin protein is frequently highly expressed in tumor and pleiotropic signaling mechanisms such as V-akt murine cells. Survivin expression is highly regulated by the cell cycle thymoma viral oncogene homolog 1 or protein kinase B and is only expressed in the G2/M phase. Survivin localizes to (AkT) and nuclear factor-KB that are typically operative dur the mitotic spindle by interaction with tubulin during mitosis. ing development and are upregulated in cancer cells. These Regulation of survivin is linked to the p53 protein and is a non-cell-cycle-dependent pathways may be dominant in direct target of the Wnt pathway; it is also upregulated by tumor cells. The fraction of survivin produced through these B-catenin. Accordingly, Survivin is a regulator of apoptosis non-cell-cycle-dependent mechanisms mediates apoptosis and acts to counter apoptosis. As an anti-apoptotic protein, it inhibition through intermolecular cooperation with cofactors is a potential target for drug therapy for cancer as its activity including the hepatitis B virus X-interacting protein, a target may promote resistance to anti-neoplastic therapeutic agents. of the oncogenic viral hepatitis B virus X protein and X-IAP, Two major pathways of apoptosis have been identified in leading to the formation of complexes that inhibit caspase-9 mammalian cells. A first pathway, designated the extrinsic processing. Moreover, Subcellular compartmentalization of pathway, is triggered by the binding of ligands to cell-surface Survivin in mitochondria seems to play a role in the anti trimeric membrane death receptors and leads to caspase-8 apoptotic function of the protein. Specifically, the existence activation. A second pathway, designated the extrinsic path ofa mitochondrial pool of Survivin was recently reported, and way, involves mitochondria, which respond to pro-apoptotic it was found that in response to cell death stimulation, mito signals by releasing cytochrome c, which in turn binds and chondrial Survivin is rapidly discharged and released into the activates the apoptotic protease-activating factor-1, causing cytosol, where it prevents caspase activation and inhibits assembly of a multiprotein caspase-activating complex (apo apoptosis. Mitochondrial Survivin may be exclusively asso ptosome) and leading to activation of caspase-9 and initiation ciated with tumor transformation. It also has been found that of a protease cascade. The extrinsic and intrinsic pathways for Survivin has a nuclear export signal and that in cancer cells the apoptosis converge on downstream effector caspases anti-apoptotic and mitotic roles of Survivin can be separated involved in apoptosis. Some of these, Such as caspase-3 and through mutation of its nuclear export signal, which abro caspase-7, are targets of Suppression by an endogenous fam gates the cytoprotective activity of the protein but still allows ily of anti-apoptotic proteins called inhibitor of apoptosis mitosis to proceed. The stability and function of survivin proteins (IAPs). Some members of this family also interfere require a physical interaction with the molecular chaperone with caspase-9 processing, the upstream initiation of the heat shock protein 90 (Hsp90), which involves the Hsp90 mitochondrial pathway of apoptosis. The human genome ATPase domain and the survivin baculovirus IAP repeat US 2016/0220537 A1 Aug. 4, 2016 30 domain. Although Survivin is expressed in tissues that are United States Patent Application Publication No. characterized by self-renewal and proliferation, such as adult 20120088770 by Odagami et al., United States Patent Appli liver cells, gastrointestinal tract mucosal cells, T cells, and cation Publication No. 20110263607 by Kouji et al., United hematopoietic progenitor cells, its expression is significantly States Patent Application Publication No. 20110092459 by lower than in transformed cells. Global deregulation of the Odagami et al., United States Patent Application Publication Survivingene may be mediated by oncogenes or loss of tumor No. 20090304695 by He et al., United States Patent Applica Suppressors such as wild-type p53 protein. There is also con tion Publication No. 20090202539 by You et al., United siderable evidence that survivin plays an important role in the States Patent Application Publication No. 20080267951 by drug-resistant phenotype of human cancer cells. For example, You et al., United States Patent Application Publication No. it has been shown that taxol-induced microtubule stabiliza 2006004.0883 by You et al., and United States Patent Appli tion and mitotic arrest increase the expression of Survivin, cation Publication No. 2003.0125287 by Kandimalla et al., all which engenders a cell Survival pathway to counteract taxol of which are incorporated herein by this reference. induced apoptosis. Other pathways may also be involved. For 0360 Additional survivin inhibitors are disclosed in: U.S. example, the mammalian target of rapamycin pathway, which Pat. No. 7,710,068 to Berezov et al. and include compounds constitutes a sensor network for stress conditions, may be of Formula (A-1) involved in resistance to taxol by increasing Survivin levels. Also, insulin-like growth factor-1-mediated mammalian tar get of rapamycin activation in prostate cancer cells can posi (A-1) tively modulate survivin levels by favoring stabilization and translation of a survivin mRNA pool and that mammalian target of rapamycin inhibition with rapamycin, alone or in combination with taxol, can abolish Survivin increase. Sur vivin may also mediate resistance to other anti-neoplastic therapeutic agents and to radiation. Therefore, agents that inhibit or block the expression or activity of survivin may be useful in treating malignancies, especially by preventing or wherein: X is hydrogen, halogen, hydroxyl, alkoxy, or C-C, reducing the development of resistance to chemotherapeutic linear or branched alkyl; and R is C-C linear or branched agents or by promoting apoptosis. alkyl or cycloalkyl optionally substituted with halogen, nitro, amine, or dioxole). Inhibitors or modulators or survivin are 0358 Bisantrene orderivatives or analogs thereof can also also disclosed in U.S. Pat. No. 8,026,355 to Hansen et al. be used with survivin inhibitors or modulators. (oligonucleotides, particularly antisense oligonucleotides, 0359 Survivin inhibitors include, but are not limited to, targeted to nucleic acids encoding Survivin) and in U.S. Pat. NSC80467 (2-methyl-1-(2-methylpropyl)-3-2-(4-nitrophe No. 7,910,742 to Wendt et al. (a compound selected from the nyl)-2-oxoethylbenzof benzimidazol-3ium-4,9-dione bro group consisting of tert-butyl 4-(((5-chloro-3-(4-(2-chloro-5- mide), YM1155 (1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3- (trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6-dihydropyri (pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphthoI2,3-d din-2-yl)-2-hydroxybenzyl)(methyl)amino)carbonyl)-1-pip imidazolium bromide), SPC3042 (a locked antisense nucleic eridinecarboxylate: N-(5-chloro-3-(4-(2-chloro-5- acid designed as an antisense 16-mer LNA gapmer (J. B. (trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- Hansen et al., “SPC3042: A Proapoptotic Survivin Inhibitor.” dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-4- Mol. Cancer Ther. 7:2736-2745 (2008)), targeting the region piperidinecarboxamide; 1-acetyl-N-(5-chloro-3-(4-(2- comprising the stop codon of the open reading frame in exon chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- 4 of the survivin transcript), NU6140 (4-(6-cyclohexyl dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-4- methoxy-9H-purin-2-ylamino)-N,N-diethylbenzamide), piperidinecarboxamide; N-(5-chloro-3-(4-(2-chloro-5- toxoflavin, gambogic acid, LLP-3 (4-(3,5-bis(benzyloxy) (trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- phenyl)-6-(5-chloro-2-hydroxyphenyl)-2-oxo-1,2-dihydro dihydropyridin-2-yl)-2-hydroxybenzyl)-N,4-dimethyl-4- pyridine-3-carbonitrile) ISIS 23722, (6S.9S) N-benzyl-6- piperidinecarboxamide: tert-butyl 4-(((5-chloro-3-(4-(2- (4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8- chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- ylmethyl)octahydro-1H-pyrazino.2.1-c.1.2.4 triazine-1- dihydropyridin-2-yl)-2-hydroxybenzyl)(methyl)amino) carboxamide, 4-(((6S.9S)-1-(benzylcarbamoyl)-2.9- carbonyl)-4-phenyl-1-piperidinecarboxylate: N-(5-chloro-3- dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H (4-(2-chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- pyrazino.2.1-c.1.2.4 triazin-6-yl)methyl)phenyl dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-4- dihydrogen phosphate, tetra-O-methyl-nordihydroguaiaretic phenyl-4-piperidinecarboxamide; N-(5-chloro-3-(4-(2- acid, butane-bridge-modified tetra-O-methyl-nordihy chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- droguaiaretic acids, including 1,4-bis(3,4-bis3-(piperdin-1- dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-1-(4- yl)propoxyphenyl-butane, tetra-Substituted nordihy pyridinyl)-4-piperidinecarboxamide: N-(5-chloro-3-(4-(2- droguaiaretic acid derivatives via ether bonds or carbamate chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- bonds, tetraglycinyl nordihydroguaiaretic acid, LY2181308, dihydropyridin-2-yl)-2-hydroxybenzyl)-1-(4-cyanophenyl)- dichloroacetic acid, and ICG-001 ((6S.9aS)-6-(4-hydroxy N-methyl-4-piperidinecarboxamide: 1-(4-acetylphenyl)-N- benzyl)-N-benzyl-8-(naphthalen-1-ylmethyl)-4,7-dioxo (5-chloro-3-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5- hexahydro-2H-pyrazino 1,2-alpyrimidine-1 (6H)-carboxam cyano-6-oxo-1,6-dihydropyridin-2-yl)-2-hydroxybenzyl)- ide). Other survivin inhibitors and methods for inhibiting the N-methyl-4-piperidinecarboxamide: 1-acetyl-N-(5-chloro expression of survivin are disclosed in U.S. Pat. No. 8,455, 3-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1, 488 to Odagami et al., U.S. Pat. No. 8.318,815 to Huanget al., 6-dihydropyridin-2-yl)-2-hydroxybenzyl)-4- U.S. Pat. No. 8,232,277 to Chen et al., U.S. Pat. No. 8,178, piperidinecarboxamide; N-(5-chloro-3-(4-(2-chloro-5- 527 to Chen et al., U.S. Pat. No. 7,959,923 to You et al., (trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- US 2016/0220537 A1 Aug. 4, 2016 dihydropyridin-2-yl)-2-hydroxybenzyl)-1-(methoxyacetyl)- N-solanesyl-N,N'-bis(3,4-dimethylbenzyl)ethylenediamine, N-methyl-4-piperidinecarboxamide: 1-butyryl-N-(5-chloro cepharanthine, quinidine, reserpine, chlorpromazine and tri 3-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1, fluoperazine (S. Akiyama et al., “Most Drugs That Reverse 6-dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-4- Multidrug Resistance Also Inhibit Photoaffinity Labeling of piperidinecarboxamide; N-(5-chloro-3-(4-(2-chloro-5- P-Glycoprotein by a Vinblastine Analog. Mol. Pharmacol. (trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- 33: 144-147 1988)); triazine derivatives (A. Dhainaut et al., dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-1-(2- “New Triazine Derivatives as Potent Modulators of Multi methylbutanoyl)-4-piperidinecarboxamide: N-(5-chloro-3- drug Resistance.” J. Med. Chem. 35: 2481-2496 (1992)); (4-(2-chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- terferadine: RU-486; dihydropyridine analogs (M. Kamiwa dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-1-(4.4.4- tari et al., “Correlation Between Reversing of Multidrug trifluorobutanoyl)-4-piperidinecarboxamide: N-(5-chloro-3- Resistance and Inhibiting of HAzidopine Photolabeling of (4-(2-chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- P-Glycoprotein by Newly Synthesized Dihydropyridine Ana dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-1-(4.4.4- logues in a Human Cell Line.” Cancer Res. 49: 3190-3195 trifluorobutanoyl)-4-piperidinecarboxamide: N-(5-chloro-3- (1989)); the staurosporine derivative NA-382 (K.-I. Miya (4-(2-chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- moto et al., “Inhibition of Multidrug Resistance by a New d-ihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-1- Staurosporine Derivative, NA-382, in Vitro and in Vivo. (tetrahydro-2-furanylcarbonyl)-4-piperidinecarboxamide; Cancer Res. 53: 1555-1559 (1993); ningalin Banalogs (U.S. 1-(3-butynoyl)-N-(5-chloro-3-(4-(2-chloro-5-(trifluorom Pat. No. 7,250,409 to Boger); other agents (U.S. Pat. No. ethyl)phenyl)-5-cyano-6-oxo-1,6-dihydropyridin-2-yl)-2- 5,786.344 to Ratain et al; cyclosporine A, Verapamil, cefop hydroxybenzyl)-N-methyl-4-piperidinecarboxamide: N-(5- eraZone, N-ethoxycarbonyl-7-oxo-staurosporine (NA-382); chloro-3-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5-cyano nifedipine, nitrendipine, nicardipine and diltiazem; other 6-oxo-1,6-dihydropyridin-2-yl)-2-hydroxybenzyl)-N- dihydropyridines; tiapamil; nisoldipine; nimodipine; nitren methyl-1-(3-nitropropanoyl)-4-piperidinecarboxamide; dipine; phenothiazines; thioxanthenes; fluiphenazine; chlor N-(5-chloro-3-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5- promazine; triflupromazine; trifluoperazine; prochlorpera cyano-6-oxo-1,6-dihydropyridin-2-yl)-2-hydroxybenzyl)-1- Zine; progesterone; metabolites of progesterone; tirilazad; (cyclopropylcarbonyl)-N-methyl-4-piperidinecarboxamide: Vincristine; vinblastine; actinomycin D; colchicine; etopo N-(5-chloro-3-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5- side; daunorubicin; doxorubicin; taxotere; taxol; tamoxifen; cyano-6-oxo-1,6-dihydropyridin-2-yl)-2-hydroxybenzyl)-1- reserpine; dipyramidole; chloroquine; propranolol, terfena (cyclopropylacetyl)-N-methyl-4-piperidinecarboxamide; dine; ivermectin; and quinidine. Additional multidrug resis N-(5-chloro-3-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5- tance reversal agents are disclosed in U.S. Pat. No. 8,673.914 cyano-6-oxo-1,6-dihydropyridin-2-yl)-2-hydroxybenzyl)-1- to Chen et al.; these multidrug resistance reversal agents are (cyclohexylcarbonyl)-N-methyl-4-piperidinecarboxamide: phosphodiesterase inhibitors, such as PDE5 inhibitors, and N-(5-chloro-3-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5- include sildenafil. Vardenafil, tadalafil, lodenafil, udenafil. cyano-6-oxo-1,6-dihydropyridin-2-yl)-2-hydroxybenzyl)- benzamidenafil, mirodenafil, avanafil. zaprinast, SLX-2101, N-methyl-1-propyl-4-piperidinecarboxamide: N-(5-chloro UK-371,800, UK-122764, icariin, DA-8159, and 3-4-(2-hy 3-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1, droxyethyl)piperazin-1-yl-7-(6-methoxypyridin-3-yl)-1-(2- 6-dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-1-(2- propoxyethyl)pyrido3,4-b-pyrazin-2(1H)-one. phenylethyl)-4-piperidinecarboxamide: N-(5-chloro-3-(4- (2-chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- 0363 (XLI) Use in Combinatorial Regimes dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-1-(2-(2, 0364 Improvements for suboptimal chemotherapeutics 6,6-trimethyl-1-cyclohexen-1-yl)ethyl)-4- including bisantrene and derivatives or analogs thereof are piperidinecarboxamide; 1-(2-(benzyloxy)ethyl)-N-(5- made by use of bisantrene or derivatives or analogs thereof in chloro-3-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5-cyano combinatorial regimes. A significant area of research is 6-oxo-1,6-dihydropyridin-2-yl)-2-hydroxybenzyl)-N- directed at methods for combining newer immunotherapies methyl-4-piperidinecarboxamide; N-(5-chloro-3-(4-(2- with older cytotoxic modalities. Specific inventive examples chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- for bisantrene and derivatives or analogs thereof include: use dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-1-(3-(5- in a combinatorial regime as a chemotherapeutic agent with at methyl-2-furyl)butyl)-4-piperidinecarboxamide: 1-acetyl-N- least one agent inducing immunoactivity; use in a combina ((4'-chloro-5-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5- torial regime as a chemotherapeutic agent with at least one cyano-6-oxo-1,6-dihydropyridin-2-yl)-4-hydroxy(1,1'- agent inducing macrophage activation; use in a combinatorial biphenyl)-3-yl)methyl)-N-methyl-4- regime as a chemotherapeutic agent with at least one cytok piperidinecarboxamide; 1-acetyl-N-(3-(4-(2-chloro-5- ine; use in a combinatorial regime as a chemotherapeutic (trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6- agent with at least one agent inhibiting telomerase; use in a dihydropyridin-2-yl)-5-cyclopentyl-2-hydroxybenzyl)-N- combinatorial regime as a chemotherapeutic agent with at methyl-4-piperidinecarboxamide). least one agent inhibiting Survivin; use in a combinatorial regime as a chemotherapeutic agent with at least one agent 0361 (XL) Use with Multidrug Resistance Reversal inducing demethylation; use in a combinatorial regime as a Agents chemotherapeutic agent with at least one adjuvant; use in a 0362 Improvements for suboptimal chemotherapeutics combinatorial regime as a chemotherapeutic agent with at including bisantrene and derivatives or analogs thereof are least one antibody; use in a combinatorial regime as a che made by use of bisantrene or derivatives or analogs thereof motherapeutic agent with at least one innate or adaptive with multidrug resistance reversal agents. Multidrug resis immune stimulator, use in a combinatorial regime as a che tance reversal agents include, but are not limited to, Vera motherapeutic agent with at least one checkpoint inhibitor; pamil, N-myristoylated protein kinase C-C. pseudo Substrate use in a combinatorial regime as a chemotherapeutic agent peptides; dexVerapamil (an enantiomer of Verapamil); with at least one mTOR antagonist; use in a combinatorial US 2016/0220537 A1 Aug. 4, 2016 32 regime as a chemotherapeutic agent with at least one Akt 0370 (1) identifying at least one factor or parameter inhibitor, use in a combinatorial regime as a chemotherapeu associated with the efficacy and/or occurrence of side tic agent with at least one notch inhibitor, use in a combina effects of the drug therapy; and torial regime as a chemotherapeutic agent with at least one 0371 (2) modifying the factor or parameter to improve HSP inhibitor; use in a combinatorial regime as a chemo the efficacy and/or reduce the side effects of the drug therapeutic agent with at least one phosphatidylinositide 3-ki therapy. nase inhibitor, use in a combinatorial regime as a chemothera 0372 Typically, the factor or parameter is selected from peutic agent with at least one kinase inhibitor; use in a the group consisting of combinatorial regime as a chemotherapeutic agent with cyt 0373 (1) dose modification: arabine; use in a combinatorial regime as a chemotherapeutic 0374 (2) route of administration: agent with taxane; use in a combinatorial regime as a chemo 0375 (3) schedule of administration: therapeutic agent with taxol; use in a combinatorial regime as 0376 (4) indications for use: an agent inducing macrophage activation with at least one 0377 (5) selection of disease stage; agent inducing telomerase inhibition; use in a combinatorial 0378 (6) other indications: regime as an agent inducing macrophage activation with at 0379 (7) patient selection: least one cytokine; use in a combinatorial regime as an agent 0380 (8) patient/disease phenotype: inducing macrophage activation with at least one agent inhib 0381 (9) patient/disease genotype: iting Survivin; use in a combinatorial regime as an agent 0382 (10) prefpost-treatment preparation inducing macrophage activation with at least one agent induc 0383 (11) toxicity management; ing demethylation; use in a combinatorial regime as an agent 0384 (12) pharmacokinetic/pharmacodynamic moni inducing macrophage activation with at least one adjuvant; toring: use in a combinatorial regime as an agent inducing macroph 0385 (13) drug combinations: age activation with at least one antibody; use in a combina 0386 (14) chemosensitization; torial regime as an agent inducing macrophage activation (0387 (15) chemopotentiation: with at least one innate or adaptive immune stimulator, use in 0388 (16) post-treatment patient management; a combinatorial regime as an agent inducing macrophage 0389 (17) alternative medicine/therapeutic support; activation with at least one checkpoint inhibitor, use in a 0390 (18) bulk drug product improvements: combinatorial regime as an agent inducing macrophage acti 0391 (19) diluent systems: Vation with at least one mTOR antagonist; use in a combina 0392 (20) solvent systems: torial regime as an agent inducing macrophage activation 0393 (21) excipients: with at least one Akt inhibitor, use in a combinatorial regime 0394 (22) dosage forms: as an agent inducing macrophage activation with at least one 0395 (23) dosage kits and packaging: notch inhibitor; use in a combinatorial regime as an agent 0396 (24) drug delivery systems; inducing macrophage activation with at least one HSP inhibi 0397 (25) drug conjugate forms; tor, use in a combinatorial regime as an agent inducing mac 0398 (26) compound analogs; rophage activation with at least one phosphatidylinositide 0399 (27) prodrugs: 3-kinase inhibitor, use in a combinatorial regime as an agent 04.00 (28) multiple drug systems; inducing macrophage activation with at least one kinase 0401 (29) biotherapeutic enhancement; inhibitor, use in a combinatorial regime as an agent inducing 0402 (30) biotherapeutic resistance modulation; macrophage activation with cytarabine; use in a combinato 0403 (31) radiation therapy enhancement; rial regime as an agent inducing macrophage activation with 0404 (32) novel mechanisms of action; taxane; or use in a combinatorial regime as an agent inducing 0405 (33) selective target cell population therapeutics: macrophage activation with taxol. 0406 (34) use with an agent enhancing its activity; 0365 (XLII) Use with Directed Antibody Conjugates 0407 (35) use to modulate DNA methylation: 0366 Improvements for suboptional chemotherapeutics 0408 (36) use to inhibit telomerase or induce telomere including bisantrene and derivatives or analogs thereof are dysfunction; made by use of bisantrene or derivatives or analogs thereof 0409 (37) use to activate macrophages or innate immu with directed antibody conjugates. nity; 0410 (38) use to inhibit expression of survivin or with 0367 (XLIII) Use with Adjuvants survivin inhibitors or modulators; 0368. Improvements for suboptional chemotherapeutics 0411 (39) use with multidrug resistance reversal including bisantrene and derivatives or analogs thereof are agents; made by use of bisantrene or derivatives or analogs thereof 0412 (40) use in combinatorial regimes: with adjuvants. The adjuvant can be, but is not limited to, 0413 (41) use with directed antibody conjugates; and GM-CSF, poly-ICLC (carboxymethylcellulose, polyi 0414 (42) use with adjuvants. nosinic-polycytidylic acid, and poly L-lysine), nanoparticles, 0415. The suboptimally administered drug therapy can microparticles, aluminum salts, squalene, QS-21 (a plant comprise administration of bisantrene or of a derivative or extract from Quillaia saponaria containing water-soluble analog of bisantrene, as described above. triterpene glycosides), Virosomes, IL-2, IL-7, IL-21, and type 0416 Typically, when the suboptimally administered drug 1 interferons. Other adjuvants are known in the art. therapy is used to treat a hyperproliferative disease, the hyper 0369 Accordingly, one aspect of the present invention is a proliferative disease is cancer. Methods according to the method to improve the efficacy and/or reduce the side effects present invention and compositions according to the present of Suboptimally administered drug therapy comprising the invention suitable for use in those methods are applicable to steps of: many forms of cancer, including, but not limited to: (A) breast US 2016/0220537 A1 Aug. 4, 2016

cancer, including: (1) ductal carcinoma, including ductal car cinoma, intestinal type, mucinous adenocarcinoma, clear cell cinoma in situ (DCIS) (comedocarcinoma, cribriform, papil adenocarcinoma, signet-ring cell carcinoma, adenoSquamous lary, micropapillary), infiltrating ductal carcinoma (IDC), carcinoma, squamous cell carcinoma, Small cell (oat) carci tubular carcinoma, mucinous (colloid) carcinoma, papillary noma, undifferentiated carcinoma, carcinoma (NOS), Sar carcinoma, metaplastic carcinoma, and inflammatory carci coma, and carcinoid tumor; (4) cancers of the colon and noma; (2) lobular carcinoma, including lobular carcinoma in rectum, including adenocarcinoma in situ, adenocarcinoma, situ (LCIS) and invasive lobular carcinoma; (3) Paget’s dis mucinous adenocarcinoma (colloid type; greater than 50% ease of the nipple; (4) Her2/neu tumors; (5) ER" tumors; and mucinous carcinoma), signet ring cell carcinoma (greater (6) triple negative tumors; (B) cancers of the female repro than 50% signet ring cell), Squamous cell (epidermoid) car ductive system, including: (1) cancers of the cervix uteri, cinoma, adenosquamous carcinoma, Small cell (oat cell) car including cervical intraepithelial neoplasia (Grade I), cervi cinoma, undifferentiated carcinoma, carcinoma (NOS), Sar cal intraepithelial neoplasia (Grade II), cervical intraepithe coma, lymphoma, and carcinoid tumor; (5) cancers of the lial neoplasia (Grade III) (squamous cell carcinoma in situ), esophagus, including squamous cell carcinoma, adenocarci keratinizing squamous cell carcinoma, nonkeratinizing squa noma, leiomyosarcoma, and lymphoma; (6) cancers of the mous cell carcinoma, Verrucous carcinoma, adenocarcinoma gallbladder, including adenocarcinoma, adenocarcinoma, in situ, adenocarcinoma in situ, endocervical type, intestinal type, adenosquamous carcinoma, carcinoma in situ, endometrioid adenocarcinoma, clear cell adenocarcinoma, carcinoma (NOS), clear cell adenocarcinoma, mucinous adenosquamous carcinoma, adenoid cystic carcinoma, Small adenocarcinoma, papillary adenocarcinoma, signet-ring cell cell carcinoma, and undifferentiated carcinoma; (2) cancers carcinoma, Small cell (oat cell) carcinoma, squamous cell of the corpus uteri, including endometrioid carcinoma, carcinoma, and undifferentiated carcinoma; (7) cancers of the adenocarcinoma, adenocanthoma (adenocarcinoma with lip and oral cavity, including squamous cell carcinoma; (8) squamous metaplasia), adenosquamous carcinoma (mixed cancers of the liver, including hepatoma (hepatocellular car adenocarcinoma and squamous cell carcinoma, mucinous cinoma), cholangiocarcinoma, hepatoblastoma, angiosar adenocarcinoma, serous adenocarcinoma, clear cell adeno coma, hepatocellular adenoma, and hemangioma; (9) cancers carcinoma, squamous cell adenocarcinoma, and undifferen of the exocrine pancreas, including duct cell carcinoma, pleo tiated adenocarcinoma; (3) cancers of the ovary, including morphic giant cell carcinoma, giant cell carcinoma, osteo serous cystadenoma, serous cystadenocarcinoma, mucinous clastoid type, adenocarcinoma, adenosquamous carcinoma, cystadenoma, mucinous cystadenocarcinoma, endometrioid mucinous (colloid) carcinoma, cystadenocarcinoma, acinar tumor, endometrioid adenocarcinoma, clear cell tumor, clear cell carcinoma, papillary carcinoma, small cell (oat cell) car cell cystadenocarcinoma, and unclassified tumor; (4) cancers cinoma, mixed cell typed, carcinoma (NOS), undifferentiated of the vagina, including squamous cell carcinoma and adeno carcinoma, endocrine cell tumors arising in the islets of carcinoma; and (5) cancers of the Vulva, including Vulvar Langerhans, and carcinoid; (10) cancers of the salivary intraepithelial neoplasia (Grade I), Vulvar intraepithelial neo glands, including acinic (acinar) cell carcinoma, adenoid cys plasia (Grade II), Vulvar intraepithelial neoplasia (Grade III) tic carcinoma (cylindroma), adenocarcinoma, squamous cell (squamous cell carcinoma in situ); squamous cell carcinoma, carcinoma, carcinoma in pleomorphic adenoma (malignant Verrucous carcinoma, Paget’s disease of the Vulva, adenocar mixed tumor), mucoepidermoid carcinoma (well differenti cinoma (NOS), basal cell carcinoma (NOS), and Bartholin's ated or low grade), and mucoepidermoid carcinoma (poorly gland carcinoma; (C) cancers of the male reproductive sys differentiated or high grade); (11) cancers of the stomach, tem, including: (1) cancers of the penis, including Squamous including adenocarcinoma, papillary adenocarcinoma, tubu cell carcinoma; (2) cancers of the prostate, including adeno lar adenocarcinoma, mucinous adenocarcinoma, signet ring carcinoma, sarcoma, and transitional cell carcinoma of the cell carcinoma, adenosquamous carcinoma, squamous cell prostate; (3) cancers of the testis, including seminomatous carcinoma, Small cell carcinoma, undifferentiated carcinoma, tumor, nonseminomatous tumor, teratoma, embryonal carci lymphoma, sarcoma, and carcinoid tumor; and (12) cancers noma, yolk sac tumor, and choriocarcinoma; (D) cancers of of the Small intestine, including adenocarcinoma, lymphoma, the cardiac system, including sarcoma (angiosarcoma, fibro carcinoid tumors, Kaposi's sarcoma, leiomyoma, heman sarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhab gioma, lipoma, neurofibroma, and fibroma; (H) cancers of the domyoma, fibroma, lipoma and teratoma; (E) cancers of the urinary system, including: (1) cancers of the kidney, includ respiratory system, including squamous cell carcinoma of the ing renal cell carcinoma, carcinoma of Bellini’s collecting larynx, primary pleural mesothelioma, and squamous cell ducts, adenocarcinoma, papillary carcinoma, tubular carci carcinoma of the pharynx, (F) cancers of the lung, including noma, granular cell carcinoma, clear cell carcinoma (hyper squamous cell carcinoma (epidermoid carcinoma), variants nephroma), sarcoma of the kidney, and nephroblastoma; (2) of squamous cell carcinoma, spindle cell carcinoma, Small cancers of the renal pelvis and ureter, including transitional cell carcinoma, carcinoma of other cells, carcinoma of inter cell carcinoma, papillary transitional cell carcinoma, squa mediate cell type, combined oat cell carcinoma, adenocarci mous cell carcinoma, and adenocarcinoma; (3) cancers of the noma, acinar adenocarcinoma, papillary adenocarcinoma, urethra, including transitional cell carcinoma, squamous cell bronchiolo-alveolar carcinoma, Solid carcinoma with mucus carcinoma, and adenocarcinoma; and (4) cancers of the uri formation, large cell carcinoma, giant cell carcinoma, clear nary bladder, including carcinoma in situ, transitional urothe cell carcinoma, and sarcoma; (G) cancers of the gastrointes lial cell carcinoma, papillary transitional cell carcinoma, tinal tract, including: (1) cancers of the ampulla of Vater, squamous cell carcinoma, adenocarcinoma, undifferentiated; including primary adenocarcinoma, carcinoid tumor, and (I) cancers of muscle, bone, and soft tissue, including: (1) lymphoma; (2) cancers of the anal canal, including adenocar cancers of bone, including: (a) bone-forming: osteosarcoma; cinoma, squamous cell carcinoma, and melanoma; (3) can (b) cartilage-forming: chondrosarcoma and mesenchymal cers of the extrahepatic bile ducts, including carcinoma in chondrosarcoma; (c) giant cell tumor, malignant; (d) Ewings situ, adenocarcinoma, papillary adenocarcinoma, adenocar sarcoma; (e) vascular tumors: hemangioendothelioma, US 2016/0220537 A1 Aug. 4, 2016 34 hemangiopericytoma, and angiosarcoma, (f) connective tis according to the present invention and compositions accord Sue tumors: fibrosarcoma, liposarcoma, malignant mesen ing to the present invention are also particularly suitable for chymoma, and undifferentiated sarcoma; and (g) other treatment of several non-malignant proliferative conditions, tumors: chordoma and adamantinoma of long bones; (2) can including psoriasis and HSV-induced shingles. cers of Soft tissues, including: alveolar soft-part sarcoma, 0417. The following improvements all apply either to angiosarcoma, epithelioid sarcoma, extraskeletal chondrosa bisantrene itself or derivatives or analogs of bisantrene as rcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malig described above indicated with respect to the specific nant fibrous histiocytoma, malignant hemangiopericytoma, improvement indicated below, unless either bisantrene or malignant mesenchymoma, malignant Schwannoma, rhab derivatives or analogs of bisantrene are specifically indicated. 0418 When the improvement is made by dose modifica domyosarcoma, synovial sarcoma, and sarcoma (NOS); (3) tion, the dose modification can be, but is not limited to, at least cancers of the nervous system, including cancers of the skull one dose modification selected from the group consisting of (osteoma, hemangioma, granuloma, Xanthoma, osteitis 0419 (a) continuous i.v. infusion for hours to days; deformans), cancers of the meninges (meningioma, menin 0420 (b) biweekly administration: giosarcoma, gliomatosis), cancers of the brain (astrocytoma, 0421 (c) doses greater than 5 mg/m/day; medulloblastoma, glioma, ependymoma, germinoma 0422 (d) progressive escalation of dosing from 1 (pilealoma), glioblastoma multiforme, oligodendroglioma, mg/m/day based on patient tolerance; Schwannoma, retinoblastoma, congenital tumors), and can 0423 (e) doses less than 1 mg/m for greater than 14 cers of the spinal cord neurofibroma, meningioma, glioma, days; sarcoma); (4) hematologic cancers, including myeloid leuke 0424 (f) use of caffeine to modulate metabolism; mia (acute and chronic), acute lymphoblastic leukemia, 0425 (g) use of isoniazid to modulate metabolism; chronic lymphocytic leukemia, myeloproliferative diseases, 0426 (h) selected and intermittent boost dose adminis multiple myeloma; myelodysplastic syndrome), Hodgkin’s trations; disease, and non-Hodgkin’s lymphoma (malignant lym 0427 (i) bolus single and multiple doses of 1-5 mg/m; phoma); (5) cancers of the endocrine system, including: (a) 0428 () oral dosing including multiple daily dosing: cancers of the thyroid gland, including papillary carcinoma 0429 (k) micro-dosing: (including those with follicular foci), follicular carcinoma, 0430 (1) immediate release dosing: medullary carcinoma, and undifferentiated (anaplastic) car 0431 (m) slow release dosing; and cinoma; and (b) neuroblastomas, including sympathicoblas 0432 (n) controlled release dosing. toma, sympathicogonioma, malignant ganglioneuroma, gan 0433 When the improvement is made by route of admin gliosympathicoblastoma, and ganglioneuroma; (6) cancers of istration, the route of administration can be, but is not limited the skin, including squamous cell carcinoma, spindle cell to, a route of administration selected from the group consist variant of squamous cell carcinoma, basal cell carcinoma, ing of adenocarcinoma developing from Sweat or sebaceous gland, 0434 (a) central venous administration; and malignant melanoma; (7) cancers of the eye, including: 0435 (b) intraperitoneal administration: (a) cancers of the conjunctiva, including carcinoma of the 0436 (c) intravenous administration; conjunctiva; (b) cancers of the eyelid, including basal cell 0437 (d) intravesicular administration for bladder can carcinoma, squamous cell carcinoma, melanoma of the eye cer, lid, and sebaceous cell carcinoma; (c) cancers of the lacrimal 0438 (e) intrathecal administration; gland, including adenocarcinoma, adenoid cystic carcinoma, 0439 (f) intra-arterial administration; carcinoma in pleomorphic adenoma, mucoepidermoid carci 0440 (g) continuous infusion; and noma, and squamous cell carcinoma; (d) cancers of the uvea, 0441 (h) intermittent infusion. including spindle cell melanoma, mixed cell melanoma, and 0442. When the improvement is made by schedule of epithelioid cell melanoma; (e) cancers of the orbit, including administration, the schedule of administration can be, but is sarcoma of the orbit, Soft tissue tumor, and sarcoma of bone; not limited to, a schedule of administration selected from the and (f) retinoblastoma. In particular, methods according to group consisting of: the present invention and compositions according to the present invention are particularly suitable for the treatment of 0443 (a) administration to avoid anaphylaxis; the following types of cancers: (1) melanoma; (2) colon can 0444 (b) daily administration; cer; (3) chronic lymphocytic leukemia; (4) skin cancer; (5) 0445 (c) weekly administration for three weeks; lung cancer, including Small-cell lung cancer and non-Small 0446 (d) weekly administration for two weeks; cell lung cancer; (6) throat cancer; (7) stomach cancer; (8) 0447 (e) biweekly administration; salivary gland cancer; (9) breast cancer, including triple 0448 (f) biweekly administration for three weeks with negative breast cancer and breast cancer characterized by a 1-2 week rest period; overexpression of Her-2-neu; (10) prostate cancer, including 0449 (g) intermittent boost dose administration; and androgen-resistant prostate cancer, (11) pancreatic cancer, 0450 (h) administration daily for one week then once (12) ovarian cancer, (13) uterine cancer, (14) endometrial per week for multiple weeks. cancer; (15) other leukemias; (16) renal cell carcinoma; (17) 0451. When the improvement is made by an indication for multiple myeloma; (18) liver cancer; (19) pituitary gland use, the indication for use can be, but is not limited to, an cancer; (20) acute myeloid leukemia; (21) oophoroma; (22) indication for use selected from the group consisting of: glioma; (23) head and neck cancer; (23) colorectal cancer, 0452 (a) use for treatment of refractory breast cancer; (24) bladder cancer; (25) HPV-induced papilloma; (26) 0453 (b) use for treatment of triple-negative breast can Hodgkin’s lymphoma; (27) non-Hodgkin’s lymphoma; (28) cer, chronic myelocytic leukemia; (29) mycosis fungoides; and 0454 (c) use for treatment of acute leukemias, includ (30) myelodysplastic syndrome. In addition, methods ing acute myelocytic leukemia (AML); US 2016/0220537 A1 Aug. 4, 2016 35

0455 (d) use for treatment of acute leukemias of child kinase. The use of tyrosine kinase inhibitors is also described hood, including acute myelocytic leukemia (AML) and in United States Patent Application Publication No. 2010/ acute lymphocytic leukemia (ALL); 0291025, incorporated herein by this reference, which is 0456 (e) use for treatment of myelodysplastic syn directed to indazole inhibitors of tyrosine kinase. The use of drome; tyrosine kinase inhibitors is also described in United States 0457 (f) use for treatment of chronic myelocytic leuke Patent Application Publication No. 2010/0190749 by Ren et mia (CML), either subsequent to or in combination with al., incorporated herein by this reference; these tyrosine the administration of tyrosine kinase inhibitors or homo kinase inhibitors are benzoxazole compounds; compounds of harringtonine; this class can also inhibit mTOR and lipid kinases such as 0458 (g) use for treatment of chronic lymphocytic leu phosphoinositide 3-kinases. The use of tyrosine kinase kemia; inhibitors is also described in U.S. Pat. No. 8.242.270 by 0459 (h) use for treatment of Hodgkin’s lymphoma; Lajeunesse et al., incorporated herein by this reference; these 0460 (i) use for treatment of non-Hodgkin’s lym tyrosine kinase inhibitors are 2-aminothiazole-5-aromatic phoma; carboxamides. Still other tyrosine kinase inhibitors are 0461 () use for treatment of mycosis fungoides; known in the art or are under development, and are described 0462 (k) use for treatment of prostate cancer, especially in B. J. Druker & N. B. Lydon, “Lessons Learned from the androgen-resistant prostate cancer, Development of an Abl Tyrosine Kinase Inhibitor for Chronic 0463 (1) use for treatment of lung small-cell carcinoma, Myelogenous Leukemia. J. Clin. Invest. 105: 3-7 (2000), either Subsequent to or in combination with the admin incorporated herein by this reference. istration of EGFR inhibitors such as erlotinib (Tarceva) 0471 Homoharringtonine (omacetaxine mepesuccinate) or gefitinib (Iressa), wherein the lung Small-cell carci has the structure shown below: noma is characterized by either wild-type or mutated

EGFR, 0464 (m) use for treatment of lung non-small cell car cinoma, subsequent to or in combination with EGFR inhibitors such as erlotinib or gefitinib, wherein the lung non-Small cell carcinoma is characterized by either wild-type or mutated EGFR: 0465 (n) use for treatment of breast cancer character ized by overexpressed Her-2-neu: 0466 (o) use for treatment of glioblastoma that is resis tant to one or both of the following therapeutic agents: temozolomide (Temodar) or bevacizumab (Avastin), or is characterized by EGFR variant III, either alone or in combination with other therapeutic agents; 0467 (p) use for treatment of malignancies character ized by overexpressed topoisomerase II; and and is a protein translation inhibitor. Homoharringtonine 0468 (q) use for treatment of malignancies character inhibits protein translation by preventing the initial elonga ized by overexpressed and/or mutated EGFR. tion step of protein synthesis. It interacts with the ribosomal 0469 Triple-negative breast cancer is a form of breast A-site and prevents the correct positioning of amino acid side cancer that is characterized by tumors that do not express chains of incoming aminoacyl-tRNAS. estrogen receptor (ER), progesterone receptor (PR), or 0472 Androgen-resistant prostate cancer, also known as HER-2 genes. This form of breast cancer represents an impor castration-resistant prostate cancer, is characterized by reac tant clinical challenge because these cancers do not respond tivation of androgen-regulated processes and is detectable by to endocrine therapy or a number of targeted agents. Current an increase in prostate-specific antigen (PSA) despite the treatment strategies for triple-negative breast cancer include administration of androgen deprivation therapy; it has been many chemotherapy agents, such as the anthracyclines, tax Suggested that Sufficient androgens remain available even anes, ixabepilone, and platinum agents, as well as selected Subsequent to the administration of androgen deprivation biologic agents and possibly anti-EGFR drugs. therapy through reactions employing progesterone as a start 0470 Tyrosine kinase inhibitors used for treatment of ing material for the synthesis of dihydrotestosterone (J. A. chronic myelocytic leukemia (CML) include, but are not Locke et al., “Androgen Levels Increase by Intratumoral De limited to, imatinib, bosutinib, nilotinib, dasatinib, erlotinib, Novo Steroidogenesis During Progression of Castration-Re afatinib, and dacomitinib. Additional tyrosine kinase inhibi sistant Prostate Cancer.” Cancer Res.68: 6407-6415 (2008), tors are known in the art. For example, the use of tyrosine incorporated herein by this reference). kinase inhibitors is described in United States Patent Appli 0473 EGFR inhibitors include, but are not limited to, cation Publication No. 2011/0206661 by Zhanget al., which erlotinib (Tarceva) andgefitinib (Iressa). These EGFR inhibi is directed to trimethoxyphenyl inhibitors of tyrosine kinase, tors specifically inhibit the EGFR tyrosine kinase. Mutations and in United States Patent Application Publication No. 2011/ in the EGFR gene may affect the sensitivity of EGFR to 0.195066, which is directed to quinolone inhibitors of tyrosine EGFR inhibitors such as erlotinib and gefitinib. At least some kinase, both of which are incorporated herein by this refer of these mutations may increase sensitivity to EGFR inhibi ence. The use of tyrosine kinase inhibitors is also described in tors (J. G. Paez et al., “EGFR Mutations in Lung Cancer: United States Patent Application Publication No. 2011/ Correlation with Clinical Response to Gefitinib Therapy.” 053968 by Zhang et al., incorporated herein by this reference, Science 304: 1497-1500 (2004), incorporated herein by this which is directed to aminopyridine inhibitors of tyrosine reference; R. Sordella et al., “Gefitinib-Sensitizing EGFR US 2016/0220537 A1 Aug. 4, 2016 36

Mutations in Lung Cancer Activate Anti-Apoptotic Path bodies can also be fused to effector proteins and membrane ways.” Science 305: 1163-1167 (2005), incorporated herein proteins. As used herein in this context, the term "monoclonal by this reference). However, relapses are frequent; at least antibodies' includes, but is not limited to, chimericantibod Some relapses are associated with a mutation at amino acid ies, humanized antibodies, antibody fragments such as Schv 790 of EGFR in which threonine is changed to methione fragments, diabodies, heavy chain antibodies (HCAbs), and (T790M) (S. Kobayashi et al., “EGFR Mutation and Resis single-domain antibodies (sdAbs). Such monoclonal anti tance of Non-Small-Cell Lung Cancer to Gefitinib. New bodies are not necessarily produced as the result of cell fusion Engl. J. Med. 352: 786-792 (2005), incorporated herein by between B cells and myeloma cells, and can be produced in this reference). other eukaryotic cells or even bacterial cells according to methods known in the art. 0474. Other EGFR inhibitors are known in the art. EGFR inhibitors include, but are not limited to, erlotinib, gefitinib, 0475 Additional EGFR inhibitors, including derivatives lapatinib, lapatinib ditosylate, afatinib, canertinib, neratinib, of erlotinib and salts thereof, are described in United States (E)-2-methoxy-N-(3-(4-(3-methyl-4-(6-methylpyridin-3- Patent Application Publication No. 2013/0012528 by Cheng, yloxy)phenylamino)cquinazolin-6-yl)allyl)acetamide (CP incorporated herein by this reference. 724,714), 2-(3,4-dihydroxyphenyl)methylene-propane 0476. Overexpression of Her-2-neu, particularly in breast dinitrile (AG 18), 2-bromo-4-(6,7-dimethoxy-4- cancer, is associated in some cases with advanced disease and quinazolinyl)amino-phenol (WHI-P154), N-(2-(4-(3- relative resistance to conventional chemotherapy. In Such chloro-4-(3-(trifluoromethyl)phenoxy)phenylamino)-5H cases, the use of cisplatin plus a recombinant humanized pyrrolo3.2-dpyrimidin-5-yl)ethyl)-3-hydroxy-3- anti-p185HER2 monoclonal antibody has been suggested methylbutanamide (TAK-285), N-4-3-chloro-4-(3- (M. D. Pegram et al., “Phase II Study of Receptor-Enhanced fluorophenyl)methoxyphenylamino-6-quinazolinyl-2- Chemosensitivity. Using Recombinant Humanized Anti propenamide 4-methylbenzenesulfonate (AST-1306), (R)— p185HER2/neu Monoclonal Antibody Plus Cisplatin in N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)-N6-(4- Patients with HER2/neu Overexpressing Metastatic Breast methyl-4,5-dihydrooxazol-2-yl)guinazoline-4,6-diamine Cancer Refractory to Chemotherapy Treatment.” J. Clin. (ARRY334543), icotinib, N-(3-chlorophenyl)-6,7- Oncol. 16: 2659-2671 (1998), incorporated herein by this dimethoxyquinazolin-4-amine (AG-1478), 2-3,5-bis(1,1- reference). The overexpression of Her-2-neu is also associ dimethylethyl)-4-hydroxyphenylmethylene-propanedini ated with changes in the regulation of a number of genes, trile (SF 6847), dacomitinib, desmethyl erlotinib. 2-(4-(3- including proline 4-hydroxylase, galectin 1, galectin 3. ethynylphenylamino)-7-(2-methoxyethoxy)guinazolin-6- fibronectin 1. p-cadherin, which are genes involved in cell yloxy)ethanol hydrochloride (OSI-420), N-(3-(5-chloro-2- matrix interactions, and genes involved with cell proliferation (4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4- and transformation. A number of genes associated with MYC ylthio)phenyl)acrylamide (WZ-8040), N-(3-(5-chloro-2-(2- signaling were also differentially expressed (A. Mackay et methoxy-4-(4-methylpiperazin-1-yl)phenylamino) al., “cDNA Microarray Analysis of Genes Associated with pyrimidin-4-yloxy)phenyl)acrylamide (WZ4002), N-(3-(5- ERBB2 (HER2/neu) Overexpression in Human Mammary chloro-2-(4-(4-methylpiperazin-1-yl)phenylamino) Luminal Epithelial Cells.” Oncogene 22: 2680-2688 (2003), pyrimidin-4-yloxy)phenyl)acrylamide (WZ3146), (E)-N- incorporated herein by this reference). benzyl-2-cyano-3-(3,4-dihydroxyphenyl)acrylamide (AG 0477 EGFR variant III is a variant of EGFR that does not 490), N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-(((3aR, respond to gefitinib, cells possessing the variant do not show 5r,6aS)-2-methyl-octahydrocyclopentacpyrrol-5-yl) reduction of phosphorylation Subsequent to treatment with methoxy)guinazolin-4-amine (XL647), N-(3-bromophenyl)- gefitinib. Additionally, although Such cells may show a degree 6,7-dimethoxyquinazolin-4-amine hydrochloride of reduction of phosphorylation of EGFR after more (PD 153035), and (S)-morpholin-3-ylmethyl 4-(1-(3-fluo extended treatment with gefitinib, these cells continue to be robenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo 1.2-f1. resistant to the antineoplastic effects of gefitinib, possibly 2.4 triazin-6-ylcarbamate (BMS-599626). Still other EGFR because the phosphorylation of Akt is unaffected in cells with inhibitors are known in the art, including monoclonal anti variant III while being inhibited in EGFR-expressing cells bodies and derivatives thereof. Such monoclonal antibodies after treatment with gefitinib (C. A. Learn, “Resistance to and derivatives thereof include cetuximab, panitumumab, Tyrosine Kinase Inhibition by Mutant Epidermal Growth matuZumab, nimotuZumab, trastuzumab, Zalutumumab, and Factor Receptor Variant III Contributes to the Neoplastic Zatuximab. In addition, such monoclonal antibodies and Phenotype of Glioblastoma Multiforme.” Clin. Cancer Res. derivatives thereof can be conjugated to therapeutic agents 10:3216-3224 (2004), incorporated herein by this reference). Such as toxins or radionuclides. The conjugation of mono Conventional treatments for glioblastoma include temozolo clonal antibodies to radionuclides is described in K. K. Bhar mide, frequently administered with radiotherapy, bevaci gava & S. A. Acharya, "Labeling of Monoclonal Antibodies Zumab (Avastin), and the protein therapeutic APG 101. with Radionuclides.” Semin. Nucl. Med. 19: 187-201 (1989), 0478. When the improvement is made by selection of dis incorporated herein by this reference. The conjugation of ease stage, the selection of disease stage can be, but is not monoclonal antibodies to non-radionucleotide therapeutic limited to, at least one selection of disease stage selected from agents is described in P. Chames et al., “Therapeutic Antibod the group consisting of ies: Successes, Limitations, and Hopes for the Future. Br. J. Pharmacol. 157: 220-233 (2009), incorporated herein by this 0479 (a) use for the treatment of localized polyp stage reference. The non-radionuclide therapeutic agents can colon cancer, include, a fragment of Pseudomonas exotoxin, diphtheria 0480 (b) use for the treatment of leukoplakia in the oral toxin, the A chain of ricin, Staphylococcus aureus entero cavity; toxin, mertansine, a calicheamicin cytotoxic agent, interleu 0481 (c) use to induce angiogenesis inhibition to pre kin-2, and other agents known in the art. Monoclonal anti vent or limit metastatic spread; US 2016/0220537 A1 Aug. 4, 2016 37

0482 (d) use against HIV with AZT, DDI, or reverse Superfamily of G protein coupled receptors includes a large transcriptase inhibitors; number of receptors. These receptors are integral membrane 0483 (e) use for recurrent leukemia, including AML: proteins characterized by amino acid sequences that contain and seven hydrophobic domains, predicted to represent the trans 0484 (f) use for recurrent breast cancer, including Her/ membrane spanning regions of the proteins. They are found in neu". ER" or triple negative breast cancer. a wide range of organisms and are involved in the transmis 0485 When the improvement is made by other indica sion of signals to the interior of cells as a result of their tions, the other indications can be, but are not limited to, at interaction with heterotrimeric G proteins. They respond to a least one other indication selected from the group consisting diverse range of agents including lipid analogues, amino acid of: derivatives, Small molecules Such as epinephrine and dopam 0486 (a) use as an anti-infective agent; ine, and various sensory stimuli. The properties of many 0487 (b) use as an antiviral agent; known GPCR are summarized in S. Watson & S. Arkinstall, 0488 (c) use as an antibacterial agent; “The G-Protein Linked Receptor Facts Book” (Academic 0489 (d) use for control of pleural effusions; Press, London, 1994), incorporated herein by this reference. 0490 (e) use as an antifungal agent; GPCR receptors include, but are not limited to, acetylcholine 0491 (f) use as an antiparasitic agent; receptors, B-adrenergic receptors, f-adrenergic receptors, 0492 (g) use for treatment of eczema: serotonin (5-hydroxytryptamine) receptors, dopamine recep 0493 (h) use for treatment of shingles: tors, adenosine receptors, angiotensin Type II receptors, 0494 (i) use for treatment of condylomata; bradykinin receptors, calcitonin receptors, calcitonin gene 0495 () use for treatment of human papilloma virus related receptors, cannabinoid receptors, cholecystokinin (HPV); and receptors, chemokine receptors, cytokine receptors, gastrin 0496 (k) use for treatment of herpes simplex virus receptors, endothelin receptors, y-aminobutyric acid (GABA) (HSV). receptors, galanin receptors, glucagon receptors, glutamate 0497. When the improvement is made by patient selection, receptors, luteinizing hormone receptors, choriogonadotro the patient selection can be, but is not limited to, a patient phin receptors, follicle-stimulating hormone receptors, thy selection carried out by a criterion selected from the group roid-stimulating hormone receptors, gonadotrophin-releas consisting of: ing hormone receptors, leukotriene receptors, Neuropeptide 0498 (a) selecting patients with a disease condition Y receptors, opioid receptors, parathyroid hormone recep characterized by a high level of a metabolic enzyme tors, platelet activating factor receptors, prostanoid (prostag Selected from the group consisting of histone deacety landin) receptors, somatostatin receptors, thyrotropin-releas lase, protein kinases, and ornithine decarboxylase; ing hormone receptors, vasopressin and oxytocin receptors. 0499 (b) selecting patients with a disease condition 0509. When the improvement is made by analysis of characterized by a low level of a metabolic enzyme patient or disease phenotype, the analysis of patient or disease Selected from the group consisting of histone deacety phenotype can be, but is not limited to, a method of analysis lase, protein kinases, and ornithine decarboxylase; of patient or disease phenotype carried out by a method 0500 (c) selecting patients with a low or high suscep selected from the group consisting of: tibility to a condition selected from the group consisting 0510 (a) use of a diagnostic tool, a diagnostic tech of thrombocytopenia and neutropenia; nique, a diagnostic kit, or a diagnostic assay to confirm 0501 (d) selecting patients intolerant of GI toxicities; a patient’s particular phenotype; 0502 (e) selecting patients characterized by over- or 0511 (b) use of a method for measurement of a marker under-expression of a gene selected from the group con Selected from the group consisting of histone deacety sisting of jun, GPCRs, signal transduction proteins, lase, ornithine decarboxylase, VEGF, a protein that is a VEGF, prostate specific genes, protein kinases, and gene product of a prostate specific gene, a protein that is telomerase; a gene product of jun, and a protein kinase; 0503 (f) selecting patients as the result of immune 0512 (c) Surrogate compound dosing: Screening: 0513 (d) low dose pre-testing for enzymatic status; 0504 (g) selecting patients as the result of DNA methy 0514 (e) determination of the multi-drug resistance lation screening; activity of cells; 0505 (h) selecting patients with recurrent disease char 0515 (f) determining expression or activation of a sig acterized by the duration of their initial response; naling or metabolic protein, where an alteration in the 0506 (i) selecting patients without mutations in p53; level of expression or activation of the signaling or meta and bolic protein indicates the therapeutic potential of a che 0507 () selecting for patients without extensive prior motherapeutic agent; treatment, especially with agents that induce multidrug 0516 (g) detection or assay of expression of biomarkers resistance. indicating sensitivity to apoptosis-inducing agents; 0508. The cellular proto-oncogene c-Jun encodes a pro 0517 (h) use of an in vitro human tumor clonal assay to tein that, in combination with c-Fos, forms the AP-1 early determine patients with enhanced responses; response transcription factor. This proto-oncogene plays a 0518 (i) use of an immunohistochemical assay to deter key role in transcription and interacts with a large number of mine overexpression of HIF-1C.; proteins affecting transcription and gene expression. It is also 0519 () assessment of p53 mutation; and involved in proliferation and apoptosis of cells that form part 0520 (k) determination of the quantity or activity of of a number of tissues, including cells of the endometrium topoisomerase 2B in cardiac cells. and glandular epithelial cells. G-protein coupled receptors 0521 Processes and kits for determination of the multi (GPCRs) are important signal transducing receptors. The drug resistance of cells are described in U.S. Pat. No. 8,445, US 2016/0220537 A1 Aug. 4, 2016

271 by Lebedeva et al., incorporated herein by this reference. shown to reverse resistance to bisantrene mediated by P-gly The processes measure the transport of at least one Xanthene coprotein and thus resensitize cells to bisantrene; bisantrene compound that is transportable across a cell membrane by is a substrate for P-glycoprotein (X. P. Zhang et al., “P-Gly one or more of MDR1, MRP, or BCRP in the presence or coprotein Mediates Profound Resistance to Bisantrene.” absence of one or more membrane transporter inhibitors. Oncol. Res. 6: 291-301 (1994), incorporated herein by this Preferably, the xanthene compound has the structure: reference). Another method of determining patient phenotype for expression of the P-glycoprotein membrane transporter is described in United States Patent Application Publication No. 2007/0009535 by Sikic et al., incorporated herein by this reference. The degree of the expression of the P-glycoprotein membrane can be determined by antibody assay. A method of determining expression or activation of a signaling or meta bolic protein, where an alteration in the level of expression or activation of the signaling or metabolic protein indicates the therapeutic potential of a chemotherapeutic agent is described in United States Patent Application Serial No. 2012/0288879 by Altiok, incorporated herein by this refer ence. Phosphorylation status or protein acetylation can be assessed. Methods for detection or assay of expression of biomarkers indicating sensitivity to apoptosis-inducing agents are described in United States Patent Application Pub lication No. 2012/0328.603, incorporated herein by this ref erence. The biomarkers can include certain fucosyltrans ferases, including fucosyltransferase 3 and wherein: (i) R'-R are each independently hydrogen, halo, fucosyltransferase 6, as well as sialyl Lewis A and/or X anti carboxyl, alkoxy, aryloxy, thiol, alkylthiol, arylthiol, azido, gens. The use of an immunohistochemical assay to determine nitro, nitroso, cyano, amino, hydroxyl, phosphonyl, Sulfonyl, overexpression of HIF-1a as a marker for sensitivity to carbonyl, boronic acid, aryl, heteroaryl, or alkyl or alkoxy anthracycline and anthracycline derivatives and analogs, optionally substituted with one or more of halo, amino, including bisantrene and derivatives and analogs thereof, is hydroxy, phosphonyl, sulfonyl, carbonyl, boronic acid, aryl, disclosed in K. Lee et al., “Anthracycline Chemotherapy or heteroaryl; (ii) heteroatom Y is independently selected Inhibits HIF-1 Transcriptional Activity and Tumor-Induced from the group consisting of O, S, Se, NR, and CR'R''; (iii) Mobilization of Circulating Angiogenic Cells.” Proc. Natl. X is independently selected from the group consisting of Acad. Sci. 106: 2353-2358 (2009), incorporated herein by this OR'', NR'R'; (iv) Z is independently selected from the reference. Topoisomerase 2B activity in cardiac cells, such as group consisting of O and R'R'': (v) each R. R', R'', R', cardiomyocytes, has been shown to be associated with devel R", R', and R'' is independently hydrogen, C-C alkyl, opment of cardiotoxicity as a consequence of administration carboxyalkyl, Substituted or non-substituted aminoalkyl, or of anthracyclines and other therapeutic agents. Although alkylsulfonate; (vi) T and U are independently hydrogen, bisantrene is considered less cardiotoxic than other anthracy C-C2 alkyl, C-C2 alkoxy, aryloxy, amino, halo, cyano, cline analogs or derivatives, cardiotoxicity may still exist. carboxy, carboxyalkyl, acetoxymethylcarbonyl, carbonyl, Topoisomerase 2B has been shown to be required for anthra Sulfonyl, phosphonyl, boronic acid, aryl, and heteroaryl; and cycline to induce DNA double-strand breaks and changes in (vii) V and W are each independently selected from OR'', the transcriptome, leading to mitochondrial dysfunction and SR', or NR'R'', such that at least one of V or W. in com generation of reactive oxygen species. Therefore, the quantity bination with NR'R'', forms a metal chelator, where each R', or activity of topoisomerase 2B can be used as a biomarker to R. R. R. R', and R' are independently hydrogen, predict risk of cardiotoxicity before administration of bisant C-C alkyl, carboxyalkyl, alkoxy, or aryloxy. The mem rene or an analog or derivative thereof (P. Veipongsa & E. T. brane transporter inhibitors can comprise general inhibitors, Yeh, “Topoisomerase 2B: A Promising Molecular Target for specific inhibitors, or a combination of general and specific Primary Prevention of Anthracycline-Induced Cardiotoxic inhibitors. General inhibitors include, but are not limited to, cyclosporin A, biricodar, tariquidar, plant polyphenols, cur ity.” Clin. Pharmacol. Ther: 95: 45-52 (2014), incorporated cumin, tRA98006, and imatinib mesylate. Specific inhibitors herein by this reference). include, but are not limited to, Valspodar, Verapamil, Vana 0522. When the improvement is made by analysis of date, PAK-104P, MK-571, FTC, Ko 134, elacridar, novobio patient or disease genotype, the analysis of patient or disease cin, probenecid, BIB-E, disulfuram, indomethacin, furo genotype can be, but is not limited to, a method of analysis of semide, Penicillin G, Sulfinpirazole, laniquidar, ZoSuquidar, patient or disease genotype carried out by a method selected ontogen, isothiocyanates, phytoestrogens, TAG-139, fla from the group consisting of vonoids, MS-209, NSAIDs, mitotane, PK1 1195, cyclospo 0523 (a) genetic tests to determine the absence or non rine D, anthranilamide, pipecolinate, quinoline, OC-144-093, functionality of ABCG2: diallyl sulfide, amooranin, agosterol A, siRNA, rifampicin, 0524 (b) genetic tests to determine the presence or amiodarone, quinidine, quinine, nifedipine, dexniguldipin, functionality of FABP7; LY455776, V-104, tricyclic izoxazoles, pluronic L61, and 0525 (c) use of a diagnostic tool, a diagnostic tech fumitremorgin C. Verapamil acts as a reversal agent and acts nique, a diagnostic kit, or a diagnostic assay to confirm to bind and inhibit the activity of P-glycoprotein. This blocks a patient’s particular genotype; the efflux of antineoplastic agents such as bisantrene and 0526 (d) use of a gene chip; thereby kills resistant cells. Verapamil has specifically been 0527 (e) use of gene expression analysis: US 2016/0220537 A1 Aug. 4, 2016 39

0528 (f) use of single nucleotide polymorphism (SNP) ATIC, ATP2A2, ATP2A3, ATP5D, ATP5G2, ATP6V1B2, analysis; BC008967, BCAT1, BCHE, BCL11B, BDNF, BHLHB2, 0529 (g) measurement of the level of a metabolite or a BIN2, BLMH, BMI1, BNIP3, BRDT, BRRN1, BTN3A3, metabolic enzyme; C11orf2, C14orf139, C15orf25, C18orf10, C1orf24, 0530 (h) determination of the presence of one or more C1orf29, C1orf38, C1OR1, C22orf18, C60rf32, CACNA1G, specific genetic variants of the MDR1 gene associated CACNB3, CALM1, CALML4, CALU, CAP350, CASP2, with increased efficacy of an antineoplastic drug trans CASP6, CASP7, CAST, CBLB, CCNA2, CCNB1 IP1, ported by MDR1 protein: CCND3, CCR7, CCR9, CD1A, CD1C, CD1D, CD1E, CD2, 0531 (i) identification of one or more biomarkers asso CD28, CD3D, CD3E, CD3G, CD37, CD44, CD47, CD59, ciated with sensitivity or resistance to bisantrene, deriva CD6, CD63, CD8A, CD8B1, CD99, CDC10, CDC14B, tives or analogs thereof, or other intercalating agents or CDH11, CDH2, CDKL5, CDKN2A, CDW52, CECR1, topoisomerase II inhibitors; and CENPB, CENTB1, CENTG2, CEP1, CG018, CHRNA3, 0532 () determination of the presence or absence of the CHS1, CIAPIN1, CKAP4, CKIP-1, CNP, COL4A1, single nucleotide polymorphisms (SNPs) rs229.109 and/ COL5A2, COL6A1, CORO1C, CRABP1, CRK, CRY1, or 72552784 associated with sensitivity to bisantrene. CSDA, CTBP1, CTSC, CTSL CUGBP2, CUTC, CXCL1, 0533. The use of gene chips is described in A. J. Lee & S. CXCR4, CXorf'9, CYFIP2, CYLD, CYR61, DATF1, Ramaswamy, “DNA Microarrays in Biological Discovery DAZAP1, DBN1, DBT, DCTN1, DDX18, DDX5, DGKA, and Patient Care' in Essentials of Genomic and Personalized DIAPH1, DKC1, DKFZP434J154, DKFZP564C186, Medicine (G. S. Ginsburg & H. F. Willard, eds., Academic DKFZP564G2022, DKFZp564J157, DKFZP564K0822, Press, Amsterdam, 2010), ch. 7, pp. 73-88, incorporated DNAJC10, DNAJC7, DNAPTP6, DOCK10, DOCK2, herein by this reference). DPAGT1, DPEP2, DPYSL3, DSIPI, DUSP1, DXS9879E, 0534. When the method is the use of single nucleotide EEF1B2, EFNB2, EHD2, EIF5A, ELK3, ENO2, EPAS1, polymorphism (SNP) analysis, the SNP analysis can be car EPB41L4B, ERCC2, ERG, ERP70, EVER1, EVI2A, EVL, ried out on a gene selected from the group consisting of EXT1, EZH2, F2R, FABP5, FAD104, FAM46A, FAU, histone deacetylase, ornithine decarboxylase, VEGF, a pros FCGR2A, FCGR2C, FER1L3, FHL1, FHOD1, FKBP1A, tate specific gene, c-Jun, and a protein kinase. The use of SNP FKBP9, FLJ10350, FLJ10539, FLJ10774, FLJ12270, analysis is described in S. Levy and Y.-H. Rogers, “DNA FLJ13373, FLJ20859, FLJ21159, F11224.57, FLJ35036, Sequencing for the Detection of Human Genome Variation” FLJ46603, FLNC, FLOT1, FMNL1, FNBP1, FOLH1, in Essentials of Genomic and Personalized Medicine (G. S. FOXF2, FSCN1, FTL, FYB, FYN, GOS2, G6PD, GALIG, Ginsburg & H. F. Willard, eds., Academic Press, Amsterdam, GALNT6, GATA2, GATA3, GFPT1, GIMAP5, GIT2, GJA1, 2010), ch. 3, pp. 27-37, incorporated herein by this reference. GLRB, GLTSCR2, GLUL, GMDS, GNAQ. GNB2, GNB5, 0535 Still other genomic techniques such as copy number GOT2, GPR65, GPRASP1, GPSM3, GRP58, GSTM2, variation analysis and analysis of DNA methylation can be GTF3A, GTSE1, GZMA, GZMB, H1F0, H1 FX, H2AFX, employed. Copy number variation analysis is described in C. H3F3A, HA-1, HEXB, HIC, HIST1H4C, HK1, HLA-A. Lee et al., “Copy Number Variation and Human Health' in HLA-B, HLA-DRA, HMGA1, HMGN2, HMMR, HNRPA1, Essentials of Genomic and Personalized Medicine (G. S. HNRPD, HNRPM, HOXA9, HRMT1L1, HSA9761, Ginsburg & H. F. Willard, eds., Academic Press, Amsterdam, HSPA5, HSU79274, HTATSF1, ICAM1, ICAM2, IER3, 2010), ch.5, pp. 46-59, incorporated herein by this reference. IFI16, IFI44, IFITM2, IFITM3, IFRG28, IGFBP2, IGSF4, DNA methylation analysis is described in S. Cottrell et al., IL13RA2, IL21R, IL2RG, IL4R, IL6, IL6R, IL6ST, IL8, “DNA Methylation Analysis: Providing New Insight into IMPDH2, INPP5D, INSIG1, IQGAP1, IQGAP2, IRS2, Human Disease' in Essentials of Genomic and Personalized ITGA5, ITM2A, JARID2, JUNEB, K-ALPHA-1, KHDRBS1, Medicine (G. S. Ginsburg & H. F. Willard, eds., Academic KIAA0355, KIAA0802, KIAA0877, KIAAO922, Press, Amsterdam, 2010), ch. 6, pp. 60-72, incorporated KIAA1078, KIAA1128, KIAA 1393, KIFC1, LAIR1, herein by this reference. LAMB1, LAMB3, LAT, LBR, LCK, LCP1, LCP2, LEF1, 0536 Specific genetic variants of the MDR1 gene encod LEPRE1, LGALS1, LGALS9, LHFPL2. LNK, LOC54103, ing the MDR protein associated with increased therapeutic LOC55831, LOC81558, LOC94105, LONP LOX, LOXL2, efficacy of an anticancer drug are disclosed in U.S. Pat. No. LPHN2, LPXN, LRMP, LRP12, LRRC5, LRRN3, LST1, 7,445,897 to Ho et al., incorporated herein by this reference, LTB, LUM, LY9, LY96, MAGEB2, MAL, MAP1B, which also discloses hybridization methods with probes MAP1LC3B, MAP4K1, MAPK1, MARCKS, MAZ, incorporating these variants to detect their presence. MCAM, MCL1, MCM5, MCM7, MDH2, MDN1, MEF2C, 0537 Methods for identification of one or more biomark MFNG, MGC17330, MGC21654, MGC2744, MGC4083, ers associated with sensitivity or resistance to chemothera MGC8721, MGC8902, MGLL, MLPH, MPHOSPH6, peutic agents are described in U.S. Pat. No. 8,445,198 to MPP1, MPZL.1, MRP63, MRPS2, MT1E, MT1 K, MUF1, Knudsen, incorporated herein by this reference. These biom MVP, MYB, MYL9, MYO1B, NAP1L1, NAP1L2, NARF, arkers can be genes or microRNA; a change in the level of NASP, NCOR2, NDN, NDUFAB1, NDUFS6, NFKBIA, expression of the gene or microRNA indicates that the cell is NID2, NIPA2, NME4, NME7, NNMT, NOL5A, NOL8, sensitive or resistant to a specific chemotherapeutic agent. NOMO2, NOTCH1, NPC1, NQO1, NR1D2, NUDC, The gene can be one or more of ACTB, ACTN4, ADA, NUP210, NUP88, NVL, NXF1, OBFC1, OCRL, OGT, ADAM9, ADAMTS1, ADD1, AF1CR, AIF1, AKAP1, OXA1 L, P2RX5, P4HA1, PACAP. PAF53, PAFAH1B3, AKAP13, AKR1C1, AKT1, ALDH2, ALDOC, ALG5, PALM2-AKAP2, PAX6, PCBP2, PCCB, PFDN5, PFN1, ALMS1, ALOX15B, AMIGO2, AMPD2, AMPD3, PFN2, PGAM1, PHEMX, PHLDA1, PIM2, PITPNC1, ANAPC5, ANP32A, ANP32B, ANXA1, AP1G2, PLACE, PLAGL1, PLAUR, PLCB1, PLEK2, PLEKHC1, APOBEC3B, APRT, ARHE, ARHGAP15, ARHGAP25, PLOD2, PLSCR1, PNAS-4, PNMA2, POLR2F, PPAP2B, ARHGDIB, ARHGEF6, ARL7, ASAH1, ASPH, ATF3, PRF1, PRG1, PRIM1, PRKCH, PRKCQ, PRKD2, PRNP

US 2016/0220537 A1 Aug. 4, 2016 41

MPR174 left, MPR174 right, MPR185 right, MPR197 right, 0575 (y) administration of an agent to control or pre MPR203 left, MPR207 right, MPR215 left, MPR216 left, vent chemotherapy-induced thrombocytopenia. MPR224 left, MPR224 right, MPR228 left, MPR234 right, 0576 Uricosurics include, but are not limited to, MPR237 left, MPR243 left, MPR244 right, MPR249 left, probenecid, benzbromarone, and Sulfinpyrazone. A particu MPR254 right, MPR74 left, MPR88 right, and MPR95 left. larly preferred uricosuric is probenecid. Uricosurics, includ 0538 Analysis for the SNPs rs229.109 and rs72552784, ing probenecid, may also have diuretic activity. associated with sensitivity to bisantrene, is disclosed in (0577 Poly-ADP ribose polymerase inhibitors are United States Patent Application Publication No. 2014/ described in G. J. Southan & C. Szabó, “Poly(ADP-Ribose) 0038836 by Higgins et al., incorporated herein by this refer Inhibitors.” Curr. Med. Chem. 10:321-240 (2003), incorpo CCC. rated herein by this reference, and include nicotinamide, 0539 When the improvement is made by pre-/post-treat 3-aminobenzamide, Substituted 3,4-dihydroisoquinolin-1 ment preparation, the method of pre-/post-treatment prepara (2H)-ones and isoquinolin-1 (2H)-ones, benzimidazoles, tion can be, but is not limited to, a method of pre-treatment or indoles, phthalazin-1 (2H)-ones, quinazolinones, isoindoli post-treatment preparation selected from the group consisting nones, phenanthridinones, and other compounds. of: 0578 Leucovorin rescue comprises administration of foli 0540 (a) the use of colchicine or an analog thereof; nic acid (leucovorin) to patients in which methotrexate has 0541 (b) the use of a uricosuric; been administered. Leucovorin is a reduced form of folic acid 0542 (c) the use of uricase; that bypasses dihydrofolate reductase and restores hemato 0543 (d) the non-oral use of nicotinamide: poietic function. Leucovorin can be administered either intra 0544 (e) the use of a sustained-release form of nicoti venously or orally. namide: 0579. In one alternative, wherein the prefpost treatment is (0545 (f) the use of an inhibitor of poly-ADP ribose the use of a uricoSuric, the uricoSuric is probenecid or an polymerase; analog thereof. 0546 (g) the use of caffeine; 0580 Filgrastim is a granulocytic colony-stimulating fac 0547 (h) the use of leucovorin rescue; tor (G-CSF) analog produced by recombinant DNA technol 0548 (i) infection control; and ogy that is used to stimulate the proliferation and differentia 0549 () the use of an anti-hypertensive agent. tion of granulocytes and is used to treat neutropenia; G-CSF 0550 When the improvement is made by toxicity manage can be used in a similar manner. GM-CSF is granulocyte ment, the method of toxicity management can be, but is not macrophage colony-stimulating factor and stimulates stem limited to, a method of toxicity management selected from cells to produce granulocytes (eosinophils, neutrophils, and the group consisting of basophils) and monocytes; its administration is useful to pre 0551 (a) the use of colchicine or an analog thereof; vent or treat infection. 0552 (b) the use of a uricosuric; 0581 Anti-inflammatory agents are well known in the art 0553 (c) the use of uricase: and include corticosteroids and non-steroidal anti-inflamma 0554 (d) the non-oral use of nicotinamide: tory agents (NSAIDs). Corticosteroids with anti-inflamma 0555 (e) the use of a sustained-release form of nicoti tory activity include, but are not limited to, hydrocortisone, namide: cortisone, beclomethasone dipropionate, betamethasone, 0556 (f) the use of an inhibitor of poly-ADP ribose dexamethasone, prednisone, methylprednisolone, triamcino polymerase; lone, fluocinolone acetonide, and fludrocortisone. Non-Ste 0557 (g) the use of caffeine; roidal anti-inflammatory agents include, but are not limited 0558 (h) the use of leucovorin rescue: to, acetylsalicylic acid (aspirin), sodium salicylate, choline 0559 (i) the use of sustained-release allopurinol: magnesium trisalicylate, Salsalate, diflunisal, Sulfasalazine, 0560 () the non-oral use of allopurinol: olsalazine, acetaminophen, indomethacin, Sulindac, tol 0561 (k) the administration of bone marrow transplant metin, diclofenac, ketorolac, ibuprofen, naproxen, flurbipro stimulants, blood, platelet infusions, Neupogen, G-CSF: fen, ketoprofen, fenoprofin, oxaprozin, mefenamic acid, or GM-CSF: meclofenamic acid, piroXicam, meloxicam, nabumetone, rofecoxib, celecoxib, etodolac, nimeSulide, aceclofenac, 0562 (1) pain management; alclofenac, alminoprofen, amfenac, ampiroXicam, apaZone, 0563 (m) infection control; and araprofen, azapropaZone, bendazac, benoxaprofen, benzy 0564) (n) administration of anti-inflammatories: damine, bermoprofen, benzpiperylon, bromfenac, bucloxic 0565 (o) administration of fluids; acid, bumadizone, butibufen, carprofen, cimicoxib, cinmeta 0566 (p) administration of corticosteroids; cin, cinnoxicam, clidanac, clofeZone, clonixin, clopirac, dar 0567 (d) administration of insulin control medications; bufelone, deracoxib, droxicam, eltenac, enfenamic acid, epi 0568 (r) administration of antipyretics; rizole, esflurbiprofen, ethenzamide, etofenamate, etoricoxib, 0569 (s) administration of anti-nausea treatments; felbinac, fenbufen, fenclofenac, fenclozic acid, fenclozine, 0570 (t) administration of anti-diarrhea treatment; fendosal, fentiazac, feprazone, filenadol, flobufen, florife 0571 (u) administration of antihistamines as pre-treat nine, flosulide, flubichin methanesulfonate, flufenamic acid, ment to prevent anaphylaxis; flufenisal, flunixin, flunoxaprofen, fluprofen, fluproduaZone, 0572 (v) administration of agents for reduction of gas furofenac, ibufenac, imrecoxib, indoprofen, isofeZolac, isox tric toxicity; epac, isoxicam, licofelone, lobuprofen, lomoxicam, lona 0573 (w) administration of steroids as pre-treatment to Zolac, loxaprofen, lumaricoxib, mabuprofen, miroprofen, prevent anaphylaxis; mofebutaZone, mofeZolac, moraZone, nepafanac, niflumic 0574 (x) administration of sympathetomimetics as pre acid, nitrofenac, nitroflurbiprofen, nitronaproxen, orpanoxin, treatment to prevent anaphylaxis; and oxaceprol, oxindanac, oXpinac, oxyphenbutaZone, pam US 2016/0220537 A1 Aug. 4, 2016 42 icogrel, parcetasal, parecoxib, parsalmide, pelubiprofen, immunoassays are well known in the art, and include radio pemedolac, phenylbutaZone, piraZolac, pirprofen, pranopro immunoassay, ELISA (enzyme-linked immunosorbent fen, salicin, Salicylamide, salicylsalicylic acid, satigrel, assay), competitive immunoassay, immunoassay employing Sudoxicam, Suprofen, talmetacin, talniflumate, taZofelone, lateral flow test strips, and other assay methods. tebufelone, tenidap, tenoxicam, tepoxalin, tiaprofenic acid, 0595 Monitoring of immune function can be carried out tiaramide, tilmacoxib, tinoridine,tiopinac, tioxaprofen, tolfe by methods known in the art, including the use of the Cylex(R) namic acid, triflusal, tropesin, ursolic acid, Valdecoxib, Ximo Immune Cell Function Assay, as described in A. Zeevi et al., profen, Zaltoprofen, Zidometacin, and Zomepirac, and the “Monitoring Immune Function During Tacrolimus Tapering salts, Solvates, analogues, congeners, bioisosteres, hydrolysis in Small Bowel Transplant Recipients.” Transplant Immunol. products, metabolites, precursors, and prodrugs thereof. 15:17-24 (2005), incorporated herein by this reference. 0582 The clinical use of corticosteroids is described in B. 0596. Immune function can also be monitored by assays P. Schimmer & K. L. Parker, Adrenocorticotropic Hormone: for upregulation of Th-1 markers such as IL-1C. TNF-C., IL-2, Adrenocortical Steroids and Their Synthetic Analogs; Inhibi IL-12, IL-18 or IFN-y. Immune function can also be moni tors of the Synthesis and Actions of Adrenocortical Hor tored by assays for down regulation of Th-2 products such as mones' in Goodman & Gilman's The Pharmacological Basis IL-4 or IL-10. Similarly, T cell activation markers like of Therapeutics (L. L. Brunton, ed., 11" ed., McGraw-Hill, CD25+, CD44+, CD62Llow, CD69+ CD71 and CD95 can be New York, 2006), ch.59, pp. 1587-1612, incorporated herein used. Macrophage activation is associated with upregulation by this reference. of the markers CD-13, CD-14, and CD-169 (importantly the 0583 Anti-nausea treatments include, but are not limited dendritic cell markers of CD-80 and CD-86) and the secretion to, ondansetron, metoclopramide, promethazine, cyclizine, of IFN-y, IL-1 B, IL-6, IL-8, IL-12, IL-18, IL-13, CSF-1, hyoscine, dronabinol, dimenhydrinate, diphenhydramine, MCP-1, TNF ol, iNOS, G-CSF, M-CSF, GM-CSF, CC13, hydroxy Zine, medizine, dolasetron, granisetron, pal CCL4, CXCL2, CXCL9, CXC10, CXCL11, CCR3, and onosetron, ramosetron, domperidone, haloperidol, chlorpro CCR5, so that expression of these markers and molecules can mazine, fluphenazine, perphenazine, prochlorperazine, be monitored by conventional methods, such as immunoas betamethasone, dexamethasone, lorazepam, and thiethylp says or immunoabsorbent procedures, for the monitoring of erazine. immune function. The ELISPOT procedure, described below, 0584 Anti-diarrheal treatments include, but are not lim can also be used. Other molecules assayed for the monitoring ited to, diphenoxylate, difenoxin, loperamide, codeine, of immune function can include PPAR-Y, the co-stimulatory racecadotril, octreoside, and berberine. molecules CD80 and CD-86, IL-17 (to assess Th-17 cell 0585 Agents for reduction of gastric toxicity include, but activation and Treg reduction), as well as several Toll-like are not limited to, ferruginol (C. Areche et al., “Gastropro receptors, including TLR2, TLR4, TLR5, TLR7, and TLR9. tective Activity of Ferruginol in Mice and Rats: Effects on 0597. The ELISPOT, or enzyme-linked immunosorbent Gastric Secretion, Endogenous Prostaglandins and Non-Pro spot assay is another method known in the art Suitable for the tein Sulfhydryls,” J. Pharm. Pharmacol. 60: 245-251 determination of immune function and described in C. Czer (2008)), incorporated herein by this reference. kinsky et al., “A Solid-Phase Enzyme-Linked Immunospot 0586. The use of an agent to control or prevent chemo (ELISPOT) Assay for Enumeration of Specific Antibody therapy-induced thrombocytopenia is disclosed in U.S. Pat. Secreting Cells,” J. Immunol. Meth., 65: 109-121 (1983), No. 8,183.342 to Matsuyama. The agent can be a Bax-inhib incorporated herein by this reference. In this assay, either a iting peptide of the following formula: XPXLXX (SEQ monoclonal or a polyclonal capture antibody is coated onto a ID NO: 2), wherein X is an amino acid with a non-polar side PVDF (polyvinylidene fluoride) microplate. The antibody is chain, X is an amino acid with a non-polar side chain; X is chosen for its specificity for the antigen in question. The plate an amino acid with a charged polar side chain, X is an amino is then blocked, typically with a serum protein that is nonre acid with a charged polar side chain, and either X" or X may active with any of the antibodies in the assay. After this, cells be absent. Preferred peptides include VPMLKE (SEQID NO: of interest are plated out at varying densities, along with an 3), VPMLK (SEQ ID NO: 4), PMLKE (SEQ ID NO. 5), antigen or a mitogen, and then placed in an incubator with PMLK (SEQ ID NO: 6), VPTLK (SEQ ID NO: 7), and appropriate conditions for the growth and proliferation of the VPALR (SEQID NO:8). cells. Cytokine (or another cell product to be detected) 0587 When the improvement is made by pharmacoki secreted by activated cells is captured locally by the antibody netic/pharmacodynamic monitoring, the pharmacokinetic/ coated on the microplate. A biotinylated polyclonal antibody pharmacodynamic monitoring can be, but is not limited to a specific for the chosen analyte (i.e., the cytokine or other cell method selected from the group consisting of: product to be detected) is added; this antibody is specific for 0588 (a) multiple determinations of blood plasma lev a distinct epitope of the target cytokine or other cell product to els; be detected. The detected cytokine or other cell product is 0589 (b) multiple determinations of at least one then visualized using streptavidin conjugated to an enzyme metabolite in blood or urine; that produces a precipitable product, Such as horseradish per 0590 (c) monitoring of immune function; oxidase oralkaline phosphatase, and a precipitating Substrate. 0591 (d) use of ELISPOT to measure immune The colored end product, detectable as a spot, typically rep responses; resents an individual cell producing the cytokine or other cell 0592 (e) determination of surface marker upregulation; product to be detected. The spots can be counted manually or and using an automated reader. 0593 (f) monitoring of checkpoint inhibition. 0598 Methods for determination of surface marker 0594 Typically, determination of blood plasma levels or upregulation are known in the art and are described in T. W. determination of at least one metabolite in blood or urine is Kuijpers et al., “Membrane Surface Antigen Expression on carried out by immunoassays. Methods for performing Neutrophils: A Reappraisal of the Use of Surface Markers for US 2016/0220537 A1 Aug. 4, 2016

Neutrophil Activation.” Blood 78: 1105-1111 (1991), incor 0611 (k) use with colchicine or an analog thereof; porated herein by this reference. For determination of surface 0612 (1) use with genistein: marker upregulation, particularly of tumor cell markers, a 0613 (m) use with etoposide; number of Surface markers can be monitored. The cancer 0.614 (n) use with cytarabine; testes (CT) antigens have all been used, including the MUC 0.615 (o) use with camptothecins; series (e.g. MUC1), the MAGE series (e.g. MAGE-A), 0616 (p) use with Vinca alkaloids; NYESO-1, and others. HER-2/neu is a favorite can be moni 0.617 (q) use with topoisomerase inhibitors; tored in breast cancer, as are estrogen receptors. The antian 0618 (r) use with 5-fluorouracil; giogenic markers like VEGF-1 or endoglin (CD-105) are also 0619 (s) use with curcumin; useful for monitoring. CA-125 has been used for colon can 0620 (t) use with rosmarinic acid; cer. Other cancer markers that can be monitored include, but 0621 (u) use with mitoguaZone: are not limited to, CA-9 (a marker of tumor related hypoxia), 0622 (v) use with meiso indigo; SCCE, the DAM series (DAM-6, DAM-10, and others), 0623 (w) use with imatinib; ELF2, Ep-CAM, GP-100, h-TERT (human telomerase), the 0624 (x) use with dasatinib; SART series (SART-1, SART-2, and SART-3), the MART 0625 (y) use with nilotinib; series (MART-1, MART-2, and others), WT-1, mutated p53, 0626 (Z) use with epigenetic modulators: and many other markers. In particular, for hematopoietic 0627 (aa) use with transcription factor inhibitors; tumors, the following markers may be useful: NuSAP1, 0628 (ab) use with taxol; CD56, MAGE-A3, PRAME, ROPN1, SCP-1, SLLP1, and 0629 (ac) use with homoharringtonine: SPO11 for AML; as described in S. Anguille et al., “Leuke mia-Associated Antigens and Their Relevance to the Immu 0630 (ad) use with pyridoxal; notherapy of Acute Myeloid Leukemia. Leukemia 26: 2186 0631 (ae) use with spirogermanium; 2 196 (2012), incorporated herein by this reference. For 0632 (af) use with caffeine; lymphoma, the following markers may be useful: TCL-1, 0633 (ag) use with nicotinamide: CD-20. HOX-11, and other markers. 0634 (ah) use with methylglyoxalbisguanylhydrazone: 0599 Methods for monitoring checkpoint inhibition are 0635 (ai) use with poly-ADP ribose polymerase known in the art and are described in V. Sudakin et al., (PARP) inhibitors: “Checkpoint Inhibition of the APC/C in HeLa Cells Is Medi 0636 (a) use with EGFR inhibitors; ated by a Complex of BUBR1, BUB3, CDC20, and MAD2,' 0637 (ak) use with Bruton's tyrosine kinase (BTK) J. Cell Biol. 154: 925-936 (2001), incorporated herein by this inhibitors: reference. Down regulation of CTLA-4, PD-1. OX-40 or 0638 (al) use with bis-thio-hydrazideamides: many other checkpoint kinases known in the art can be moni 0639 (am) use with succinimide or maleimide deriva tored. Similarly, reduction of regulatory T cells (Tregs), regu tives as inhibitors of topoisomerase II; latory DC, and regulatory neutrophils are prima facie evi 0640 (an) use with histone deacetylase (HDAC) inhibi dence of checkpoint blockade and these cells can be tors; monitored for evidence of checkpoint inhibition by conven 0641 (ao) use with immunostimulants; tional immunoassay methods, such as immunoassay of cell 0642 (ap) use with telomerase inhibitors; surface markers. T cell activation is mediated by the presen 0643 (aq) use with agents that inhibit the expression or tation of antigen by dendritic cells; a differentiated myeloid activity of Her2: cell considered by Some a type of macrophage. Classical 0644 (ar) use with agents that inhibit the expression or macrophages themselves can have antigen presentation capa activity of estrogen receptors; bilities. In the same way that tumor killing T cells are acti 0.645 (as) use with agents that inhibit the expression or vated by antigen presentation, so are tumor protecting regu activity of antigens associated with specific tumor tar latory T cells and there are various subclasses of Tregs now getS. identified. Thus, changes in the manner in which antigens are 0646 (at) use with G-quadruplex ligands; presented by myeloid cells, and alterations in the T cell phe 0647 (au) use with polycyclic lysophosphatidic recep notypes mediated by cytokines produced by macrophages, tor antagonists; can determine whether or not the predominantactivated T cell 0648 (av) use with anti-CTGF agents: phenotypes kill or protect tumor cells. Thus, a theoretical 0649 (aw) use with myeloid differentiation inducing relationship exists between macrophage activation and killer agents; VS regulatory T cell activation. 0650 (ax) use with covalent diabodies binding to a 0600 When the improvement is made by drug combina tumor-associated antigen; tion, the drug combination can be, but is not limited to, a drug 0651 (ay) use with bispecific antibodies that have a combination selected from the group consisting of cell-penetrating determinant and an intracellular target 0601 (a) use with fraudulent nucleosides; binding determinant; 0602 (b) use with fraudulent nucleotides; 0652 (az) use with multidomain molecules that com 0603 (c) use with thymidylate synthetase inhibitors; prise a cell binding ligand that binds to cells in the tumor 0604 (d) use with signal transduction inhibitors; stroma Such as endothelial cells, fibroblasts, or immune 0605 (e) use with cisplatin or platinum analogs; cells and an oligonucleotide that inhibits the nonsense 0606 (f) use with alkylating agents: mediated decay pathway; 0607 (g) use with anti-tubulin agents: 0653 (ba) use with tumor-specificantibodies binding to 0608 (h) use with antimetabolites; a portion of the CD44 protein or a binding protein 0609 (i) use with berberine; derived from the light-chain or heavy-chain comple 0610 () use with apigenin: mentary-determining regions of Such antibodies; US 2016/0220537 A1 Aug. 4, 2016 44

0654 (bb) use with inhibitors of CXCR4; 0674) Anti-tubulin agents include, but are not limited to, 0655 (bc) use with pyruvate dehydrogenase kinase Vinca alkaloids, taxanes, podophyllotoxin, halichondrin B, (PDK1) inhibitors; and homohalichondrin B. 0656 (bd) use with epherin receptor targeting agents; 0675 Antimetabolites include, but are not limited to: 0657 (be) use with binding proteins for Axl; methotrexate, pemetrexed, 5-fluorouracil, capecitabine, cyt 0658 (bf) use with Wnt pathway inhibitors together arabine, gemcitabine, 6-mercaptopurine, and pentostatin, with MAPK pathway inhibitors; alanosine, AG2037 (Pfizer), 5-FU-fibrinogen, acanthifolic 0659 (bg) use with TEC family kinase inhibitors: acid, aminothiadiazole, brequinar Sodium, carmofur, Ciba 0660 (bh) use with substituted macrocyclic com Geigy CGP-30694, cyclopentyl cytosine, cytarabine phos pounds with proteasome activity; phate stearate, cytarabine conjugates, Lilly DATHF, Merrill 0661 (bi) use with peptide-based PACE4 inhibitors; Dow DDFC, deazaguanine, dideoxycytidine, 0662 (b) use with azaindole derivatives as JAK3 dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxu inhibitors; ridine, fludarabine phosphate, N-(2-furanidyl)-5-fluorou 0663 (bk) use with inhibitors of Myc; racil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly 0664 (bl) use with inhibitors of furin and other pro LY-188011, Lilly LY-264618, methobenzaprim, methotrex protein convertases; ate, Wellcome MZPES, norspermidine, NCI NSC-127716, 0665 (bm) use with GPBP-1 inhibitors, optionally NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, together with a p21 inhibitor; Warner-Lambert PALA, piritrexim, plicamycin, Asahi 0666 (bn) use with PGE inhibitors; and Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, 0667 (bo) use with activatable antibodies targeting Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tumor-specific markers. tyrosine protein kinase inhibitors, Taiho UFT and uricytin. 0668 Topoisomerase inhibitors include, but are not lim 0676 Berberine has antibiotic activity and prevents and ited to, irinotecan, topotecan, camptothecin, lamellarin D, Suppresses the expression of pro-inflammatory cytokines and amsacrine, etoposide, etoposide phosphate, teniposide, doxo E-selectin, as well as increasing adiponectin expression. rubicin, 4-2-(3,5-dioxo-1-piperazinyl)-1-methylpropylpip 0677 Apigenin is a flavone that can reverse the adverse erazine-2,6-dione (ICRF-193), doxorubicin, daunorubicin, effects of cyclosporine and has chemoprotective activity, mitroxantrone, tenoposide, actinomycin-D, and Ofloxin. either alone or derivatized with a Sugar. 0669 Fraudulent nucleosides include, but are not limited to, cytosine arabinoside, gemcitabine, and fludarabine; other 0678 Colchicine is a tricyclic alkaloid that exerts its activ fraudulent nucleosides are known in the art. ity by binding to the protein tubulin. Analogs of colchicine include, but are not limited to, cholchiceinamide, N-de 0670 Fraudulent nucleotides include, but are not limited sacetylthiocolchicine, demecolcine, N-acetyliodocolchinol, to, tenofovir disoproxil fumarate and adefovir dipivoxil; other trimethylcolchicinie acid (TMCA) methyl ether, N-acetyl fraudulent nucleotides are known in the art. colchinol, TMCA ethyl ether, isocolchicine, isocolchiceina 0671 Thymidylate synthetase inhibitors include, but are mide, iso-TMCA methyl ether, colchiceine, TMCA, N-ben not limited to, raltitrexed, pemetrexed, nolatrexed, ZD9331, Zoyl TMCA, colchicosamide, colchicoside, colchinol and GS7094L, fluorouracil, and BGC 945. colchinoic acid (M. N. Zweig & C. F. Chignell, “Interaction 0672 Signal transduction inhibitors are described in A. V. of Some Colchicine Analogs, Vinblastine and Podophyllo Lee et al., “New Mechanisms of Signal Transduction Inhibi toxin with Rat Brain Microtubule Protein. Biochem. Phar tor Action: Receptor Tyrosine Kinase Down-Regulation and macol. 22: 2141-2150 (1973) and B. Yang et al., “Syntheses Blockade of Signal Transactivation. Clin. Cancer Res. 9: and Biological Evaluation of Ring C-Modified Colchicine 516s (2003), incorporated herein in its entirety by this refer Analogs.” Bioorg. Med. Chem. Lett. 20:3831-3833 (2010)), CCC. both of which are incorporated herein by this reference. 0673 Alkylating agents include, but are not limited to, 0679 Genistein is an isoflavone with the systemic name Shionogi 254-S, aldo-phosphamide analogues, altretamine, 5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one. anaxirone, Boehringer Mannheim BBR-2207, bendamus tine, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, Genistein has a number of biological activities, including carmustine, Chinoin-139, Chinoin-153, chlorambucil, cispl activation of PPARs, inhibition of several tyrosine kinases, atin, cyclophosphamide, American Cyanamid CL-286558, inhibition of topoisomerase, antioxidative activity, activation Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto of Nrf2 antioxidative response, activation of estrogen recep DACHP(Myr), dianhydrogalactitol, dibromodulcitol, other tor beta, and inhibition of the mammalian hexose transporter Substituted hexitols, diphenylspiromustine, diplatinum cyto GLUT2. static, Erba distamycin derivatives, Chugai DWA-2114R, ITI 0680 Etoposide is an anticancer agent that acts primarily E09, elmustine, Erbamont FCE-24517, estramustine phos as a topoisomerase II inhibitor. Etoposide forms a ternary phate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI complex with DNA and the topoisomerase II enzyme, pre 17230, hepsulfam, ifosfamide, iproplatin, lomustine, mafos vents re-ligation of the DNA strands and thus induces DNA famide, melphalan, mitolactol, Nippon Kayaku NK-121, NCI Strand breakage and promotes apoptosis of the cancer cells. NSC-264395, NCINSC-342215, oxaliplatin, Upjohn PCNU, 0681 Cytarabine is a nucleoside analog replacing the prednimustine, Proter PTT-119, ranimustine, semustine, ribose with arabinose. It can be incorporated into DNA and SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus also inhibits both DNA and RNA polymerases and nucleotide tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, reductase. It is particularly useful in the treatment of acute teroxirone, tetraplatin and trimelamol, uramustine, as myeloid leukemia and acute lymphocytic leukemia, described in U.S. Pat. No. 7,446,122 by Chao et al., incorpo 0682 Camptothecins include camptothecin, homocamp rated herein by this reference. tothecin, topotecan, irinotecan, DB 67, BNP 1350, exatecan, US 2016/0220537 A1 Aug. 4, 2016

lurtotecan, ST 1481, and CKD 602. These compounds act as 0692 Dasatinib is an inhibitor of BCR/ABL and Src fam topoisomerase I inhibitors and block DNA synthesis in cancer ily tyrosine kinases and is used to treat chronic myelogenous cells. leukemia and acute lymphoblastic leukemia. 0683 Vinca alkaloids include vinblastine, Vincristine, 0693 Nilotinib is another tyrosine kinase inhibitor vindesine, and vinorelbine. approved for the treatment of chronic myelogenous leukemia; 0684 Topoisomerase inhibitors include topoisomerase I it inhibits the kinases BCR/ABL, KIT, LCK, EPHA3, and a inhibitors and topoisomerase II inhibitors. Topoisomerase I number of other kinases. inhibitors include the camptothecins and lamellarin D. Topoi 0694 Epigenetic modulators include polyamine-based Somerase II inhibitors include, in addition to amonafide and epigenetic modulators, such as the polyamine-based epige derivatives and analogs thereof, etoposide, teniposide, doxo netic modulators described in S. K. Sharma et al., rubicin, daunorubicin, mitoxantrone, amsacrine, ellipticines, “Polyamine-Based Small Molecule Epigenetic Modulators.” and aurintricarboxylic acid. A number of plant-derived natu Med. Chem. Commun. 3: 14-21 (2012), and L. G. Wang & J. rally-occurring phenolic compounds, such as genistein, quer W. Chiao, “Prostate Cancer Chemopreventive Activity of cetin, and resveratrol, exhibit inhibitory activity toward both Phenethyl Isothiocyanate Through Epigenetic Regulation topoisomerase I and topoisomerase II. (Review), Int. J. Oncol. 37: 533-539 (2010), both incorpo 0685 5-fluorouracil is a base analog that acts as a rated herein by this reference. thymidylate synthase inhibitor and thereby inhibits DNA 0695 Transcription factor inhibitors include 1-(4- synthesis. When deprived of a sufficient supply of thymidine, hexaphenyl)-2-propane-1-one, 3-fluoro-4-2-hydroxy-2-(5. rapidly dividing cancer cells die by a process known as thym 5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl) ineless death. acetylamino-benzoic acid (BMS 961), 4-5-8-(1- 0686 Curcumin is believed to have anti-neoplastic, anti Methylethyl)-4-phenyl-2-quinolinyl)-1H-pyrrolo-2-benzoic inflammatory, antioxidant, anti-ischemic, anti-arthritic, and acid (ER-50891), 7-Ethenyl-2-(3-fluoro-4-hydroxyphenyl)- anti-amyloid properties and also has hepatoprotective activ 5-benzoxazolol (ERB 041), and other compounds. Transcrip ity. tion factor inhibitors are described in T. Berg, “Inhibition of Transcription Factors with Small Organic Molecules. Curr. 0687 Rosmarinic acid is a naturally-occurring phenolic Opin. Chem. Biol. 12: 464–471 (2008), incorporated herein antioxidant that also has anti-inflammatory activity. by this reference. 0688 MitoguaZone is an inhibitor of polyamine biosyn 0696 Tetrandrine has the chemical structure 6,6'7.12-tet thesis through competitive inhibition of S-adenosylmethion ramethoxy-2,2'-dimethyl-1B-berbaman and is a calcium ine decarboxylase. channel blocker that has anti-inflammatory, immunologic, 0689 Meiso indigo is active via several, possibly novel and antiallergenic effects, as well as an anti-arrhythmic effect mechanisms of action. It has cell cycle specific effects, similar to that of quinidine. It has been isolated from including arrest in G(O)/G1 for AML cell lines and G2/M Stephania tetranda and other Asian herbs. arrest for HT-29 colorectal cell lines. It also stimulates apo (0697 VEGF inhibitors include bevacizumab (Avastin), ptosis through a number of mechanisms, including the which is a monoclonal antibody against VEGF, itraconazole, upregulation of p21 and p27 and the down regulation of Bcl-2 and Suramin, as well as batimastat and marimastat, which are in primary AML cells, as well as upregulation of Bak and Bax matrix metalloproteinase inhibitors, and cannabinoids and in AML cells (DKO insensitive to chemotherapy), and a novel derivatives thereof. caspase-dependent pathway in K562 cells. Meisoindigo also 0698 Cancer vaccines are being developed. Typically, has effects on mitochondria, but with no change in Bcl-2. cancer vaccines are based on an immune response to a protein Bax, and Bid protein expression. or proteins occurring in cancer cells that does not occur in 0690 Meiso indigo also stimulates the cleavage of pro normal cells. Cancer vaccines include Provenge for meta caspase 3, 8, 9 and PARP in HL-60 myeloid cells. Meisoin static hormone-refractory prostate cancer, Oncophage for digo also is directed to multiple cellular targets, which are kidney cancer, CimaVax-EGF for lung cancer, MOBILAN, possibly synergistic and complementary. For example, it pro NeuVenge for Her2/neu expressing cancers such as breast motes differentiation of human myeloblastic leukemic cells, cancer, colon cancer, bladder cancer, and ovarian cancer, accompanied by down regulation of c-myb gene expression. StimuVax for breast cancer, and others. Cancer vaccines are It also promotes inhibition of DNA and RNA synthesis in described in S. Pejawar-Gaddy & O. Finn, “CancerVaccines: W256 cells, microtubule assembly, glycogen synthase Accomplishments and Challenges.” Crit. Rev. Oncol. Hema kinase-3J3 (GSK-3.3) (at 5-50 nM), CDK1/cyclin B, and tol. 67:93-102 (2008), incorporated herein by this reference. CDK5/p25 (tau microtubule protein phosphorylation). Addi 0699 The use of methylglyoxalbisguanylhydrazone in tionally, meisoindigo decreases B-catenin and c-myc (HL-60 cancer therapy has been described in D. D. Von Hoff, cells, but not in K562), affects the Wnt pathway through “MGBG: Teaching an Old Drug New Tricks.” Ann. Oncol. 5: inhibiting GSK-3B and down regulating B-catenin and c-myc 487-493 (1994), incorporated herein by this reference. protein expression. Meisoindigo also promotes upregulation (0700 Poly-ADP ribose polymerase inhibitors are of CD11b, promoting myeloid differentiation, and upregula described in G. J. Southan & C. Szabó, “Poly(ADP-Ribose) tion of Ahi-1 in Jurkat cells (inducing phosphorylation of Inhibitors.” Curr. Med. Chem. 10:321-240 (2003), incorpo c-Myb). Furthermore, meisoindigo exhibits antiangiogenic rated herein by this reference, and include nicotinamide, effects, including decreased VEGF protection, VCAM-1, 3-aminobenzamide, Substituted 3,4-dihydroisoquinolin-1 tubule formulation in HUVEC, and ECV304 apoptosis. (2H)-ones and isoquinolin-1 (2H)-ones, benzimidazoles, 0691 Imatinib is an inhibitor of the receptor tyrosine indoles, phthalazin-1 (2H)-ones, quinazolinones, isoindoli kinase enzyme ABL and is used to treat chronic myelogenous nones, phenanthridinones, and other compounds. Poly-ADP leukemia, gastrointestinal Stromal tumors, and other hyper ribose polymerase (PARP) inhibitors include, but are not proliferative disorders. limited to: (1) derivatives of tetracycline as described in U.S. US 2016/0220537 A1 Aug. 4, 2016 46

Pat. No. 8.338,477 to Duncan et al.; (2) 3,4-dihydro-5-me but are not limited to: LFM-A13 (C-cyano-B-hydroxy-3-me thyl-1(2H)-isoquinoline, 3-aminobenzamide, 6-aminonicoti thyl-N-(2,5-dibromophenyl)propenamide: terreic acid ((1R, namide, and 8-hydroxy-2-methyl-4(3H)-quinazolinone, as 6S)-3-Hydroxy-4-methyl-7-Oxabicyclo4.1.0 hept-3-ene-2, described in U.S. Pat. No. 8.324,282 by Gerson et al.; (3) 5-dione); ibrutinib: pyrazolo 3,4-dipyrimidine and pyrrolo 6-(5H)-phenanthridinone and 1.5-isoquinolinediol, as 2,3-dipyrimidine compounds as disclosed in U.S. Pat. No. described in U.S. Pat. No. 8,324.262 by Yuan et al.; (4) (R)- 8.377.946 to Chen et al., incorporated herein by this refer 3-2-(2-hydroxymethylpyrrolidin-1-yl)ethyl-5-methyl-2H ence; 2,4-disubstituted pyrimidines as disclosed in U.S. Pat. isoquinolin-1-one, as described in U.S. Pat. No. 8.309,573 to Fujio et al.; (5) 6-alkenyl-substituted 2-quinolinones, 6-phe No. 8.338.439 to Singh et al., incorporated herein by this nylalkyl-substituted quinolinones, 6-alkenyl-substituted reference; 6-phenyl-imidazol-2-alpyridine and 6-phenyl 2-quinoxalinones, 6-phenylalkyl-substituted 2-quinoxalino imidazo[1,2-bipyridazine derivatives, as disclosed in U.S. nes, Substituted 6-cyclohexylalkyl Substituted 2-quinolino Pat. No. 8.324.211 to Dewdney et al., incorporated herein by nes, 6-cyclohexylalkyl Substituted 2-quinoxalinones, Substi this reference; 5-phenyl-1H-pyridin-2-one, 6-phenyl-2H-py tuted pyridones, quinazolinone derivatives, phthalazine ridazin-3-one, and 5-phenyl-1H-pyrazin-2-one derivatives, derivatives, quinazolinedione derivatives, and Substituted as disclosed in U.S. Pat. No. 8,318,719 to Dewdney et al. and 2-alkyl quinazolinone derivatives, as described in U.S. Pat. 8.2997.077, incorporated herein by this reference: 1-(3-(4- No. 8,299,256 to Vialard et al.; (6) 5-bromoisoquinoline, as amino-3-(4-phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin described in U.S. Pat. No. 8,299,088 to Mateucci et al.; (7) 1-yl)piperidin-lyl)prop-2-en-1-one, (E)-1-(3-(4-amino-3- 5-bis-(2-chloroethyl)amino-1-methyl-2-benzimidazolebu (4-phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) tyric acid, 4-iodo-3-nitrobenzamide, 8-fluoro-5-(4-(methy piperidin-1-yl)but-2-en-1-one, 1-(3-(4-amino-3-(4- lamino)methyl)phenyl)-3,4-dihydro-2H-azepino 5.4.3-cd phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) indol-1 (6H)-one phosphoric acid, and N-3-(3,4-dihydro-4- piperidin-1-yl)sulfonylethene, 1-(3-(4-amino-3-(4- oXo-1-phthalazinyl)phenyl-4-morpholinebutanamide phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) methanesulfonate, as described in U.S. Pat. No. 8,227,807 to piperidin-1-yl)prop-2-yn-1-one, 1-(4-(4-amino-3-(4- Gallagher et al.; (8) pyridazinone derivatives, as described in phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) U.S. Pat. No. 8,268,827 to Branca et al.; (9) 4-3-(4-cyclo piperidin-1-yl)prop-2-en-1-one, N-((1 S.4s)-4-(4-amino-3- propanecarbonyl-piperazine-1-carbonyl)-4-fluorobenzyl (4-phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) 2H-phthalazin-1-one, as described in U.S. Pat. No. 8,247.416 cyclohexyl)acrylamide, 1-((R)-3-(4-amino-3-(4- to Menear et al., (10) tetraaza phenalen-3-one compounds, as phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) described in U.S. Pat. No. 8.236,802 to Xu et al.; (11) 2-sub pyrrolidin-1-yl)prop-2-en-1-one, 1-(S)-3-(4-amino-3-(4- stituted-1H-benzimidazole-4-carboxamides, as described in phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) U.S. Pat. No. 8,217,070 to Zhu et al.; (12) substituted 2-alkyl pyrrolidin-1-yl)prop-2-en-1-one, 1-((R)-3-(4-amino-3-(4- quinazolinones, as described in U.S. Pat. No. 8,188,103 to phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) Vander Aa et al., (13) 1H-benzimidazole-4-carboxamides, as piperidin-1-yl)prop-2-en-1-one, 1-((S)-3-(4-amino-3-(4- described in U.S. Pat. No. 8,183,250 to Penning et al.; (13) phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) indenoisoquinolinone analogs, as described in U.S. Pat. No. piperidin-1-yl)prop-2-en-1-one, and (E)-1-(3-(4-amino-3- 8,119,654 to Jagtap et al., (14) benzoxazole carboxamides, (4-phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) described in U.S. Pat. No. 8,088,760 to Chu et al: (15) diaza piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one, aS benzo delanthracen-3-one compounds, described in U.S. disclosed in U.S. Pat. No. 8,236,812 to Honigberg et al., Pat. No. 8,058,075 to Xu et al.: (16) dihydropyridophthalazi incorporated herein by this reference; pyrazolo 3,4-dipyrim idines, as disclosed in U.S. Pat. No. 8,232,280, incorporated nones, described in U.S. Pat. No. 8.012,976 to Wang et al., herein by this reference: 2-(4-fluoro-2-methylphenylamino)- (17) substituted azaindoles, described in U.S. Pat. No. 8,008, 1,6-dimethyl-7-3-(4-methyl-4-oxo-4 (1.4lazaphosphi 491 to Jiang et al.; (18) fused tricyclic compounds, described nan-1-yl)-propenyl-1,8-dihydro-imidazo 4.5-hisoquino in U.S. Pat. No. 7.956,064 to Chua et al.; (19) substituted lin-9-one, 2-(2,6-dichloro-phenylamino)-1,6-dimethyl-7-3- 6a, 7.8.9-tetrahydropyrido3.2-elpyrrolo 1,2-alpyrazin-6 (4-methyl-4-OXO-471.4lazaphosphinan-1-yl)-propenyl-1, (5H)-ones, described in U.S. Pat. No. 7,928,105 to Gangloff 8-dihydro-imidazo[4,5-h-isoquinolin-9-one, 2-(4-fluoro-2- et al.; and (20) thieno 2.3-cisoquinolines, described in U.S. methylphenylamino)-1,6-dimethyl-7-3-(4-oxo-4-phenyl Pat. No. 7,825,129. Other PARP inhibitors are known in the 4 -1.4lazaphosphinan-1-yl)-propenyl-1,8-dihydro art. imidazo 4.5-hisoquinolin-9-one, 2-(3-fluoro-6- 0701 EGFR inhibitors, including both small molecules methylphenylamino)-1,6-dimethyl-7-3-(4-oxo-4-phenyl and monoclonal antibodies, are described above. Other 4 -1.4lazaphosphinan-1-yl)-propenyl-1,8-dihydro EGFR inhibitors are known in the art. imidazo 4.5-hisoquinolin-9-one, 2-(2,6- 0702 Bruton's tyrosine kinase (BTK) is a kinase enzyme dichlorophenylamino)-1,6-dimethyl-7-3-(4-oxo-4-phenyl that plays a key role in the maturation of B cells and in mast 4 -1.4lazaphosphinan-1-yl)-propenyl-1,8-dihydro cell activation through the high-affinity IgE receptor. Defi imidazo 4.5-hisoquinolin-9-one, 2-(2,4-dichloro-6- ciencies in BTK activity are associated with the primary methylphenylamino)-1,6-dimethyl-7-3-(4-oxo-4-phenyl immunodeficiency disease X-linked agammaglobulinemia. 4 -1.4lazaphosphinan-1-yl)-propenyl-1,8-dihydro The Btk gene is located on the X-chromosome. BTK contains imidazo 4.5-hisoquinolin-9-one, 2-(3-fluoro-6- a PH domain that binds phosphatidylinositol (3,4,5)-triphos methylphenylamino)-1,6-dimethyl-7-2-(4-oxo-4-phenyl phate (PIP3). PIP3 induces BTK to phosphorylate phospho 4 -1.4lazaphosphinan-1-yl)-propenyl-1,8-dihydro lipase C, which in turn hydrolyzes phosphatidyl inositol imidazo 4.5-hisoquinolin-9-one, 2-(2,4-dichloro-6- diphosphate into two second messengers, inositol triphos methylphenylamino)-1,6-dimethyl-7-3-(4-oxo-4-phenyl phate and diacylglycerol, which in turn modulate the activity 4 -1.4lazaphosphinan-1-yl)-propyl-1,8-dihydro-imidazo of downstream proteins in B cells. BTK inhibitors include, 4.5-hisoquinolin-9-one, 2-(4-fluoro-2-

US 2016/0220537 A1 Aug. 4, 2016 50 malignancies, in U.S. Pat. No. 7,763,658 to Koya et al., incor mutant form of the serine/threonine kinase BRAF, BRAF porated herein by this reference. Other bis-thio-hydrazide V600E, including vemafuranib; (xii) small-molecule agents amides are also disclosed. that inhibit the tyrosine kinase activity of the EML4-ALK 0704. Use with succinimide or maleimide derivatives as fusion protein, including crizotinib; (xiii) Small-molecule Topoisomerase II inhibitors is disclosed in United States agents that are inhibitors of histone deacetylase (HDAC) Patent Application Publication 2007/0196360 by Jensen et activity, including Vorinostat and romidepsin; (xiv) small al., incorporated herein by this reference. molecule agents that modulate the activity of retinoic acid 0705 HDAC inhibitors include, but are not limited to, receptors, retinoid X receptors, or both, including beXarotene, compounds disclosed in PCT Patent Application Publication alitretinoin, and tretinoin, (XV) Small-molecule agents that are No. WO 02/22577 by Bair et al., including, but not limited to, proteasome inhibitors, including bortezomib and carfil N-hydroxy-3-4-(2-hydroxyethyl)2-(1H-indol-3-yl) Zomib; (Xvi) Small-molecule agents that are antifolates and ethyl-aminomethylphenyl-2E-2-propenamide, Suberoy selectively accumulate in cells expressing RFC-1, overex lanilide hydroxamic acid, 4-(2-amino-phenylcarbamoyl)- pressed in malignant cells, including pralatrexate: (Xvii) benzyl-carbamic acid pyridine-3-ylmethyl ester and monoclonal antibodies that bind to VEGF or block activity of derivatives thereof, butyric acid, pyroxamide, trichostatin A, proteins involved in VEGF signaling, including bevaci oXamflatin, apicidin, depsipeptide, depudecin, trapoxin, HC Zumab; (xviii) recombinant fusion proteins that bind to toxin, and sodium phenylbutyrate. VEGF, including Ziv-aflibercept; (xix) small-molecule agents 0706. Immunostimulants include, but are not limited to, that bind to VEGF or block activity of proteins involved in deoxycholic acid, tetrachlorodecaoxide, imiquimod, and VEGF signaling, including Sorafenib, Sunitinib, paZopanib residuimod. (which has other activities as well), regorafenib (which has 0707 Agents that inhibit the expression or activity of Her2 other activities as well), and cabozanitib (which has other include, but are not limited to, lapatinib ditosylate, afatinib, activities as well); and (XX) monoclonal antibodies binding to lapatinib, CP-724714 ((E)-2-methoxy-N-(3-(4-(3-methyl-4- tumor markers that trigger an anti-neoplastic immune (6-methylpyridin-3-yloxy)phenylamino)quinazolin-6-yl)al response, including rituximab (binding to CD20), alemtu lyl)acetamide), mulbritinib, canertinib, CUDC-101 (7-(4-(3- Zumab (binding to CD52), ofatumumab (binding to CD20), ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N- ipilimumab (binding to CTLA-4), to situmomab (binding to hydroxyheptanamide), Tyrphostin AG 879 (2-(2E)-3-3,5-bis CD20; this monoclonal antibody can be conjugated to the (1,1-dimethylethyl)-4-hydroxyphenyl-2-cyano-2- radioisotope ''I), and ibritumomab (binding to CD20; this propenethioamide), TAK-285 (N-(2-(4-(3-chloro-4-(3- monoclonal antibody can be conjugated to '''In or 'Y). (trifluoromethyl)phenoxy)phenylamino)-5H-pyrrolo 3,2-d 0710 Agents that are G-quadruplex ligands include, but pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide), are not limited to, 3,11-difluoro-6,8,13-trimethyl-8H-quino Arry 380 (N-(4-(12,4triazolo 1.5-alpyridin-7-yloxy)-3- 4.3.2-klacridinium methosulfate, BRACO-19 (9-4-(N.N- methylphenyl)-6-(5-((2-(methylsulfonyl)ethylamino)me dimethylamino)phenylamino-3,6-bis(3-pyrrolidino-propi thyl)furan-2-yl)guinazolin-4-amine), AV412, AZD8931 (2- onamido)acridine), and telomestatin. These agents are (4-(4-(3-chloro-2-fluorophenylamino)-7- described in United States Patent Application Publication No. methoxyquinazolin-6-yloxy)piperidin-1-yl)-N- 2008/0279961 by Burger, incorporated herein by this refer methylacetamide), neratinib, AEE788 ((R)-6-(4-((4- ence, and in U.S. Pat. No. 7,115,619 to Stevens et al., incor ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H porated herein by this reference. pyrrolo2,3-dipyrimidin-4-amine), and BMS-599626 (S)- 0711 Polycyclic compounds that are lysophosphatidic morpholin-3-ylmethyl 4-(1-(3-fluorobenzyl)-1H-indazol-5- receptor antagonists are disclosed in U.S. Pat. No. 8,664.220 ylamino)-5-methylpyrrolo 1.2-f 1.2.4 triazin-6- to Clark et al. The polycyclic lysophosphatidic receptor ylcarbamate). antagonist can be selected from the group consisting of 1-4'- 0708 Agents that inhibit the expression or activity of 4-(2-benzyl-cyclohexylamino)-3-methyl-isoxazol-5-yl)-bi estrogen receptors include, but are not limited to, fulvestrant. phenyl-4-yl)-cyclopropanecarboxylic acid; 1-4-3-methyl 0709 Agents that inhibit the expression or activity of anti 4-(4-o-tolyl-piperazine-1-carbonyl)-isoxazol-5-yl)- gens associated with specific tumor targets include, but are biphenyl-4-yl)-cyclopropanecarboxylic acid; 1-(4-4-4-(3. not limited to: (i) agents that inhibit the binding of estrogen to 4-dichloro-benzenesulfonyl)-piperazine-1-carbonyl-3- the estrogen receptor, including tamoxifen, toremifene, and methyl-isoxazol-5-yl)-biphenyl-4-yl)- fulvestrant; (ii) aromatase inhibitors, including anastroZole, cyclopropanecarboxylic acid; 1-4-3-methyl-4-(3- exemestane, and letrozole; (iii) tyrosine kinase inhibitors, phenethyl-oxiranyl)-isoxazol-5-yl)-biphenyl-4-yl)- including imatinib mesylate, dasatinib, nilotinib, and bosu cyclopropanecarboxylic acid; 1-43-methyl-4-(2-oxo-4- tinib; (iv) antibodies binding to HER-2 or blocking its activ phenyl-pyrrolidin-1-ylmethyl)-isoxazol-5-yl)-biphenyl-4- ity, including trastuzumab and pertuZumab, (v) Small-mol yl)-cyclopropanecarboxylic acid; 1-4-3-methyl-4-(4- ecule agents that inhibit the tyrosine kinase activity of HER phenyl-piperidin-1-ylmethyl)-isoxazol-5-yl)-biphenyl-4- 2, including lapatinib, (vi) Small-molecule agents that inhibit yl)-cyclopropanecarboxylic acid; 1-4'-[4-(2-imino-5- the tyrosine kinase activity of EGFR, including gefitinib and phenyl-1,3,4-oxadiazol-3-ylmethyl)-3-methyl-isoxazol-5- erlotinib; (vii) monoclonal antibodies binding to EGFR, yl)-biphenyl-4-yl)-cyclopropanecarboxylic acid; 1-4-4 including cetuximab and panitumumab; (viii) Small-mol ((S)-4-benzyl-2-oxo-oxazolidin-3-ylmethyl)-3-methyl ecule agents that inhibit the serine/threonine kinase mTOR, isoxazol-5-yl)-biphenyl-4-yl)-cyclopropanecarboxylic acid; including temsirolimus; (ix) Small-molecule agents that bind 1-4'-3-methyl-4((S)-2-oxo-4-phenyl-oxazolidin-3-ylm to immunophilin FK-binding protein 12, including everoli ethyl)-isoxazol-5-yl)-biphenyl-4-yl)-cyclopropanecarboxy mus; (X) Small-molecule agents that block the activity of lic acid; 1-4-3-methyl-4R,5S)-4-methyl-2-oxo-5-phenyl multiple tyrosine kinase enzymes, including Vandetanib; (xi) oxazolidin-3-ylmethylyisoxazol-5-yl)-biphenyl-4-yl)- Small-molecule agents that block the activity of an activated cyclopropanecarboxylic acid; 1-4-3-methyl-4-((4S.5R)-4-

US 2016/0220537 A1 Aug. 4, 2016 52

0712 Anti-CTGF agents are disclosed in United States helial cells, fibroblasts, or immune cells and that are used with Patent Application Publication No. 2014/0065162 by Lipson an oligonucleotide that inhibits the nonsense-mediated decay et al. Anti-CTGF (connective tissue growth factor) agents pathway are disclosed in United States Patent Application include, but are not limited to, anti-CTGF antibody, anti Publication No. 2013/0224237 by Gilboa. The oligonucle CTGF antibody fragment, anti-CTGF antibody mimetic or otide can be a short interfering RNA (sRNA); a micro-inter anti-CTGF oligonucleotide; the anti-CTGF oligonucleotide fering RNA (miRNA); antisense oligonucleotides; a small, can be an antisense oligonucleotide, siRNA, shRNA or temporal RNA (stRNA); a short, hairpin RNA (shRNA), or miRNA. combinations thereof. Typically, the oligonucleotide inhibits 0713 Myeloid differentiation inducing agents are dis the function or the expression of at least one factor associated closed in United States Patent Application Publication No. with the NMD pathway comprising at least one of RENT1, 2014/0018383 by Wald, including, but not limited to, securi RENT2, eIF4A, UPF1, UPF2, UPF3B, RNPS1, Y14, nine and securinine analogs. MAGOH, NMD1, SMG, or combinations thereof. The target 0714 Covalent diabodies binding to a tumor-associated of the cell binding ligand can be vascular endothelial growth antigen are disclosed in United States Patent Application factor (VEGF), vascular endothelial growth factor receptor Publication No. 2013/0295121 by Johnson et al. The diabody (VEGFR-2), Tie2; fibronectin, vitronectin, collagen, laminin, can comprise a first polypeptide chain and a second polypep fibroblast antigens, fibroblast activation protein (FAP), glu tide chain: (I) which first polypeptide chain comprises: (i) a cose-regulated protein 78 (GRP78), stromal derived factor 1 first domain comprising a binding region of a light chain (SDF-1), MCP-1, MIP-1C., MIP-1 BRANTES, exotaxin IL-8, variable domain of a first immunoglobulin (VL1) specific for C3a, P-selectin, E-selectin, LFA-1, VLA-4, VLA-5, CD44, a first epitope; and (ii) a second domain comprising a binding MMP activation, VEGF, EGF, PDGF, VCAM, ECAM, region of a heavy chain variable domain of a second immu G-CSF, GM-CSF, SCF, EPO, tenascin, neurophilin, MAd noglobulin (VH2) specific for a second epitope; and which CAM-1, neuropilin-1, C.4 integrins, C.5 integrins, or beta first domain and second domains are covalently linked Such defensins 3 and 4. that the first domain and second domain do not associate to 0717 Tumor-specific antibodies binding to a portion of form an epitope binding site; (II) which second polypeptide the CD44 protein or a binding protein derived from the light chain comprises: (i) a fourth domain comprising a binding chain or heavy-chain complementary-determining regions of region of a light chain variable domain of the second immu such antibodies are disclosed in United States Patent Appli noglobulin (VL2); and (ii) a fifth domain comprising a bind cation Publication No. 2013/0217865 by Glover et al. ing region of a heavy chain variable domain of the first immu 0718. Inhibitors of CXCR4 are disclosed in United States noglobulin (VH1), and which fourth domain and fifth domain Patent Application Publication No. 2013/0216531 by Jain et are covalently linked such that the fourth domain and fifth al. The CXCR4 inhibitor can be selected from the group domain do not associate to form an epitope binding site; consisting of 1,1'-1,4-phenylene-bis(methylene)-bis-1,4,8. wherein: (A) the first domain and the fifth domain associate to 11-tetraazacyclotetradecane (AMD-3100); Mozobil: Plerix form a first binding site (VL1)(VH1) that binds the first afor, NOXA12: CTCE-9908: ALX40-4C; T22; T 140; Met epitope; (B) said second domain and said fourth domain SDF-1 B: T134: AMD-3465; N'-(1-H-benzimidazol-2- associate to form a second binding site (VL2)(VH2) that ylmethyl)-N1-(5,6,7,8-tetrahydroquinoline-8-yl)-butane-1, binds the second epitope; (C) at least one of said first or said 4-diamine; CTCF-0214; CTCF-9908; CP-1221 (linear second polypeptide chains of said diabody additionally com peptides, cyclic peptides, natural amino-acids, unnatural prises an E-coil or a K-coil separator; and (D) wherein when amino acids, and peptidomimetic compounds); 4F-ben said separator of said first or second polypeptide is an E-coil, ZoylTN24003: KRH-1120; KRH-1636; KRH-2731; said separator of said serum-protein binding polypeptide is a polyphemusin analogue: ALX40-4C; T-140; T-140 analogs K-coil, and when said separator of said first or second and derivatives; TN14003: TC14012: TE14011; and any polypeptide is an K-coil, said separator of said serum-protein combinations thereof. Additionally, the CXCR4 inhibitor can binding polypeptide is an E-coil. be used with a VEGF inhibitor, such as a VEGF inhibitor 0715 Bispecific antibodies that have a cell-penetrating selected from the group consisting of ABT-869: AEE-788: determinant and an intracellular target-binding determinant AG-13736: AG-028262; Angiostatin; bevacizumab; AVE are disclosed in United States Patent Application Publication 8062: AZD-2171; Sorafenib; BMS-387032; CEP-7055; No. 2013/0266570 by Weisbart et al. In one alternative, the CHIR-258; GFKI; CP-547632; CP-564959; E-7080: bispecific antibodies have Fv fragments with a cell-penetrat 786034; GW-654652: IMC-1C11; KRN-951; PKC-412: ing determinant and a second FV fragment with an intracel PTK-787: SU 11248: SU-5416: SU-6668; AVE-0005; thali lular target-binding determinant. In one embodiment, the domide; XL-647; XL-999; ZD-6474; ZK-304709; Pazo intracellular target-binding determinant is an E3 ubiquitin panib; CDP791; Enzastaurin; BIBF 1120; BAY 573952; BAY protein ligase, or tumor Suppressor-interacting protein, Such 734506; XL 184: IMC-1121B, CEP 701; SU 014813; SU as MDM2. In one embodiment, the intracellular target-bind 10944: SU 12662: OSI-930; BMS 582664; ZD-6126: Ima ing determinant may target an oncoprotein Such as a myc or tinib: Glivec: Gleevec, STI-571; CGP-57148: RAD-001; ras oncoprotein. In another embodiment, the intracellular BMS-354825; Volociximab: CCI-779: 17-AAG; DMXAA; target-binding determinant may target DNA repair proteins CI-1040; C1-1033; (5-5-fluoro-2-oxo-1,2-dihydroindol Such as a RAD52 protein, ataxia telangiectasia mutated pro (3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic tein (ATM), CHK2 or CHK1 proteins, or BCL2 protein. acid 2-diethylaminoethylamide); 4TBPPAPC: AMG 706: Additional examples of proteins associated with DNA repair Nexavar(R); and PTK/ZK. In another alternative, the CXCR4 include but are not limited to BRCA1, MDC1, 53BP1, p53, inhibitor can be used with a p38 MAPK inhibitor. The p38 ATR, and p21. MAPK inhibitor can be selected from the group consisting of 0716. Multidomain molecules that comprise a cell binding antisense p38 MAPK nucleic acids and fragments thereof, ligand that binds to cells in the tumor stroma Such as endot antibodies that bind p38 MAPK and fragments thereof, US 2016/0220537 A1 Aug. 4, 2016

EO-1428, SB239063, SB281832, VX-702, VX-745, ZM336372, RPR 200765A, N-(3-tert-butyl-1-methyl-5- (A-2) pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea, OH SB203580, SB2021.90, PD169316, fr-167653, trans-1-(4-hy droxycyclohexyl)-4-(4-fluorophenyl)-5-(2 methoxypyridi midin-4-yl)imidazole, 2-(4-chlorophenyl)-4-)4-fluorophe -- na N nyl)-5-pyridin-4-yl-1,2-dihydropyrazol-3-one, and any O 2H(R'), combinations thereof. 0719 Pyruvate dehydrogenase kinase (PDK1) inhibitors are disclosed in PCT Patent Application Publication No. WO wherein: (i) R' is alkyl, hydroxyl, amino, alkoxy, aryl, alk 2013/174997 by Villalba et al. and include dichloroacetate, enyl, alkynyl, or alkylenearyl; (ii) Het is heteroaryl; and (iii) antisense RNA, small inhibitory RNA, short hairpin RNA, m and n are each independently 0, 1, 2, 3, or 4. and ribozymes. 0728. Inhibitors of furin and other pro-protein convertases 0720 Epherin receptor targeting agents are disclosed in are disclosed in PCT Patent Application Publication No. WO PCT Patent Application Publication No. WO 2013/106824 by 2013/138666 by Stronginet al. The inhibitors can have the Xiong et al. and include peptide targeting agents such as structure of Formula (A-3): TNYLFSPNGPIA (SEQ ID NO: 9) or TNYLFSPNGPI ARAW (SEQIDNO: 10), YSAYPDSVPMMS (SEQID NO: 11) or a cyclic peptide including a lactambridge. (A-3) 0721 Binding proteins for Axl are disclosed in PCT Patent O R O Application Publication No. WO 2013/064684 by Beau-Lar 1'n Voretal. and include monoclonal antibodies. The protein Axl sus---N N Y binds to the ligand Gas6 and has been shown to regulate H H R4 various cellular processes including cell proliferation, adhe O 5 O X Sion, migration and Survival in a large variety of cells in vitro. 0722 Wnt pathway inhibitors, used together with MAPK pathway inhibitors, are disclosed in PCT Patent Application Publication No. WO 2013/086260 by Hoey et al. The Wnt wherein: (i) R is alkyl, cycloalkyl, heteroalicyclyl, aryl, or pathway inhibitor can be an antibody that binds a frizzled heteroaryl; (ii) R is alkyl, cycloalkyl, or heteroalicyclyl; (iii) (FZD) protein or a portion thereof. Alternatively, the Wnt R is —Z-guanidine or —Z C(NH)—NH, wherein Z is pathway inhibitor can be a soluble receptor. The MAPK path aryl or heteroaryl; (iv) R is W C(NH)—NR', wherein way inhibitor can be a MEK inhibitor, such as BAY 86-9766 W is aryl, thiophenyl, furanyl, oxazolyl pyrrolyl, or picoli (RDEA119), PD0325901, CI-1040, PD98059, PD318088, nyl, and wherein R' is hydrogen or hydroxyl (v) Rs is —U- GSK1 120212 (JTP-74057), AZD8330 (ARRY-424704), guanidine, wherein U is alkyl, cycloalkyl, heteroalicyclyl, AZD6244 (ARRY-142886), ARRY-162, ARRY-300, aryl, or heteroaryl; (vi) X is —CH2—, —CH2CH2—, AS703026, UO126, CH4987655, or TAK-733, or a Raf - CH-NHC(=O) , —CHCHC(=O)NH-, or -CHC inhibitor such as GDC-0879, PLX-4720, PLX-4032 (vemu (=O)NH , and (vii) Y is —CH2. —S(=O) , or rafenib), RAF265, BAY 73-4506, BAY 43-9006 (sorafenib), —C(=O)—. SB590885, XL281 (BMS-908662), or GSK 21 18436436. 0729 GPBP-1 inhibitors, which can optionally be used 0723. TEC family kinase inhibitors are disclosed in PCT together with a p21 inhibitor, are disclosed in PCT Applica Patent Application Publication WO 2014/071231 by Buggy tion Publication No. WO 2014/006020 by Saus et al. The et al. and in PCT Patent Application WO 2014/071231 by GPBP-1 inhibitors comprise three phenyl moieties linked by Buggy et al. Typically, the TEC family kinase inhibitor is a methylene linkages wherein the phenyl moieties are variously covalent inhibitor, such as ibrutinib. substituted. The p21 inhibitor can be, but is not limited to, 0724 Substituted macrocyclic compounds with protea p21-specific antibodies, p21-specific siRNA, p21-specific some activity are disclosed in PCT Patent Application Publi shRNA, p21-specific antisense nucleic acids, and p21 expres cation No. WO 2013/188750 by Pirrung et al. The com sion inhibitors. The p21 expression inhibitor can be, but is not pounds can be structurally related to glidobactins. limited to, flavopiridol, temsirolimus, roXithromyin, ralox 0725 Peptide-based PACE4 inhibitors are disclosed in ifene hydrochloride, rifampicin, megestrol acetate, pri PCT Patent Application Publication No. WO 2013/029180 by maquine diphosphate, losartan potassium, Valsartan, perhex Day et al. iline maleate, or nisoldipine. An inhibitor of ATP-binding cassette transporter 7 (ABCC7) can also be used; the inhibitor 0726 AZaindole derivatives as JAK3 inhibitors are dis of ABCC7 can be, but is not limited to, ABCC7-specific closed in PCT Patent Application Publication No. WO 2014/ antibodies, ABCC7-specific siRNA, ABCC7-specific 081732 by Goldstein et al. The compounds can be N-(3-(7- shRNA, ABCC7-specific antisense nucleic acids, and pivaloyl-5H-pyrrolo2,3-bipyrazin-2-yl)phenyl)acrylamide: ABCC7 expression inhibitors. The ABCC7 expression 2-(3-acrylamidophenyl)-N-(tert-butyl)-5H-pyrrolo2,3-b inhibitor can be, but is not limited to, 3-(3-trifluoromethyl) pyrazine-7-carboxamide; or N-(tert-butyl)-2-(3-(4-(dim phenyl-5-(4-carboxyphenyl)methylene-2-thioxo-4-thia ethylamino)but-2-enamido)phenyl)-5H-pyrrolo2,3-b- Zolidinone, 7,9-dimethyl-11-phenyl-6-(5-methylfuran-2-yl)- pyrazine-7-carboxamide. 5,6-dihydro-pyrimido-4,5'-3.4 pyrrolo 1,2-aquinoxaline 0727. Inhibitors of Myc are disclosed in PCT Patent 8, 10-(7H,9H)-dione, lonidamine, chromanol 293B, Application Publication No. WO 2014/059429 by Gudkov et glibenclamide, and N-(2-naphthalenyl)-((3,5-dibromo-2,4- al. The inhibitors can have the structure of Formula (A-2): dihydroxyphenyl)methylene)glycine hydrazide. US 2016/0220537 A1 Aug. 4, 2016 54

(0730 PGE inhibitors are disclosed in U.S. Pat. No. 6,245, body or antibody fragment (AB) that binds specifically to a 790 to Hattorietal. and include oxazole compounds, includ target, wherein: the NB comprises a polypeptide that does not ing compounds of Formula (A-4) bind specifically to the AB; the CL is a polypeptide that comprises a Substrate (S) for an enzyme; the CL is positioned in the activatable antibody such that in an uncleaved state, the (A-4) NB interferes with binding of the AB to the target and in a R2 /F N R3 cleaved state, the NB does not interfere with binding of the AB to the target; the NB does not inhibit cleavage of the CL by the enzyme; and the activatable antibody in the uncleaved R. 3)--(DCK X R4 state has the structural arrangement from N-terminus to C-ter minus as follows: NB-CL-AB or AB-CL-NB; and (iii) an wherein: activatable antibody comprising: a binding partner (BP) for a (0731 (i) R' is: lower alkyl substituted with hydroxyl, non-binding steric moiety (NB); a cleavable linker (CL); and carboxyl, or protected carboxyl; carboxyl; protected an antibody or antibody fragment (AB) that binds specifically carboxyl; carbamoyl; a heterocyclic group; cyano; to a target, wherein: the BP is a polypeptide that binds to the hydroxyl; halo-lower alkylsulfonyloxy; lower alkoxy NB when exposed thereto; the NB does not bind specifically optionally substituted with hydroxyl or carbamoyl: aryl to the AB; the CL is a polypeptide that comprises a substrate substituted with carboxyl, protected carboxyl, carbam (S) for an enzyme; the CL is positioned in the activatable oyl, or heterocyclyl; or amino optionally substituted antibody Such that in an uncleaved state in the presence of the with protected carboxyl or lower alkylsulfonyl: NB, the NB interferes with binding of the AB to the target and in a cleaved state, the NB does not interfere with binding of (0732 (ii) R is hydrogen or lower alkyl: the AB to the target and the BP does not interfere with binding (0733 (iii) R is aryl optionally substituted with halo of the AB to the target; and the NB and the BP do not inhibit gen, cleavage of the CL by the enzyme. (0734) (iv) R' is aryloptionally substituted with halogen; 0738. When the improvement is made by use of bisantrene 0735 (v) Q is a group of Subformula (A-4(a)) or a bisantrene derivative or analog for chemosensitization, the chemosensitization can include, but is not limited to: 0739 (a) use as a chemosensitizer in combination with (A-4(a)) topoisomerase inhibitors; 0740 (b) use as a chemosensitizer in combination with -A-G-A-A2 fraudulent nucleosides; 0741 (c) use as a chemosensitizer in combination with wherein: (A)-A"- is a single bond or lower alkylene; (B) the fraudulent nucleotides; moiety of Subformula (A-4(b)) 0742 (d) use as a chemosensitizer in combination with thymidylate synthetase inhibitors; 0743 (e) use as a chemosensitizer in combination with signal transduction inhibitors; 0744 (f) use as a chemosensitizer in combination with cisplatin or platinum analogs; () 0745 (g) use as a chemosensitizer in combination with alkylating agents; is cyclo(C5-Co.)alkene, cyclo(C-C)alkane, bicyclo(C-C) 0746 (h) use as a chemosensitizer in combination with alkene, or bicyclo(C5-Co.)alkane; and (C) -A- is a single anti-tubulin agents; bond or lower alkylene; and 0747 (i) use as a chemosensitizer in combination with (0736 (vi) X is O, NH, or S. Additional compounds antimetabolites; include SC560; sulforaphane; curcumin; ketorolac, bro 0748 () use as a chemosensitizer in combination with mfenac; and nepafenac. berberine; 0737 Activatable antibodies targeting tumor specific 0749 (k) use as a chemosensitizer in combination with markers are disclosed in United States Patent Application apigenin, Publication No. 2014/0023664 by Lowman et al. The activat able antibody can be selected from the group consisting of 0750 (1) use as a chemosensitizer in combination with activatable antibodies (i) an activatable antibody comprising: colchicine or analogs of colchicine; a non-binding steric moiety (NB); a cleavable linker (CL): 0751 (m) use as a chemosensitizer in combination with and an antibody or antibody fragment (AB) that binds spe genistein; cifically to a target, wherein: the NB comprises a polypeptide 0752 (n) use as a chemosensitizer in combination with that does not bind specifically to the AB; the CL is a polypep etoposide; tide of up to 50 amino acids in length that comprises a Sub 0753 (o) use as a chemosensitizer in combination with strate (S) for an enzyme; the CL is positioned in the activat cytarabine; able antibody such that in an uncleaved state, the NB 0754 (p) use as a chemosensitizer in combination with interferes with binding of the AB to the target and in a cleaved camptothecins; state, the NB does not interfere with binding of the AB to the 0755 (q) use as a chemosensitizer in combination with target; and the NB does not inhibit cleavage of the CL by the Vinca alkaloids; enzyme; (ii) an activatable antibody comprising: a non-bind 0756 (r) use as a chemosensitizer in combination with ing steric moiety (NB); a cleavable linker (CL); and an anti 5-fluorouracil; US 2016/0220537 A1 Aug. 4, 2016 55

0757 (s) use as a chemosensitizer in combination with treatment Support can be, but is not limited to, a method curcumin; selected from the group consisting of: 0758 (t) use as a chemosensitizer in combination with 0792 (a) hypnosis: roSmarinic acid; and 0793 (b) acupuncture; 0759 (u) use as a chemosensitizer in combination with 0794) (c) meditation: mitoguaZone. 0795 (d) administration of a herbal medication created 0760. When the improvement is made by use of bisantrene either synthetically or through extraction; and or a bisantrene analog or derivative for chemopotentiation, 0796 (e) applied kinesiology. the chemopotentiation can include, but is not limited to: 0797. In one alternative, when the method is administra 0761 (a) use as a chemopotentiator in combination with tion of a herbal medication created either synthetically or topoisomerase inhibitors; through extraction, the herbal medication created either syn 0762 (b) use as a chemopotentiator in combination thetically or through extraction can be selected from the with fraudulent nucleosides; group consisting of: 0763 (c) use as a chemopotentiator in combination with 0798 (a) a natural anti-inflammatory; fraudulent nucleotides; 0764 (d) use as a chemopotentiator in combination 0799 (b) an immunostimulant; with thymidylate synthetase inhibitors; 0800 (c) an antimicrobial; and 0765 (e) use as a chemopotentiator in combination with 0801 (d) a flavonoid, isoflavone, or flavone. signal transduction inhibitors; 0802. When the herbal medication created either syntheti 0766 (f) use as a chemopotentiator in combination with cally or through extraction is a natural anti-inflammatory, the cisplatin or platinum analogs; natural anti-inflammatory can be selected from the group 0767 (g) use as a chemopotentiator in combination consisting of rhein and parthenolide. When the herbal medi with alkylating agents; cation created either synthetically or through extraction is an 0768 (h) use as a chemopotentiator in combination immunostimulant, the immunostimulant can be a product with anti-tubulin agents; found in or isolated from Echinacea. When the herbal medi 0769 (i) use as a chemopotentiator in combination with cation created either synthetically or through extraction is an antimetabolites; anti-microbial, the anti-microbial can be berberine. When the 0770 () use as a chemopotentiator in combination with herbal medication created either synthetically or through berberine; extraction is a flavonoid or flavone, the flavonoid, isoflavone, 0771 (k) use as a chemopotentiator in combination or flavone can be selected from the group consisting of api with apigenin, genin, genistein, apigenenin, genistein, genistin, 6"-O-malo 0772 (1) use as a chemopotentiator in combination with nylgenistin, 6"-O-acetylgenistin, daidzein, daidzin, 6"-O- colchicine or analogs of colchicine; malonyldaidzin, 6"-O-acetylgenistin, glycitein, glycitin, 0773 (m) use as a chemopotentiator in combination 6"-O-malonylglycitin, and 6-O-acetylglycitin. with genistein; 0803. When the improvement is made by a bulk drug 0774 (n) use as a chemopotentiator in combination product improvement, the bulk drug product can be, but is not with etoposide; limited to, a bulk drug product improvement selected from the 0775 (o) use as a chemopotentiator in combination group consisting of: with cytarabine; 0804 (a) preparation as a free base form: 0776 (p) use as a chemopotentiator in combination (0805 (b) salt formation: with camptothecins; 0806 (c) preparation as a homogeneous crystalline 0777 (d) use as a chemopotentiator in combination Structure: with Vinca alkaloids; 0807 (d) amorphous structure; 0778 (r)use as a chemopotentiator in combination with 0808 (e) preparation as a pure isomer; 5-fluorouracil; (0809 (f) increased purity: 0779 (s) use as a chemopotentiator in combination with 0810 (g) preparation with lower residual solvent con curcumin; tent; and 0780 (t) use as a chemopotentiator in combination with 0811 (h) preparation with lower residual heavy metal roSmarinic acid; and COntent. 0781 (u) use as a chemopotentiator in combination 0812. When the improvement is made by use of a diluent, with mitoguaZone. the diluent can be, but is not limited to, a diluent selected from 0782. When the improvement is made by post-treatment the group consisting of management, the post-treatment management can be, but is not limited to, a method selected from the group consisting of 0813 (a) an emulsion; 0783 (a) a therapy associated with pain management; 0814 (b) dimethylsulfoxide (DMSO); 0784 (b) nutritional support; 0815 (c) N-methylformamide (NMF) 0785 (c) administration of an anti-emetic: 0816 (d) dimethylformamide (DMF) 0786) (d) an anti-nausea therapy: 0817 (e) dimethylacetamide (DMA): 0787 (e) administration of an anti-inflammatory agent; 0818 (f) ethanol: 0788 (f) administration of an antipyretic agent; 0819 (g) benzyl alcohol: 0789 (g) administration of an immune stimulant; and 0820 (h) dextrose-containing water for injection; 0790 (h) administration of a growth factor. 0821 (i) Cremophor; 0791) When the improvement is made by alternative medi 0822 () cyclodextrins; and cine/post-treatment Support, the alternative medicine/post 0823) (k) PEG. US 2016/0220537 A1 Aug. 4, 2016 56

0824 When the improvement is made by use of a solvent hydro-5,6-dimethoxy-2(1H)-isoindoleheptanenitrile hydro system, the solvent system can be, but is not limited to, a chloride, C.-(3,4-dimethoxyphenyl)-7,8-dihydro-O-(4-me Solvent system selected from the group consisting of: thylphenyl)thiol-1,3-dioxolo 4.5-gquinoline-6(5H)- 0825 (a) an emulsion; heptanenitrile, C.-(4-chlorobutyl)-3,4-dimethoxy-O-(4- methylphenyl)-thiobenzeneacetonitrile, C.-(3-chloro-2- 0826 (b) DMSO; methylpropyl)-3,4-dimethoxy-O-(4-methyl-phenyl)thio 0827 (c) NMF; benzeneacetonitrile, C.-(11-bromoundecyl)-3,4-dimethoxy 0828 (d) DMF; C-(4-methylphenyl)-thiobenzeneacetonitrile, C-(5- 0829 (e) DMA; chloropentyl)-3,4-dimethoxy-O-(4-methylphenyl)-thio 0830) (f)ethanol: benzeneacetonitrile, C.-(5-bromooctyl)-3,4-dimethoxy-C.- 0831 (g) benzyl alcohol; (4-methylphenyl)-thiobenzeneacetonitrile, C-(5- 0832. (h) dextrose-containing water for injection; iodopentyl)-3,4-dimethoxy-O-(4-methylphenyl)-thio 0833 (i) Cremophor; benzeneacetonitrile, C-(5-aminopentyl)-3,4-dimethoxy-C.- 0834 (i) PEG; and (4-methylphenyl)-thiobenzeneacetonitrile, C-(5- 0835 (k) salt systems. chlorohexyl)-3,4-dimethoxy-O-(4-methylphenyl)-thio 0836. When the improvement is made by use of an excipi benzeneacetonitrile, 4-4-chloro-1-(4-methylphenyl)thio ent, the excipient can be, but is not limited to, an excipient butyl-1,2-dimethoxybenzene, 4-6-bromo-1-(4- selected from the group consisting of: methylphenyl)thiohexyl-1,2-dimethoxybenzene, C-3,4- 0837 (a) mannitol; dimethoxyphenyl)-3-(hydroxymethyl)-O-(4-methylphenyl) 0838 (b) albumin; thiobenzenepropanenitrile, 3-(chloromethyl)-C.- 0839 (c) EDTA; (dimethoxyphenyl)-O-(4-methylphenyl)thio 0840 (d) sodium bisulfite: benzenepropanenitrile, 4-6-bromo-1-(4-methylphenyl) 0841 (e) benzyl alcohol: thioheptyl-1,2-dimethoxybenzene, 5-7-bromo-1-(4- 0842 (f) carbonate buffers: methylphenyl)thioheptyl-2-methoxy-phenoxy(1.2- 0843 (g) phosphate buffers; dimethylethyl)dimethylsilane, C.-(5-chloropentyl)-O- 0844 (h) PEG: (cyclohexylthio)-3,4-dimethoxybenzeneacetonitrile, C.-(5- 0845 (i) vitamin A; aminopentyl)-O-(cyclohexylthio)-3,4- 0846 () vitamin D; dimethoxybenzeneacetonitrile, 5-6-bromo-1-(4- 0847 (k) vitamin E: methylphenyl)thiohexyl-1,3-benzodioxole, 1-6-bromo-1- 0848 (1) esterase inhibitors; (methylphenyl)thiohexyl)-4-(trifluoromethoxy)benzene, 0849 (m) cytochrome P450 inhibitors; 1-6-bromo-1-(4-fluorophenyl)hexylthiol-4-methylben 0850 (n) multi-drug resistance (MDR) inhibitors; Zene, C.-(5-bromopentyl)-3,4-dimethoxy-O-(4-methylphe 0851 (o) organic resins; and nyl)-thiobenzeneacetonitrile, (7-bromo-1-phenylheptyl) 0852 (p) detergents. thiobenzene, C.-(5-bromopentyl)-O-(cyclohexylthio)-3,4- 0853 Suitable esterase inhibitors include, but are not lim dimethoxybenzeneacetonitrile, 7-bromo-2-(3,4- ited to, ebelactone A and ebelactone B. dimethoxyphenyl)-2-(2-pyridylthio)-heptanonitrile, and 0854) Suitable cytochrome P450 inhibitors include, but C.-(5-hydroxypentyl)-3,4-dimethoxy-O-(methylphenyl)- are not limited to, 1-aminobenzotriazole, N-hydroxy-N-(4- thiobenzeneacetic acid methyl ester. U.S. Pat. No. 6,372.775 butyl-2-methylphenyl)formamidine, ketoconazole, methox to Rabindran et al., incorporated by this reference, discloses salen, metyrapone, roquefortine C, proadifen, 2.3',4,5-tet the use of fumitremorgin A, B, and Cand diketopiperazines as ramethylstilbene, and troleandomycin. MDR inhibitors. 0855 Suitable MDR inhibitors include, but are not limited 0856 Suitable organic resins include, but are not limited to, 5'-methoxyhydnocarpin, INF240, INF271, INF277, INF to, a partially neutralized polyacrylic acid, as described in 392, INF 55, reserpine, and GG918. MDR inhibitors are U.S. Pat. No. 8,158,616 to Rodgers et al., incorporated herein described in M. Zloh & S. Gibbons, “Molecular Similarity of by this reference. MDR9 Inhibitors.” Int. J. Mol. Sci. 5:37-47 (2004), incorpo 0857 Suitable detergents include, but are not limited to, rated herein by this reference. Other MDR inhibitors, nonionic detergents such as a polysorbate or apoloxamer, and described therein as MDR reversal agents, suitable for use are described in PCT Patent Application Publication No. with bisantrene or a derivative or analog thereof, are disclosed WO/1997/039768 by Bjornet al., incorporated herein by this in U.S. Pat. No. 5,550,149 to Powell et al., U.S. Pat. No. reference. 5,561,141 to Powell et al., and U.S. Pat. No. 5,639,887 to 0858. When the improvement is made by use of a dosage Powell et al., all of which are incorporated herein by this form, the dosage form can be, but is not limited to, a dosage reference; these compounds are bicyclic amines including, form selected from the group consisting of: but not limited to, C.-(3,4-dimethoxyphenyl)-1,3-dihydro-5, 0859 (a) tablets; 6-dimethoxy-O-(4-methylphenyl)thiol-2H-isoindole-2- 0860) (b) capsules; heptanenitrile, 2-7-(3,4-dimethoxyphenyl)-7-(4-meth 0861 (c) topical gels: ylphenyl)thioheptyl-2,3-dihydro-5,6-dimethoxy-1H 0862 (d) topical creams: isoindole, 5.6 dichloro-O-(3,4-dimethoxyphenyl)-1,3- 0863 (e) patches: dihydro-O-(4-methylphenyl)thio-2-H-isoindole-2- 0864 (f) suppositories: heptanenitrile, C-(3,4-dimethoxyphenyl)-1,3-dihydro-5-2- 0865 (g) lyophilized dosage fills; (1H-imidazol-1-yl)ethoxy-6-methoxy-O-(4-methylphenyl) 0866 (h) immediate-release formulations; thiol-2H-isoindole-2-heptanenitrile dihydrochloride, C.-(3,4- 0867 (i) slow-release formulations: dimethoxyphenyl)-1,3-dihydro-5,6-dimethoxy-O-(4- 0868 () controlled-release formulations: methylphenyl)thio-2H-isoindole-2-heptanoic acid methyl 0869 (k) liquid in capsules; and ester, C.-(cyclohexylthio)-O-(3,4-dimethoxyphenyl)-1,3-di 0870 (1) liposomal formulations. US 2016/0220537 A1 Aug. 4, 2016 57

0871 Formulation of pharmaceutical compositions in tab gums, cellulose ethers, acrylic resins, protein derived mate lets, capsules, and topical gels, topical creams or Supposito rials, waxes, shellac, and oils such as hydrogenated castor oil ries is well known in the art and is described, for example, in or hydrogenated vegetable oil. However, any pharmaceuti United States Patent Application Publication No. 2004/ cally acceptable hydrophobic or hydrophilic controlled-re 0023290 by Griffin et al., incorporated herein by this refer lease material which is capable of imparting controlled-re CCC. lease of the amonafide or derivative or analog thereof may be 0872 Formulation of pharmaceutical compositions as used in accordance with the present invention. Preferred con patches Such as transdermal patches is well known in the art trolled-release polymers include alkylcelluloses such as eth and is described, for example, in U.S. Pat. No. 7,728,042 to ylcellulose, acrylic and methacrylic acid polymers and Eros et al., incorporated herein by this reference. copolymers, and cellulose ethers, especially hydroxyalkyl 0873 Lyophilized dosage fills are also well known in the celluloses (e.g., hydroxypropylmethylcellulose) and car art. One general method for the preparation of Such lyo boxyalkylcelluloses. Preferred acrylic and methacrylic acid philized dosage fills, applicable to dibromodulcitol and polymers and copolymers include methyl methacrylate, derivatives thereof, comprises the following steps: methyl methacrylate copolymers, ethoxyethyl methacrylates, 0874) (1) Dissolve the drug in water for injection pre cyanoethyl methacrylate, aminoalkyl methacrylate copoly cooled to below 10° C. Dilute to final volume with cold mer, poly(acrylic acid), poly(methacrylic acid), methacrylic water for injection to yield a 40 mg/mL Solution. acid alkylamine copolymer, poly(methyl methacrylate), poly 0875 (2) Filter the bulk solution through an 0.2-lum (methacrylic acid) (anhydride), polymethacrylate, polyacry filter into a receiving container under aseptic conditions. lamide, poly(methacrylic acid anhydride), and glycidyl meth The formulation and filtration should be completed in 1 acrylate copolymers. hour. 0886 Aliposomal formulation suitable for bisantrene or a derivative or analog thereof comprises Small unilamellar or 0876 (3) Fill nominal 1.0 mL filtered solution into ster multilamellar liposomes of size range between 0.01 and 100 ilized glass vials in a controlled target range under asep uM, and between about 50-95% liposome-entrapped bisant tic conditions. rene, composed of hydrogenated Soy phosphatidylcholine, 0877 (4) After the filling, all vials are placed with rub distearoyl phosphatidylglycerol, and cholesterol of natural or ber stoppers inserted in the “lyophilization position' and synthetic origin lipids, in aqueous solution which can be loaded in the pre-chilled lyophilizer. For the lyophilizer, reconstituted from a lyophilized form to an injectable lipo shelf temperature is set at +5° C. and held for 1 hour; Some Suspension. The composition is prepared by reconsti shelf temperature is then adjusted to -5°C. and held for tuting a lyophilized bisantrenefliposome composition to a one hour, and the condenser, set to -60° C., turned on. liposome concentrate, then diluting the concentrate for 0878 (5) The vials are then frozen to 30° C. or below parenteral administration for the treatment of cancer. and held for no less than 3 hours, typically 4 hours. 0887 When the improvement is made by use of dosage 0879 (6) Vacuum is then turned on, the shelf tempera kits and packaging, the dosage kits and packaging can be, but ture is adjusted to -5°C., and primary drying is per are not limited to, dosage kits and packaging selected from formed for 8 hours; the shelf temperature is again the group consisting of the use of amber vials to protect from adjusted to -5°C. and drying is carried out for at least 5 light and the use of stoppers with specialized coatings to hours. improve shelf-life stability. Other forms of dosage kits and 0880 (7) Secondary drying is started after the con packaging are also known in the art and can include, for denser (set at -60° C.) and vacuum are turned on. In example, vials, ampules, jars, intravenous bags, or other con secondary drying, the shelf temperature is controlled at tainers. +5°C. for 1 to 3 hours, typically 1.5 hours, then at 25°C. 0888. When the improvement is made by use of a drug for 1 to 3 hours, typically 1.5 hours, and finally at 35-40° delivery system, the drug delivery system can be, but is not C. for at least 5 hours, typically for 9 hours, or until the limited to, a drug delivery system selected from the group product is completely dried. consisting of: 0881 (8) Break the vacuum with filtered inert gas (e.g., 0889 (a) oral dosage forms: nitrogen). Stopper the vials in the lyophilizer. (0890 (b) nanocrystals; 0882 (9) Vials are removed from the lyophilizer cham 0891 (c) nanoparticles: ber and sealed with aluminum flip-offseals. All vials are (0892) (d) cosolvents: visually inspected and labeled with approved labels. (0893 (e) slurries: 0883. Immediate-release formulations are described in (0894 (f) syrups: U.S. Pat. No. 8,148,393 to van Dalen et al., incorporated (0895 (g) bioerodible polymers: herein by this reference. Immediate-release formulations can (0896 (h) liposomes: include, for example, conventional film-coated tablets. 0897 (i) slow-release injectable gels: 0884 Slow-release formulations are described in U.S. Pat. (0898) () microspheres: No. 8,178,125 to Wen et al., incorporated herein by this 0899 (k) amphiphilic block copolymer systems; reference. Slow-release formulations can include, for 0900 (1) emulsion vehicles comprising an emulsion of example, microemulsions or liquid crystals. C-tocopherol stabilized by biocompatible surfactants; 0885 Controlled-release formulations are described in 0901) (m) biodegradable polymer compositions con U.S. Pat. No. 8,231,898 to Oshlacket al., incorporated herein taining phosphorus and desaminotyrosyl L-tyrosine by this reference. Controlled-release formulations can linkages in the polymer backbone; include, for example, a matrix that includes a controlled 0902 (n) substantially anhydrous injectable semi-solid release material. Such a controlled-release material can compositions comprising a water immiscible fatty acid include hydrophilic and/or hydrophobic materials, such as matrix and a cytostatic agent; US 2016/0220537 A1 Aug. 4, 2016 58

(0903 (o) lipophilic vehicles: N-methylglucamide; n-nonanoyl B-D-glucopyranoside; 0904 (p) pH-dependent carriers that include a com octanoyl-N-methylglucamide; n-octyl B-D-glucopyranoside; pound that includes at least one ionizable group; and octyl B-D-thioglucopyranoside. 0905 (q) pH-dependent carriers that include a mono 0910 Pharmaceutically acceptable cosolvents are carboxylic acid having at least 8 carbons and less than described in U.S. Pat. No. 8,207,195 to Navratil et al., incor about 10% by weight of Zwitterionic phospholipids; porated herein by this reference, and include, but are not 0906 (r) liposomes comprising the bisantrene or the limited to, water, methanol, ethanol. 1-propanol, isopropanol, derivative or analog thereof followed by administration 1-butanol, isobutanol, t-butanol, acetone, methyl ethyl of a lipid nanoparticle comprising a triggering agent; ketone, acetonitrile, ethyl acetate, benzene, toluene, Xylene and (S), ethylene glycol, dichloromethane, 1,2-dichloroethane, 0907 (s) nonpegylated liposomes. N-methylformamide, N,N-dimethylformamide, N-methy (0908 Nanocrystals are described in U.S. Pat. No. 7,101, lacetamide, pyridine, dioxane, and diethyl ether. 576 to Hovey et al., incorporated herein by this reference. 0911 Slurries for use in pharmaceutical formulations are 0909 Nanoparticles for drug delivery are described in described in United States Patent Application Publication No. U.S. Pat. No. 8.258,132 to Bosch et al., incorporated herein 2006/0229277 by Laxminarayan, incorporated herein by this by this reference. Typically, Such nanoparticles have an aver reference. age particle size of the active ingredient of less than about 0912 Syrups for use in pharmaceutical formulations are 1000 nm, more preferably, less than about 400 nm, and most described in U.S. Pat. No. 8.252,930 to Stoit et al., incorpo preferably, less than about 250 nm. The nanoparticles can be rated herein by this reference. Such syrups can include the coated with a surface stabilizer, such as, but not limited to, active ingredient and a syrup-forming component such as gelatin, casein, lecithin (phosphatides), dextran, gum acacia, Sugar or Sugar alcohols and a mixture of ethanol, water, glyc cholesterol, tragacanth, Stearic acid, benzalkonium chloride, erol, propylene glycol and polyethylene glycol. If desired, calcium Stearate, glycerol monostearate, cetostearyl alcohol, Such liquid preparations may contain coloring agents, flavor cetomacrogol emulsifying wax, Sorbitan esters, polyoxyeth ing agents, preservatives, saccharine and carboxymethyl cel ylene alkyl ethers (e.g., macrogol ethers such as cetomac lulose or other thickening agents. rogol 1000), polyoxyethylene castor oil derivatives, polyoxy (0913 Bioerodible polymers are described in U.S. Pat. No. ethylene Sorbitan fatty acid esters (e.g., the commercially 7.318.931 to Okumu et al., incorporated herein by this refer available Tweens(R such as e.g., Tween 20R) and Tween 80R ence. A bioerodible polymer decomposes when placed inside (ICISpeciality Chemicals); polyethylene glycols (e.g., Car an organism, as measured by a decline in the molecular bowaxes 3550R) and 934(R) (Union Carbide)), polyoxyethyl weight of the polymer over time. Polymer molecular weights ene Stearates, colloidal silicon dioxide, phosphates, sodium can be determined by a variety of methods including size dodecylsulfate, carboxymethylcellulose calcium, carboxym exclusion chromatography (SEC), and are generally ethylcellulose sodium, methylcellulose, hydroxyethylcellu expressed as weight averages or number averages. A polymer lose, hydroxypropylcellulose, hydroxypropylmethyl-cellu is bioerodible if, when in phosphate buffered saline (PBS) of lose, hydroxypropylmethyl-cellulose phthalate, pH 7.4 and a temperature of 37° C., its weight-average noncrystalline cellulose, magnesium aluminium silicate, tri molecular weight is reduced by at least 25% over a period of ethanolamine, polyvinyl alcohol (PVA), polyvinylpyrroli 6 months as measured by SEC. Useful bioerodible polymers done (PVP), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer include polyesters, such as poly(caprolactone), poly(glycolic with ethylene oxide and formaldehyde (also known as tylox acid), poly(lactic acid), and poly(hydroxybutryate); polyan apol, Superione, and triton), poloxamers (e.g., Pluronics hydrides, such as poly(adipic anhydride) and poly(maleic F68(R) and F108(R), which are block copolymers of ethylene anhydride); polydioxanone; polyamines; polyamides; poly oxide and propylene oxide); poloxamines (e.g., Tetronic urethanes; polyesteramides; polyorthoesters; polyacetals; 908(R), also known as Poloxamine 908R, which is a tetrafunc polyketals; polycarbonates; polyorthocarbonates; polyphos tional block copolymer derived from sequential addition of phaZenes; poly(malic acid); poly(amino acids); polyvi propylene oxide and ethylene oxide to ethylenediamine nylpyrrolidone; poly(methyl vinyl ether); poly(alkylene (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic oxalate); poly(alkylene Succinate); polyhydroxycellulose; 1508(R) (T-1508) (BASF Wyandotte Corporation), dialkylest chitin; chitosan; and copolymers and mixtures thereof. ers of sodium sulfosuccinic acid (e.g., Aerosol OTR), which is a dioctyl ester of Sodium Sulfo Succinic acid (American 0914 Liposomes are well known as drug delivery Cyanamid)), dioctyl sodium sulfosuccinate (DOSS), docu vehicles. Liposome preparation is described in European sate sodium (Ashland Chem. Co., Columbus, Ohio); Duponol Patent Application Publication No. EP 1332755 by Wenget P(R), which is a sodium lauryl sulfate (DuPont); Triton al., incorporated herein by this reference. Nonpegylated lipo X-200R, which is an alkyl aryl polyether sulfonate (Rohm somes for drug delivery, specifically delivery of doxorubicin, and Haas); Crodestas F-110R, which is a mixture of sucrose are described in J. Baselga et al., “Phase III Trial of Nonp Stearate and Sucrose distearate (Croda Inc.), p-isononylphe egylated Liposomal Doxorubicin in Combination with Tras noxy-poly-(glycidol), also known as Olin-IOG(R) or Surfac tuzumab and Paclitaxel in HER2-Positive Metastatic Breast tant 10-G(R) (Olin Chemicals, Stamford, Conn.); Crodestas Cancer.” Ann. Oncol. 25: 592-598 (2014), incorporated SL-40R (Croda, Inc.); and SA90HCO, which is CHCH herein by this reference. (CON(CH) OCH (CHOH)(CHOH), (Eastman Kodak 0915 Slow release injectable gels are known in the art and Co.); decanoyl-N-methylglucamide; n-decyl B-D-glucopyra are described, for example, in B. Jeong et al., “Drug Release noside; n-decyl B-D-maltopyranoside; n-dodecyl B-D-glu from Biodegradable Injectable Thermosensitive Hydrogel of copyranoside; n-dodecyl B-D-maltoside; heptanoyl-N-me PEG-PLGA-PEG Triblock Copolymers,” J. Controlled thyl-glucamide; n-heptyl-B-D-glucopyranoside; n-heptyl Release 63: 155-163 (2000), incorporated herein by this ref B-D-thioglucoside; n-hexyl B-D-glucopyranoside; nonanoyl CCC. US 2016/0220537 A1 Aug. 4, 2016 59

0916. The use of microspheres for drug delivery is known about 60 carbonatoms, usually not more than about 50 carbon in the art and is described, for example, in H. Okada & H. atoms. Of particular interest are glycerides having fatty acids Taguchi. “Biodegradable Microspheres in Drug Delivery.” offrom about 12 to 24 carbonatoms, saturated or unsaturated, Crit. Rev. Ther. Drug Carrier Sys. 12: 1-99 (1995), incorpo naturally occurring or synthetic. The alcohols will usually rated herein by this reference. have from about 1 to 6, usually 1 to 5, more usually 1 to 3 0917. Another drug delivery system potentially usable hydroxyl groups and not more than two ether groups and will with bisantrene and analogs and derivatives thereof is the usually be from 2 to 6, more usually 2 to 3 carbon atoms. The amphiphilic block copolymer system described in U.S. Pat. fatty acid esters of the subject invention will not include esters No. 7,311.901 to Seo et al., incorporated herein by this ref which are modified with additional functional groups which erence. In general, the amphiphilic block copolymer com increase the water Solubility properties of the esters, e.g. Such prises a hydrophilic block and a hydrophobic block with a as polyoxyethylated castor oil or other alkyleneoxy modified terminal hydroxyl group, wherein the terminal hydroxyl fatty acid esters. The fatty acid esters may be added as par group of the hydrophobic block is substituted with a toco tially pure fractions or complex mixtures Such as Saturated or pherol or cholesterol group. U.S. Pat. No. 7,311.901 to Seo et partially Saturated glycerides, e.g. oils and fats. Any carboxy al. further describes polymeric compositions capable of lic acid ester oil which is physiologically acceptable can be forming stable micelles in an aqueous solution, comprising employed as the matrix component, where the oil may be a the amphiphilic block copolymerand a polylactic acid deriva single or combination of oils, which may or may not be tive wherein one or both ends of the polylactic acid derivative partially hydrogenated. Specific physiologically acceptable are covalently bound to at least one carboxyl group. oils of interest include vegetable oils, such as sesame, peanut, 0918 Yet another drug delivery system potentially useful Soybean, cottonseed, corn, olive, persic, castor, and the like. with bisantrene and analogs and derivatives thereof is the 0921 Lipophilic vehicles are described in U.S. Pat. No. emulsion vehicle described in U.S. Pat. No. 6,485,383 to 7.148.211 to Mazess et al., incorporated herein by this refer Lambert et al., incorporated herein by this reference. In gen ence. These lipophilic vehicles include polysorbate 20 as a eral, this emulsion vehicle comprises an emulsion of C-toco non-ionic Solubilizer, butylated hydroxytoluene as a lipo pherol stabilized by biocompatible surfactants. Also included philic antioxidant, optionally, ethanol, and an aqueous in the emulsion is pegylated vitamin E. Pegylated C-toco vehicle. Other alcohols or polyols can be used in place of or pherol includes polyethylene glycol Subunits attached by a together with ethanol. Other non-ionic solubilizers can be Succinic acid diester at the ring hydroxyl of vitamin E and used. Other lipophilic antioxidants can be used. serves as a primary surfactant and a stabilizer as well as a 0922. The use of pH-dependent carriers that include a secondary solvent in emulsions of C-tocopherol. compound that includes at least one ionizable group is dis 0919. Yet another drug delivery system potentially useful closed in United States Patent Application Publication No. with bisantrene and analogs and derivatives thereof are the 2014/0094526 by Marathi et al. The at least one ionizable biodegradable polymer compositions described in U.S. Pat. group can be a carboxylic acid group, hydroxy group, amino No. 6,238.687 to Mao et al., incorporated herein by this group, amide groups, or other similarly ionizable groups. The reference. These polymers contain phosphorus and desami carriers are immiscible in water or soluble in oils, and, for notyrosyl L-tyrosine linkages in the polymer backbone. weak acids, the ionizable groups have a pKa value greater 0920 Yet another drug delivery system potentially useful than or equal to about pH 3.5. with bisantrene and analogs and derivatives thereof are the 0923. The use of pH-dependent carriers that include a pharmaceutically acceptable Substantially anhydrous inject monocarboxylic acid having at least 8 carbons and less than able semi-solid compositions described in U.S. Pat. No. about 10% by weight of Zwitterionic phospholipids is dis 5,573,781 to Brown et al., incorporated herein by this refer closed in United States Patent Application Publication No. ence. The compositions comprise a water immiscible fatty 2014/0094439 by Marathi et al. acid matrix and a cytostatic agent, Such as bisantrene or a 0924. The use of liposomes comprising the bisantrene or derivative or analog thereof. Typically, the matrix material the derivative or analog thereof followed by administration of will be fatty acid ester compositions, having the desired flow a lipid nanoparticle comprising a triggering agent is disclosed able and Viscosity characteristics, either as a natural charac in PCT Patent Application Publication No. WO 2013/066903 teristic or as a result of additives. Suitable lipid compositions by Yang et al. The triggering agent can be non-ionic, such as will comprise fatty acid esters, either a single fatty acid ester TPGS or polyoxyethylene stearate. or a mixture of fatty acid esters, which are biodegradable in 0925. When the improvement is made by use of a drug the host, by themselves or in combination with one or more conjugate form, the drug conjugate form can be, but is not physiologically acceptable thickening agents, particularly limited to, a drug conjugate form selected from the group fatty acid salts or synthetic and/or longer chain fatty acid consisting of: esters, e.g. waxy esters. Suitable fatty acid ester compositions 0926 (a) a polymer system; will comprise a single or mixture offatty acid esters, and may 0927 (b) polylactides; comprise two or more different fatty acid esters, usually not 0928 (c) polyglycolides; more than ten different fatty acid esters. Suitable fatty acid 0929 (d) amino acids: esters include mono-, di- and tri-glycerides, as well as mono and dibasic acid esters, e.g. ethyl oleate, isopropyl myristate, 0930 (e) peptides; or other such esters, where the carboxylic acid group will 0931 (f) multivalent linkers: usually have at least 6, more usually at least 8 carbon atoms, 0932 (g) conjugates to fatty acids: preferably at least about 12 carbon atoms, and may be satu 0933 (h) conjugates to fatty alcohols; rated or unsaturated, usually having not more than 3 sites of 0934 (i) conjugates to elastin-like peptide; ethylenic unsaturation per acid moiety, and the fatty acid 0935 () conjugates with polyclonal or monoclonal esters will have at least 8 carbon atoms and not more than antibodies, proteins, or peptides; US 2016/0220537 A1 Aug. 4, 2016 60

0936 (k) conjugates with cell-binding agents through a decanoic; hexadecanoic (palmitic); heptadecanoic charged or pro-charged cross-linker, (margaric); octadecanoic (stearic); 12-hydroxy Stearic; nona 0937 (1) conjugates to antibodies targeted to tumor decanoic, eicosanoic (arachidic); heneicosanoic; docosanoic markers; (behenic); tricosanoic, tetracosanoic (lignoceric); 10-unde 0938 (m) biodegradable polymer-bioactive moiety cenoic (hendecenoic); 11-dodecenoic; 12-tridecenoic; 9-tet conjugates: radecenoic (myristoleic); 9-trans-tetradecenoic (myriste 0939 (n) conjugates with 2-nitroimidazole compounds laidic); 10-pentadecenoic, 10-trans-pentadecenoic; with a secondary basic nitrogen atom and a linker; 9-hexadecenoic (palmitoleic); 8-trans-hexadecenoic (palm 0940 (o) conjugates with ladder frame polyether com itelaidic); 10-heptadecenoic, 10-trans-heptadecenoic, 6-oc pounds, including those derived from brevenal, brevisin, tamulamide, brevetoxins, hemibrevetoxins, gambierols, tadecenoic (petroselinic), 6-trans-octadecenoic (petrose and gambieric acids; laidic); 8-octadecenoic (oleic): 9-11-octadecenoic 0941 (p) conjugates to antibodies having one or more (vaccenic); 11-trans-octadecenoic (transvaccenic); 9-cis-12 non-natural amino acid residues at specific positions in hydroxy-octadecenoic (ricinoleic); 9-trans-12-hydroxy-octa the heavy or light chains; decenoic (ricinelaidic); 7-nonadecenoic; 7-trans-nonade 0942 (q) conjugates to a sialoadhesin binding moiety; cenoic, 10-nonadecenoic, 10-trans-nonadecenoic, 10-13 0943 (r) pheophorbide-C conjugates; nonadecadienoic, 10-13-trans-nonadecadienoic, 8-12 0944 (s) conjugates to multi-component nanochains: octadecadienoic (linoleic); 9-trans-12-trans octadecadienoic 0945 (t) conjugates to activatable antibodies that (linoelaidic); octadecadienoic (conjugated): 9-12-15-octade include a masking moiety, a cleavable moiety, and an catrienoic (linolenic), 6-9-12-octadecatrienoic (Y-linolenic); antibody binding specifically to interleukin-6: 11-trans-eicosenoic, 8-eicosenoic, 11-eicosenoic; 5-eicose 0946 (u) conjugates including hydrophilic linkers; noic; 11-14-eicosadienoic, 8-11-14-eicosatrienoic (homo-y- 0947 (v) conjugates to antibodies specific for p97; linolenic); 11-14-17-eicosatrienoic; 5-8-11-14-eicosatet 0948 (w) conjugates including a modified amino acid raenoic (arachidonic); 5-8-11-14-17-eicosapentaenoic; 7-10 incorporating an azido group; 13-16-19-docosapentaenoic: 13-docosenoic (erucic); 0949 (x) conjugates to albumin; and 13-transdocosenoic (brassidic); 13-16-docosadienoic; 0950 (y) conjugates to folate. 13-16-19-docosatrienoic, 7-10-13-16-docosatetraenoic, 4-7- 0951 Polylactide conjugates are well known in the art and 10-13-16-19-docosahexaenoic (docosahexaenoic; DHA); are described, for example, in R. Tong & C. Cheng, "Con 12-heneicosenoic, 12-15-heneicosadienoic; 14-tricosenoic; trolled Synthesis of Camptothecin-Polylactide Conjugates and 15-tetracosenoic (nervonic). and Nanoconjugates. Bioconjugate Chem. 21: 111-121 0956 Conjugates to elastin-like peptides are described in (2010), incorporated by this reference. U.S. Pat. No. 8,252.740 to Raucher et al., incorporated herein 0952 Polyglycolide conjugates are also well known in the by this reference. Delivery by these conjugates is thermally art and are described, for example, in PCT Patent Application activated. In one alternative, the conjugate comprises: (i) the Publication No. WO 2003/070823 by Elmaleh et al., incor cell-penetrating peptide Tat; (ii) an elastin-like peptide for porated herein by this reference. thermal targeting; (iii) a GFLG (SEQID NO: 12) peptide as 0953. Multivalent linkers are known in the art and are a cleavable linker; (iv) a cysteine residue; and (v) bisantrene described, for example, in United States Patent Application or a derivative of bisantrene. Publication No. 2007/0207952 by Silva et al., incorporated herein by this reference. For example, multivalent linkers can 0957 Conjugates with polyclonal or monoclonal antibod contain a thiophilic group for reaction with a reactive cys ies, proteins, or peptides are disclosed in U.S. Pat. No. 8,389, teine, and multiple nucleophilic groups (such as NH or OH) 697 to Beria et al., incorporated herein by this reference. or electrophilic groups (such as activated esters) that permit These compounds incorporating bisantrene or a derivative or attachment of a plurality of biologically active moieties to the analog of bisantrene are characterized by the general formula: linker. Bis-L-Z-T, 0954 Conjugates to fatty acids are described in U.S. Pat. No. 7,235,538 to Webb et al., incorporated herein by this wherein: (i) Bis is a residue of bisantrene or a derivative or reference. The fatty acid is preferably a C-C unbranched analog thereof; (ii) L is a linker; (iii) Z is a spacer; (iv) m is an fatty acid such as caprylic acid, capric acid, lauric acid, myris integer from 1 to 30; and (v) T is a carrier Such as a protein, tic acid, palmitic acid, palmitoleic acid, Stearic acid, oleic peptide, monoclonal or polyclonal antibody or a chemically acid, vaccinic acid, linoleic acid, C-linolenic acid, eleostearic modified moiety thereof suitable to be attached to the Bis acid, B-linolenic acid, gondoic acid, dihomo-y-linolenic acid, L-Z moiety or moieties, or a polymeric character. In these arachidonic acid, eicopentaenoic acid, docosenoic acid, conjugates, the linker L is typically is —CHO— —N(R), docosatetraenoic acid, docosapentaenoic acid, docosa (C-C2 alkylene)-X'. - N(R)-, -N(R), (C-C2 alky hexaenoic acid, and nervonic acid. lene)-, —N(R), (C-C alkenylene)-, N(R)(CH2CH2O), . 0955 Conjugates to fatty alcohols are disclosed in U.S. or the structures Pat. No. 7,816,398 to Swindell et al., incorporated herein by this reference. The fatty alcohol conjugates have the general structure RO C(O)—OX, where X is an antineoplastic agent moiety of an antineoplastic agent XOH, R is a Cs—O. fatty acid group of a fatty alcohol ROH wherein R is one of the A-N- following fatty acids: octanoic (caprylic); nonanoic (pelar gonic); decanoic (capric); undecanoic (hendecanoic); dode canoic (lauric); tridecanoic, tetradecanoic (myristic); penta US 2016/0220537 A1 Aug. 4, 2016 61

can be, but is not limited to, a tertiary, quaternary, or primary amine or a nitrogen-containing heterocycle; (ii) a group. Such as, but not limited to, a N-hydroxySuccinimide ester, male imido group, haloacetyl group, or hydrazide group, capable /-cry of reaction with a cell-binding agent; and (iii) a group. Such as, but not limited to, disulfide, maleimide, haloacetyl, or hydrazide, capable of reaction with a drug. Other groups can, alternatively, be used as the groups capable of reaction with the cell-binding agent and the drug. The cross-linker may include a phenyl or Substituted phenyl moiety or an optional O polyethyleneoxy group. The cell-binding agent can be, for example, antibodies (including monoclonal antibodies or antibody fragments), adnectins, interferons, lymphokines, where the wavy lines indicate the attachments to Bis and Z: Z hormones, growth factors, vitamins, nutrient-transport mol is an optional spacer selected from —CHC(O)—, —CH2C ecules Such as transferrin, or any other cell-binding agent. (O)NR(C-C alkylene)-, and the structures 0959 Conjugates to antibodies targeted to tumor markers, in Some cases with an amino-dextran intermediate carrier, are described in L. B. Shih et al., “Anthracycline Immunoconju gates Prepared by a Site-Specific Linkage via an Amino Dextran Intermediate Carrier Cancer Res. 51: 4192-4198 (1991), incorporated herein by this reference. In the proce dure described in this reference, the drug is first conjugated to amino-dextran and the conjugate to the drug with amino dextran is then attached using site-specific attachment to the antibody. Other conjugation procedures for linking therapeu tic agents such as bisantrene or a derivative or analog thereof are known in the art. 0960 Biodegradable polymer-bioactive moiety conju gates are disclosed in U.S. Pat. No. 8,535,655 to O'Sheaetal. The releasable bioactive moieties being pendant from and covalently bonded to the biodegradable polymer backbone; X is a reactive functional group selected from maleimide, the biodegradable polymer backbone is formed from mono thiol, amino, bromide, p-toluenesulfonate, iodide, hydroxyl, meric units that are each coupled via a biodegradable moiety, carboxyl, pyridyl disulfide, and N-hydroxysuccinimide: R is and the bioactive moieties are capable of being released at a hydrogen, C-C2 alkyl, or Co-Co aryl; R' and Rare inde rate equal to or faster than the rate of biodegradation of the pendently selected from an amino acid side chain: Z' is polymer backbone. Typically, the copolymer is formed with selected from —S , —CHC(O)— —(CH2CH2O), CHC at least one polyisocyanate, and the polyisocyanate is selected (O)— —(CH2CH2O)CH2—, and —(C-C alkylene)-; m from the group consisting of m-phenylene diisocyanate, is 0 or 1; n is 1; and T is a carrier moiety as described below. p-phenylene diisocyanate, 2,4-toluene diisocyanate, 2,6-tolu Carrier moieties may be derived from polyclonal antibodies ene diisocyanate, 1.6-hexamethylene diisocyanate, 1,4-hex raised against tumor associated antigens; or from monoclonal amethylene diisocyanate, 1.3-cyclohexane diisocyanate, 1,4- antibodies binding to antigens preferentially or selectively cyclohexane diisocyanate, hexahydro-toluene diisocyanate expressed on tumor cell populations; or from natural or and its isomers, isophorone diisocyanate, dicyclo-hexyl recombinant peptides or proteins or growth factors preferen methane diisocyanates, 1.5-napthylene diisocyanate, 4,4'- tially or selectively binding to tumor cells; or from natural or diphenylmethane diisocyanate, 2,4'-diphenylmethane diiso synthetic polymeric carriers such as polylysine, polyglutamic cyanate, 4,4'-biphenylene diisocyanate, 3,3'-dimethoxy-4,4'- acid, polyaspartic acid and their analogues and derivatives, or biphenylene diisocyanate, 3,3'-dimethyl-diphenylpropane-4, Such as dextran or other polymeric carbohydrate analogues 4'-diisocyanate, 2.4.6-toluene triisocyanate, 4,4'-dimethyl and their derivatives; or from Synthetic copolymers such as diphenylmethane-2.2.5.5'-tetraisocyanate, and alkyl esters those derived from N-(2-hydroxypropyl)methacrylamide of lysine diisocyanate. (HPMA), or from poly(amino acid) copolymers such as poly (GluNa, Ala, Tyr) which are useful as targetable drug-carriers 0961 Conjugates with 2-nitroimidazole compounds with for lung tissue. The carrier portion may be also derived from a secondary basic nitrogen atom and a linker are disclosed in portions of the above mentioned peptides or proteins obtained U.S. Pat. No. 8,518,371 to Lee et al. through recombinant DNA techniques. 0962 Conjugates with ladder frame polyether compounds 0958 Conjugates with cell-binding agents through a are disclosed in United States Patent Application Publication charged or pro-charged cross-linker are disclosed in United No. 2014/00736.04 by Bourdelais et al. The polyether com States Patent Application Publication No. 2009/0274713 by pounds can be derived from brevenal, brevisin, tamulamide, Chari et al., incorporated herein by this reference. In general, brevetoxins, hemibrevetoxins, gambierols, and gambieric the cross-linkers possess three elements: (i) a Substituent that acids. is either charged or that will become charged when a conju 0963 Conjugates to antibodies having one or more non gate employing the cross-linker is metabolized in Vivo: the natural amino acid residues at specific positions in the heavy charge can be either anionic, which can be, but is not limited or light chains are disclosed in United States Patent Applica to, carboxylate, Sulfonate, or phosphate, or cationic, which tion Publication No. 2014/0046030 by Thanos et al. US 2016/0220537 A1 Aug. 4, 2016 62

0964 Conjugates to a sialoadhesin binding moiety are 146-150, incorporated herein by this reference. The reactivity disclosed in United States Patent Application Publication No. of the cysteine residues can be optimized by appropriate 2013/0273080 by Elewaut et al. The sialoadhesin binding selection of the neighboring amino acid residues. For moiety can be an antibody, or a fragment thereof, a siaload example, a histidine residue adjacent to the cysteine residue hesin ligand or a small molecule. The antibody can be a will increase the reactivity of the cysteine residue. Other monoclonal antibody. Sialoadhesin ligands can be natural combinations of reactive amino acids and electrophilic sialylated ligands for sialoadhesin, including CD43, galac reagents are known in the art. For example, maleimides can tose-type C-type lectin 1, and MUC1 antigen. react with amino groups, such as the e-amino group of the side 0965 Pheophorbide-C. conjugates are disclosed in United chain of lysine, particularly at higher pH ranges. Aryl halides States Patent Application Publication No. 2013/0210756 by can also react with Such amino groups. Haloacetyl derivatives Kim et al. The conjugates typically include a chemical linker, can react with the imidazolyl side chain nitrogens of histidine, including, but not limited to, a hydroxycinnamoyl moiety or the thioether group of the side chain of methionine, and the an aminobenzyloxycarbonyl moiety. .epsilon.-amino group of the side chain of lysine. Many other 0966 Conjugates to multi-component nanochains are dis electrophilic reagents are known that will react with the closed in PCT Patent Application Publication No. WO 2013/ e-amino group of the side chain of lysine, including, but not 056092 by Karathanasis et al. The multicomponent limited to, isothiocyanates, isocyanates, acyl azides, N-hy nanochains can include at least three nanoparticles linked droxysuccinimide esters, Sulfonyl chlorides, epoxides, together to form the nanochain. The nanochain can be linked oxiranes, carbonates, imidoesters, carbodiimides, and anhy to the bisantrene or analog or derivative thereof. drides. These are described in G. T. Hermanson, “Bioconju 0967 Conjugates including activatable antibodies that gate Techniques' (Academic Press, San Diego, 1996), pp. include a masking moiety, a cleavable moiety, and an anti 137-146, incorporated herein by this reference. Additionally, body binding specifically to interleukin-6 are disclosed in electrophilic reagents are known that will react with carboxy PCT Patent Application Publication No. WO 2014/052462 by late side chains such as those of aspartate and glutamate. Such West et al. The activatable antibody can include one or two as diaZoalkanes and diazoacetyl compounds, carbony diimi linking peptides. dazole, and carbodiimides. These are described in G. T. Her 0968. The use of conjugates including hydrophilic linkers manson, “Bioconjugate Techniques' (Academic Press, San is disclosed in PCT Patent Application Publication No. WO Diego, 1996), pp. 152-154, incorporated herein by this refer 2014/080251 by Zhao. ence. Furthermore, electrophilic reagents are known that will 0969. The use of conjugates including antibodies specific react with hydroxyl groups such as those in the side chains of for p97 is disclosed in PCT Patent Application Publication serine and threonine, including reactive haloalkane deriva No. WO 2013/006706 by Hutchison et al. tives. These are described in G.T. Hermanson, “Bioconjugate 0970. The use of conjugates including a modified amino Techniques.” (Academic Press, San Diego, 1996), pp. 154 acid incorporating an azido group is disclosed in PCT Patent 158, incorporated herein by this reference. In another alter Application Publication No. WO 2014/036492 by Stafford et native embodiment, the relative positions of electrophile and al. The conjugates can include an antibody. The use of con nucleophile (i.e., a molecule reactive with an electrophile) are jugates to albumin is disclosed in F. Kratz. “DOXO-EMCH reversed so that the protein has an amino acid residue with an (INNO-206): The First Albumin-Binding Prodrug of Doxo electrophilic group that is reactive with a nucleophile and the rubicin to Enter Clinical Trials. Expert Opin. Invest. Drugs targeting molecule includes therein a nucleophilic group. 16: 855-866 (2007), incorporated herein by this reference. This includes the reaction of aldehydes (the electrophile) with Such conjugates can include 6-maleimidocaproyl hydrazone hydroxylamine (the nucleophile), described above, but is derivatives of bisantrene or derivatives or analogs thereof; the more general than that reaction; other groups can be used as 6-maleimidocaproyl hydrazone moiety binds selectively to electrophile and nucleophile. Suitable groups are well known the cysteine-34 amino acid residue of albumin via the male in organic chemistry and need not be described further in imide moiety. The bisantrene orderivative or analog thereof is detail. then released from the albumin carrier after cleavage of the 0972. Additional combinations of reactive groups for acid-sensitive hydraZone linker in the acidic environment of cross-linking are known in the art. For example, amino tumors. The use of conjugates linked to folate is disclosed in groups can be reacted with isothiocyanates, isocyanates, acyl J. Clarhaut et al., “A Galactosidase-Responsive Doxorubicin azides, N-hydroxysuccinimide (NHS) esters, sulfonyl chlo Folate Conjugate for Selective Targeting of Acute Myelog rides, aldehydes, glyoxals, epoxides, oxiranes, carbonates, enous Leukemia Blasts, Leukemia Res. 37: 948-955 (2013), alkylating agents, imidoesters, carbodiimides, and anhy incorporated herein by this reference. drides. Thiol groups can be reacted with haloacetyl or alkyl 0971 Suitable reagents for cross-linking many combina halide derivatives, maleimides, aziridines, acryloyl deriva tions of functional groups are known in the art. For example, tives, acylating agents, or other thiol groups by way of oxi electrophilic groups can react with many functional groups, dation and the formation of mixed disulfides. Carboxy groups including those present in proteins or polypeptides. Various can be reacted with diazoalkanes, diazoacetyl compounds, combinations of reactive amino acids and electrophiles are carbonyldiimidazole, carbodiimides. Hydroxyl groups can known in the art and can be used. For example, N-terminal be reacted with epoxides, oxiranes, carbonyldiimidazole, cysteines, containing thiol groups, can be reacted with halo N,N'-disuccinimidyl carbonate, N-hydroxysuccinimidyl gens or maleimides. Thiol groups are known to have reactiv chloroformate, periodate (for oxidation), alkyl halogens, or ity with a large number of coupling agents, such as alkyl isocyanates. Aldehyde and ketone groups can react with halides, haloacetyl derivatives, maleimides, aziridines, acry hydrazines, reagents forming Schiffbases, and other groups loyl derivatives, arylating agents such as aryl halides, and in reductive amination reactions or Mannich condensation others. These are described in G. T. Hermanson, “Bioconju reactions. Still other reactions suitable for cross-linking reac gate Techniques' (Academic Press, San Diego, 1996), pp. tions are known in the art. Such cross-linking reagents and US 2016/0220537 A1 Aug. 4, 2016

reactions are described in G. T. Hermanson, “Bioconjugate (3) a stabilizing group; and (4) optionally, a linker group not Techniques” (Academic Press, San Diego, 1996), incorpo cleavable by plasmin. In this prodrug arrangement, the oli rated herein by this reference. gopeptide is directly linked to the stabilizing group at a first 0973 When the improvement is made by use of a com attachment site of the oligopeptide and the oligopeptide is pound analog, the compound analog can be, but is not limited directly linked to the therapeutically active agent (i.e., amona to, a compound analog selected from the group consisting of fide or a derivative or analog of amonafide) or indirectly 0974 (a) alteration of side chains to increase or linked through the linker group to the therapeutically active decrease lipophilicity; agent at a second attachment site of the oligopeptide. The 0975 (b) addition of an additional chemical function stabilizing group hinders cleavage of the oligopeptide by ality to alter a property selected from the group consist enzymes present in whole blood. The prodrug incorporating ing of reactivity, electron affinity, and binding capacity; the therapeutically active agent is cleavable by plasmin. and 0988 Yet another potential prodrug system for bisantrene 0976) (c) alteration of salt form. and derivatives or analogs of bisantrene is the use of the drug 0977. When the improvement is made by use of a prodrug complex of U.S. Pat. No. 6,368.598 to D'Amico et al., incor system, the prodrug system can be, but is not limited to, a porated herein by this reference. In general, such a drug prodrug system selected from the group consisting of: complex comprises a targeting carrier molecule that is selec 0978 (a) the use of enzyme sensitive esters; tively distributed to a specific cell type or tissue containing the 0979 (b) the use of dimers: specific cell type; a linker which is acted upon by a molecule 0980 (c) the use of Schiffbases: that is present at an effective concentration in the environs of 0981 (d) the use of pyridoxal complexes: the specific cell type; and a therapeutically active agent to be 0982) (e) the use of caffeine complexes; delivered to the specific cell type, such as, in this application, 0983 (f) the use of plasmin-activated prodrugs: bisantrene or a derivative or analog of bisantrene. In one 0984 (g) the use of a drug targeting complex compris application, the cell type is cells of the prostate and the drug ing a targeting carrier molecule that is selectively dis complex is cleaved by the activity of prostate specific antigen tributed to a specific cell type or tissue containing the (PSA). specific cell type; a linker which is acted upon by a 0989. The use of a prodrug molecule comprising a conju molecule that is present at an effective concentration in gate of bisantrene or a derivative or analog of bisantrene, a the environs of the specific cell type; and a therapeuti protease-specific cleavable peptide, and optionally, a target cally active agent to be delivered to the specific cell type: ing peptide, with the prodrug molecule being Substantially and inactive prior to degradation of the protease-specific cleav 0985 (h) the use of a prodrug molecule comprising a able peptide by a proteolytic enzyme within or in close proX conjugate of bisantrene or a derivative or analog of imity to the cancer cell is described in U.S. Pat. No. 8.314,060 bisantrene, a protease-specific cleavable peptide, and to Gengrinovitch, incorporated herein by this reference. optionally, a targeting peptide, with the prodrug mol 0990 When the improvement is made by use of a multiple ecule being Substantially inactive prior to degradation of drug system, the multiple drug system can be, but is not the protease-specific cleavable peptide by a proteolytic limited to, a multiple drug system selected from the group enzyme within or in close proximity to the cancer cell. consisting of the use of bisantrene or a derivative or analog of 0986 The use of prodrug systems is described in T. Järv amonafide with: inen et al., “Design and Pharmaceutical Applications of Pro 0991 (a) inhibitors of multi-drug resistance: drugs' in Drug Discovery Handbook (S. C. Gad, ed., Wiley 0992 (b) specific drug resistance inhibitors; Interscience, Hoboken, N.J., 2005), ch. 17, pp. 733-796, 0993 (c) specific inhibitors of selective enzymes; incorporated herein by this reference. This publication 0994) (d) signal transduction inhibitors; describes the use of enzyme sensitive esters as prodrugs. The 0995 (e) meiso indigo; use of dimers as prodrugs is described in U.S. Pat. No. 7.879, 0996 (f) imatinib: 896 to Allegretti et al., incorporated herein by this reference. 0997 (g) hydroxyurea; The use of peptides in prodrugs is described in S. Prasadet al., 0998 (h) dasatinib: “Delivering Multiple Anticancer Peptides as a Single Prodrug 0999 (i) capecitabine; Using Lysyl-Lysine as a Facile Linker. J. Peptide Sci. 13: 1000 () nilotinib: 458-467 (2007), incorporated herein by this reference. The 1001 (k) repair inhibition agents: use of Schiff bases as prodrugs is described in U.S. Pat. No. 1002 (1) topoisomerase inhibitors with non-overlap 7,619,005 to Epstein et al., incorporated herein by this refer ping side effects; ence. The use of caffeine complexes as prodrugs is described 1003 (m) PARP inhibitors: in U.S. Pat. No. 6,443,898 to Unger et al., incorporated herein 1004 (n) a taxane: by this reference. 1005 (o) cytarabine: 0987 Another potential prodrug system for bisantrene or 1006 (p) microtubule inhibitors; analogs or derivatives of bisantrene is the use of a plasmin 1007 (q) EGFR inhibitors; and activated prodrug as described in U.S. Pat. No. 7,402.556 to 1008 (r) HDAC inhibitors. Trouet et al., incorporated herein by this reference. In general, 1009 Multi-drug resistance inhibitors are described in these prodrugs comprise: (1) the therapeutically active agent U.S. Pat. No. 6,011,069 to Inomata et al., incorporated herein capable of entering a target cell, in this case, bisantrene or a by this reference. Verapamil and calcium influx blocking derivative or analog of bisantrene as described above; (2) an agents have this property and have been used for this purpose. oligopeptide having the formula X-Y, wherein X is a plasmin Additional multi-drug resistance inhibitors of particular util peptide Substrate of 2-4 amino acids and Y is a peptide frag ity for increasing the activity of antineoplastic drugs are ment comprising 1-2 amino acids having large side chains; described in U.S. Pat. No. 5,436.243 to Sachs et al., incorpo US 2016/0220537 A1 Aug. 4, 2016 64 rated herein by this reference, including aminoanthraquino 1011 Signal transduction inhibitors are described in A. V. nes, preferably 1.4bis(N-substituted anthraquinones). Addi Lee et al., “New Mechanisms of Signal Transduction Inhibi tional multi-drug resistance inhibitors of particular utility for tor Action: Receptor Tyrosine Kinase Down-Regulation and increasing the activity of antineoplastic drugs are also Blockade of Signal Transactivation.” Clin. Cancer Res. 9: described in U.S. Pat. No. 5,639,887 to Powell et al., incor 516s (2003), incorporated herein in its entirety by this refer porated herein by this reference, including the following ence. Signal transduction inhibitors can include, but are not compounds: C-(4-chlorobutyl)-3,4-dimethoxy-O-(4-meth limited to, BCL/ABL kinase inhibitors, epidermal growth ylphenyl)-thiobenzeneacetonitrile; C.-(3-chloro-2-methyl factor (EGF) receptor inhibitors, her-2/neu receptor inhibi propyl)-3,4-dimethoxy-O-(4-methyl-phenyl)thiobenzene tors, and farnesyl transferase inhibitors, as described in U.S. acetonitrile; C-(11-bromoundecyl)-3,4-dimethoxy-O-(4- Pat. No. 8,008,281 by Prendergast et al., incorporated herein methylphenyl)-thiobenzeneacetonitrile; C-(5- by this reference. 1012 Repair inhibition agents are described in N. M. Mar chloropentyl)-3,4-dimethoxy-O-(4-methylphenyl)-thio tin, “DNA Repair Inhibition and Cancer Therapy.J. Photo benzeneacetonitrile; C.-(5-bromooctyl)-3,4-dimethoxy-C.- chem. Photobiol. B 63: 162-170 (2001), incorporated herein (4-methylphenyl)-thiobenzeneacetonitrile; C-(5- by this reference. iodopentyl)-3,4-dimethoxy-O-(4-methylphenyl)-thio 1013 HDAC inhibitors are described in further detail benzeneacetonitrile; C-(5-aminopentyl)-3,4-dimethoxy-C.- below with respect to the use of bisantrene and derivatives or (4-methylphenyl)-thiobenzeneacetonitrile; C-(5- analogs thereof to inhibit DNA methylation. chlorohexyl)-3,4-dimethoxy-O-(4-methylphenyl)-thio 1014 When the improvement is made by biotherapeutic benzeneacetonitrile: 4-4-chloro-1-(4-methylphenyl)thio enhancement, the biotherapeutic enhancement can be per butyl-1,2-dimethoxybenzene: 4-6-bromo-1-(4- formed by use in combination as sensitizers/potentiators with methylphenyl)thiohexyl-1,2-dimethoxybenzene: C-3,4- atherapeutic agent or technique that can be, but is not limited dimethoxyphenyl)-3-(hydroxymethyl)-O-(4-methylphenyl) to, a therapeutic agent or technique selected from the group thiobenzenepropanenitrile; 1. 3-(chloromethyl)-C.- consisting of: (dimethoxyphenyl)-O-(4-methylphenyl)thio 1015 (a) biological response modifiers; benzenepropanenitrile; 4-6-bromo-1-(4-methylphenyl) 1016 (b) cytokines; thioheptyl-1,2-dimethoxybenzene: 5-7-bromo-1-(4- 1017 (c) lymphokines: methylphenyl)thioheptyl-2-methoxy-phenoxy(1.2- 1018 (d) therapeutic antibodies: dimethyl ethyl)dimethylsilane; C-(5-chloropentyl)-O- 1019 (e) antisense therapies; (cyclohexylthio)-3,4-dimethoxybenzeneacetonitrile; C-(5- 1020 (f) gene therapies; aminopentyl)-O-(cyclohexylthio)-3,4- 1021 (g) ribozymes; dimethoxybenzeneacetonitrile; 5-6-bromo-1-(4- 1022 (h) RNA interference: methylphenyl)thiohexyl-1,3-benzodioxole: 1-6-bromo-1- 1023 (i) vaccines (cellular and non-cellular); (methylphenyl)thiohexyl)-4-(trifluoromethoxy)benzene: 1024 () stem cells; and 1-6-bromo-1-(4-fluorophenyl)hexylthiol-4-methylben 1025 (k) autologous cell transplants. Zene; C-(5-bromopentyl)-3,4-dimethoxy-O-(4-methylphe 1026 Biological response modifiers are described in T. E. nyl)-thiobenzeneacetonitrile; (7-bromo-1-phenylheptyl) G. K. Murthy et al., “Biological Response Modifiers. Int. J. thiobenzene: C-(5-bromopentyl)-O-(cyclohexylthio)-3,4- Pharmtech Res. 2:2152-2160 (2010), incorporated herein by dimethoxybenzeneacetonitrile; 7-bromo-2-(3,4- this reference. dimethoxyphenyl)-2-(2-pyridylthio)-heptanonitrile; and 1027 Antisense therapies are described, for example, in C.-(5-hydroxypentyl)-3,4-dimethoxy-O-(methylphenyl)- B. Weiss et al., “Antisense RNA Gene Therapy for Studying thiobenzeneacetic acid methyl ester. U.S. Pat. No. 5,994,130 and Modulating Biological Processes. Cell. Mol. Life Sci. to Shyan, incorporated herein by this reference, discloses 55:334-358 (1999), incorporated herein by this reference. another multi-drug resistance protein, MRP-B and methods 1028 Ribozymes are described, for example, in S. Pas of inhibition thereof, including the use of antisense nucle colo, “RNA-Based Therapies” in Drug Discovery Handbook otides. United States Patent Application Publication 2002/ (S.C. Gad, ed., Wiley-Interscience, Hoboken, N.J., 2005), ch. 0156015 by Rabindran et al., incorporated herein by this 27, pp. 1273-1278, incorporated herein by this reference. reference, discloses agents that are capable of reversing mul 1029 RNA interference is described, for example, in S. tidrug resistance, including fumitremorgin A, fumitremorgin Pascolo, “RNA-Based Therapies’ in Drug Discovery Hand B, fumitremorgin C, and diketopiperazines. United States book (S. C. Gad, ed., Wiley-Interscience, Hoboken, N.J., Patent Application Publication No. 2007/0009535 by Sikic et 2005), ch. 27, pp. 1278-1283, incorporated herein by this al., incorporated herein by this reference, discloses P-glyco reference. protein efflux pump inhibitors such as ZoSuquidar, tariquidar, 1030. When the biotherapeutic enhancement is use in and tesmilifene. Still additional multidrug resistance inhibi combination as sensitizers/potentiators with a therapeutic tors are disclosed in United States Patent Application 2008/ antibody, the therapeutic antibody can be, but is not limited to, 0207738 by Kiss, incorporated herein by this reference, a therapeutic antibody selected from the group consisting of including 9H-xanthene-9-carboxylic acid-3-4-2-(4-trim bevacizumab (Avastin), rituximab (Rituxan), trastuzumab ethylsilanyl-methoxy-benzoyloxy)-ethyl-piperazin-1- (Herceptin), and cetuximab (Erbitux). yl)propyl ester dihydrochloride. 1031 Cancer vaccines are being developed. Typically, 1010 Specific drug resistance inhibitors are described in cancer vaccines are based on an immune response to a protein T. Hideshima et al., “The Proteasome Inhibitor PS-341 Inhib or proteins occurring in cancer cells that does not occur in its Growth, Induces Apoptosis, and Overcomes Drug Resis normal cells Such as, Oncophage for kidney cancer, tance in Human Multiple Myeloma Cells. Cancer Res.61: CimaVax-EGF for lung cancer, MOBILAN, Neuvenge for 3071-3076 (2001), incorporated herein by this reference. Her2/neu expressing cancers such as breast cancer, colon US 2016/0220537 A1 Aug. 4, 2016

cancer, bladder cancer, and ovarian cancer, Stimuvax for 1055) Hypoxic cell sensitizers are described in C. C. Ling breast cancer, and others. Cancer vaccines are described in S. et al., “The Effect of Hypoxic Cell Sensitizers at Different Pejawar-Gaddy & O. Finn, "Cancer Vaccines: Accomplish Irradiation Dose Rates.” Radiation Res. 109:396–406 (1987), ments and Challenges.” Crit. Rev. Oncol. Hematol. 67: incorporated herein by this reference. Radiation sensitizers 93-102 (2008), incorporated herein by this reference, by acti are described in T. S. Lawrence, "Radiation Sensitizers and Vating cells via autologous transplant such as Provenge, or via Targeted Therapies.” Oncology 17 (Suppl. 13) 23-28 (2003), checkpoint blockade, such as Ipilimumab. incorporated herein by this reference. Radiation protectors 1032 Therapeutic applications of the use of stem cells for are described in S. B. Vuyyuri et al., “Evaluation of D-Me the treatment of malignancies are also being developed. One thionine as a Novel Oral Radiation Protector for Prevention of avenue for the use of stem cells in the treatment of malignan Mucositis.” Clin. Cancer Res. 14: 2161-2170 (2008), incor cies involves the administration of stem cells to initiate porated herein by this reference. Photosensitizers are immuno-reconstruction following high dose chemotherapy described in R. R. Allison & C. H. Sibata, "Oncologic Pho or radiation. Typically, in this alternative, the stem cells used todynamic Therapy Photosensitizers: A Clinical Review. are hemopoietic stem cells (HSGs). This use of stem cells is Photodiagnosis Photodynamic Ther. 7: 61-75 (2010), incor described in J. Sagar et al., “Role of Stem Cells in Cancer porated herein by this reference. Radiation repair inhibitors Therapy and Cancer Stem Cells: A Review.” Cancer Cell and DNA repair inhibitors are described in M. Hingorani et Internat. 7:9 (2007), incorporated herein by this reference. al., “Evaluation of Repair of Radiation-Induced DNA Dam This may be particularly useful formalignancies affecting the age Enhances Expression from Replication-Defective Aden immune system, such as lymphomas. Another use of stem oviral Vectors.” Cancer Res.68:9771-9778 (2008), incorpo cells in cancer therapy is by targeting malignant cells directly rated herein by this reference. Thiol depleters are described in with stem cells. Stem cells have tumoritropic migratory prop K. D. Held et al., “Postirradiation Sensitization of Mamma erties, and can be modified by the insertion of transgenes with lian Cells by the Thiol-Depleting Agent Dimethyl Fumarate.” antitumor effects. Transgene effects can include direct tumor Radiation Res. 127:75-80 (1991), incorporated herein by this cell killing, promotion of local immune responses, oncolytic reference. Vaso-targeted agents are described in A. L. Seyn Virus production, and prodrug activation schemes. This use of haeve et al., "Tumor Necrosis Factor C. Mediates Homoge stem cells in cancer therapy is described in M. F. Corsten & K. neous Distribution of Liposomes in Murine Melanoma that Shah, "Therapeutic Stem-Cells for Cancer Treatment: Hopes Contributes to a Better Tumor Response.” Cancer Res. 67: and Hurdles in Tactical Warfare. Lancet Oncol. 9: 376-384 9455-9462 (2007), incorporated herein by this reference. (2008), incorporated herein by this reference. Bioreductive alkylating agents include tirapazamine, 1033. When the improvement is made by use of biothera described in W. A. Denny, "Prospects for Hypoxia-Activated peutic resistance modulation, the biotherapeutic resistance Anticancer Drugs.” Curr. Med. Chem. 4: 395-399 (2004), modulation can be, but is not limited to, use against tumors incorporated herein by this reference. Bioreductive alkylating resistant to a therapeutic agent or technique selected from the agents also include nitroimidazoles, such as metronidazole, group consisting of: tinidazole, and nimorazole, and other substituted nitrohetero 1034 (a) biological response modifiers: cycles, described in A. Mital. “Synthetic Nitroimidazoles: 1035 (b) cytokines; Biological Activities and Mutagenicity Relationships.” Sci. 1036) (c) lymphokines: Pharm. 77: 497-520 (2009) and in M. R. Juchau, “Bioactiva 1037 (d) therapeutic antibodies: tion in Chemical Teratogenesis.” Annu. Rev. Pharmacol. 1038 (e) antisense therapies; Toxicol. 29: 165-187 (1989). 1039 (f) gene therapies; 1056) When the improvement is made by use of a novel mechanism of action, the novel mechanism of action can be, 1040 (g) ribozymes; and but is not limited to, a novel mechanism of action that is a 1041 (h) RNA interference. therapeutic interaction with a target or mechanism selected 1042. When the biotherapeutic resistance modulation is from the group consisting of: use against tumors resistant to therapeutic antibodies, the 1057 (a) inhibitors of poly-ADP ribose polymerase: therapeuticantibody can be, but is not limited to, atherapeutic 1058 (b) agents that affect vasculature: antibody selected from the group consisting of bevacizumab 1059 (c) agents that promote vasodilation: (Avastin), rituximab (Rituxan), trastuzumab (Herceptin), and 1060 (d) oncogenic targeted agents: cetuximab (Erbitux). 1043. When the improvement is made by radiation therapy 1061 (e) signal transduction inhibitors: enhancement, the radiation therapy enhancement can be, but 1062 (f) agents inducing EGFR inhibition: is not limited to, a radiation therapy enhancement agent or 1063) (g) agents inducing Protein Kinase C inhibition: technique selected from the group consisting of: 1064 (h) agents inducing Phospholipase C down regu lation; 1044 (a) use with hypoxic cell sensitizers; 1065 (i) agents includingjun down regulation: 1045 (b) use with radiation sensitizers/protectors; 1066 (j) agents modulating expression of histone 1046 (c) use with photosensitizers; genes: 1047 (d) use with radiation repair inhibitors: 1067 (k) agents modulating expression of VEGF; 1048 (e) use with thiol depletion; 1068 (1) agents modulating expression of ornithine 1049 (f) use with vaso-targeted agents: decarboxylase; 1050 (g) use with radioactive seeds: 1069 (m) agents modulating expression of jun D; 1051 (h) use with radionuclides: 1070 (n) agents modulating expression of V-jun: 1052 (i) use with radiolabeled antibodies; and 1071 (o) agents modulating expression of GPCRs: 1053 (i) use with brachytherapy; and 1072 (p) agents modulating expression of protein 1054 (k) use with bioreductive alkylating agents. kinase A: US 2016/0220537 A1 Aug. 4, 2016 66

1073 (q) agents modulating expression of protein vention is described in M. Gao et al., “Differential and kinases other than protein kinase A. Antagonistic Effects of V-Jun and c-Jun, Cancer Res. 56: 1074 (r) agents modulating expression of telomerase: 4229-4235 (1996), incorporated herein by this reference. The 1075 (S) agents modulating expression of prostate spe role of protein kinase A as a target for therapeutic intervention cific genes: is described in P. C. Gordge et al., “Elevation of Protein 1076 (t) agents modulating expression of histone Kinase A and Protein Kinase C in Malignant as Compared deacetylase; and With Normal Breast Tissue.” Eur: J. Cancer 12: 2120-2126 1077 (u) agents modulating expression of checkpoint (1996), incorporated herein by this reference. The role of regulators such as CTLA-4, PD-1, PD-2, and OX-40; telomerase as a target fortherapeutic intervention is described and in E. K. Parkinson et al., “Telomerase as a Novel and Poten 1078 (V) agents modulating expression of mTOR and tially Selective Target for Cancer Chemotherapy.” Ann. Med. related molecules such as Akt3 and PI3K. 35: 466-475 (2003), incorporated herein by this reference. 1079. Inhibitors of poly ADP-ribose polymerase include The role of histone deacetylase as a target for therapeutic veliparib (ABT-888), AGO14699, iniparib (BSI-201), carbo intervention is described in A. Melnick & J. D. Licht, "His platin, gemcitabine, INO-1001, MK4827, nicotinamide, ola tone Deacetylases as Therapeutic Targets in Hematologic parib, paclitaxel, temozolomide, and topotecan, and are Malignancies. Curr. Opin. Hematol. 9: 322-332 (2002), described in E. A. Comen & M. Robson, “Inhibition of Poly incorporated herein by this reference. (ADP)-Ribose Polymerase as a Therapeutic Strategy for 1080 CHK2 checkpoint kinase is a serine/threonine pro Breast Cancer. Oncology 24: 55-62 (2010), incorporated tein kinase which is required for checkpoint-mediated cell herein by this reference. Agents promoting vasodilation cycle arrest, activation of DNA repair and apoptosis in include levosimendan, described in W. G. Toiler et al., "Levo response to the presence of DNA double-strand breaks. simendan, a New Inotropic and Vasodilator Agent. Anesthe CHK2 checkpoint kinase may also negatively regulate cell Siology 104: 556-569 (2006), incorporated herein by this cycle progression during unperturbed cell cycles. Following reference. EGFR inhibition is described in G. Giaccone & J. activation, CHK2 checkpoint kinase phosphorylates numer A. Rodriguez, “EGFR Inhibitors: What Have We Learned ous effectors preferentially at the consensus sequence L-X- from the Treatment of Lung Cancer. Nat. Clin. Pract. Oncol. R-X-S/T (SEQ ID NO: 13). CHK2 checkpoint kinase regu 11:554-561 (2005), incorporated herein by this reference. lates cell cycle checkpoint arrest through phosphorylation of Protein kinase Cinhibition is described in N. C. Swannie & S. CDC25A, CDC25B and CDC25C, inhibiting their activity. B. Kaye, “Protein Kinase CInhibitors.” Curr. Oncol. Rep. 4: The inhibition of CDC25 phosphatase activity leads to 37-46 (2002), incorporated herein by this reference. Phos increased inhibitory tyrosine phosphorylation of CDK-cyclin pholipase C down regulation is described in A. M. Martelli et complexes and blocks cell cycle progression. CHK2 check al., “Phosphoinositide Signaling in Nuclei of Friend Cells: point kinase may also phosphorylate NEK6 which is involved Phospholipase C B Downregulation Is Related to Cell Differ in G2/M cell cycle arrest. CHK2 checkpoint kinase also regu entiation.” Cancer Res. 54: 2536-2540 (1994), incorporated lates also phosphorylate NEK6 which is involved in G2/M herein by this reference. Down regulation of Jun (specifically, cell cycle arrest. CHK2 checkpoint kinase also phosphory c-Jun) is described in A. A. P. Zada et al., “Downregulation of lates NEK6 which is involved in G2/M cell cycle arrest. c-Jun Expression and Cell Cycle Regulatory Molecules in Additionally, CHK2 checkpoint kinase stimulates the tran Acute Myeloid Leukemia Cells Upon CD44 Ligation. Onco Scription of genes involved in DNA repair (including gene 22: 2296-2308 (2003), incorporated herein by this ref BRCA2) through the phosphorylation and activation of the erence. The role of histone genes as a target for therapeutic transcription factor FOXM1. CHK2 checkpoint kinase also intervention is described in B. Calabretta et al., “Altered regulates apoptosis through the phosphorylation of p53/ Expression of G1-Specific Genes in Human Malignant TP53, MDM4 and PML; phosphorylation of p53/TP53 at Myeloid Cells.” Proc. Natl. Acad. Sci. USA 83: 1495-1498 Ser20 by CHK2 may alleviate inhibition by MDM2, leading (1986), incorporated herein by this reference. The role of to accumulation of active p53/TP53. Phosphorylation of VEGF as a target for therapeutic intervention is described in MDM4 may also reduce degradation of p53/TP53. CHK2 A. Zielke et al., “VEGF-Mediated Angiogenesis of Human checkpoint kinase also controls the transcription of pro-apo Pheochromocytomas Is Associated to Malignancy and Inhib ptotic genes through phosphorylation of the transcription fac ited by anti-VEGF Antibodies in Experimental Tumors. Sur tor. It is also believed to act as a tumor suppressor. It may also gery 132: 1056-1063 (2002), incorporated herein by this ref have a DNA damage-independent function in mitotic spindle erence. The role of ornithine decarboxylase as a target for assembly by phosphorylating BRCA1. Its absence may be a therapeutic intervention is described in J. A. Nilsson et al., cause of the chromosomal instability observed in some can “Targeting Ornithine Decarboxylase in Myc-Induced Lym cer cells. A deletion mutation at position 1100 of CHEK2, phomagenesis Prevents Tumor Formation.” Cancer Cell 7: which encodes the CHK2 checkpoint kinase, is associated 433-444 (2005), incorporated herein by this reference. The with an increased risk of breast cancer, particularly in the role of ubiquitin C as a target for therapeutic intervention is European population (H. Meijers-Heiboer et al., “Low-Pen described in C. Aghajanian et al., “A Phase I Trial of the Novel etrance Susceptibility to Breast Cancer Due to CHEK2(*) Proteasome Inhibitor PS341 in Advanced Solid Tumor 1100deIC in Noncarriers of BRCA1 or BRCA2 Mutations.” Malignancies.” Clin. Cancer Res. 8: 2505-2511 (2002), Nat. Genet. 31: 55-59 (2002), incorporated herein by this incorporated herein by this reference. The role of Jun D as a reference). The activity of CHK2 checkpoint kinase is further target for therapeutic intervention is described in M. M. Caf described in J. Liet al., “Structural and Functional Versatility farel et al., “Juni) Is Involved in the Antiproliferative Effect of of the FHA Domain in DNA-Damage Signaling by the Tumor A-Tetrahydrocannibinol on Human Breast Cancer Cells.” Suppressor Chk2,' Mol. Cell 9: 1045-1054 (2002), incorpo Oncogene 27: 5033-5044 (2008), incorporated herein by this rated herein by this reference. Inhibitors and modulators of reference. The role of V-Jun as a target for therapeutic inter the activity of CHK2 checkpoint kinases are known in the art, US 2016/0220537 A1 Aug. 4, 2016 67 and are described, for example, in U.S. Pat. No. 8,334.309 to 1101 (a) use to activate macrophages; Klein et al., U.S. Pat. No. 8,329,709 to Banka et al., U.S. Pat. 1102 (b) use to induce innate immunity; and No. 8,329,701 to Mitchell et al., U.S. Pat. No. 8,318,740 to 1103 (c) use to induce adaptive immunity. Wu, U.S. Pat. No. 8,318,735 to Shipps, Jr. et al., U.S. Pat. No. 1104. When the improvement is made by use of bisantrene 8.252,795 to Finket al., U.S. Pat. No. 8,227,605 to Shipps, Jr., or a derivative or analog thereof to inhibit expression of et al., U.S. Pat. No. 8,211,054 to Guzi et al., U.S. Pat. No. Survivin or by use of bisantrene or a derivative or analog 8,202,876 to Albaugh et al., and U.S. Pat. No. 8,168,651 to thereof with an inhibitor of Survivin, the use of bisantrene or Chua et al., all of which are incorporated herein by this a derivative or analog of bisantrene can be, but is not limited reference. to, a use selected from the group consisting of: 1081) When the improvement is made by use of selective 1105 (a) use to inhibit expression of survivin; and target cell population therapeutics, the use of selective target 1106 (b) use with an inhibitor of survivin. cell population therapeutics can be, but is not limited to, a use 1107 Inhibitors of survivin are described above. selected from the group consisting of: 1108 When the improvement is made by use of bisantrene 1082 (a) use against radiation sensitive cells; or a derivative or analog thereof with a multidrug resistance 1083 (b) use against radiation resistant cells; reversal agent, the use of bisantrene or a derivative or analog 1084 (c) use against energy depleted cells; and of bisantrene can be, but is not limited to, use with a multidrug 1085 (d) use against endothelial cells. resistance reversal agent to reduce multidrug resistance. Mul 1086. When the improvement is made by use with an agent tidrug resistance reversal agents are described above; a par to enhance the activity of bisantrene and analogs and deriva ticularly useful multidrug resistance reversal agent is Vera tives thereof, the agent to enhance the activity of bisantrene pamil. and analogs and derivatives thereof can be, but is not limited 1109 When the improvement is made by use in combina to, an agent selected from the group consisting of torial regimes, bisantrene and derivatives or analogs thereof 1087 (a) nicotinamide: can be employed in Such combinatorial regimes, typically by 1088 (b) caffeine; combining newer immunotherapies with older cytotoxic modalities. Combinatorial therapy is described in L. S. Lie 1089 (c) tetandrine; and bovitch et al., “Developing Combinatorial Multi-Component 1090 (d) berberine. Therapies (CMCT) of Drugs That Are More Specific and 1091. When the improvement is made by use of bisantrene Have Fewer Side Effects Than Traditional One Drug Thera or a derivative or analog thereof to modulate DNA methyla pies.” Nonlinear Biomed. Phys. 1: 11 (2007), and in B. Al tion, the use of bisantrene or a derivative or analog thereof to Lazikani et al., “Combinatorial Drug Therapy for Cancer in modulate DNA methylation can be, but is not limited to, a use the Post-Genomic Era,” Nat. Biotechnol. 10: 679-692 (2012), selected from the group consisting of: both incorporated herein by this reference. Combinations for 1092 (a) use to promote gene silencing; and combinatorial therapeutics can be selected based on genom 1093 (b) use with a drug that inhibits DNA methyla ics or proteomics; for example, therapeutic agents can be tion. chosen based on interactions with receptors or kinases in a 1094. The use of bisantrene or a derivative or analog single pathway or in pathways that interact. The use of bisant thereof to promote gene silencing is described in L. Suarez & rene or a derivative or analog thereof in a combinatorial S. D. Gore, “Demethylation Demystification.” Blood 121: regime can be, but is not limited to: 1488-1489 (2011), incorporated herein by this reference. 1110 (a) use in a combinatorial regime as a chemo 1095 Drugs that inhibit DNA methylation include, but are therapeutic agent with at least one agent inducing immu not limited to, 5'-azacytidine, 5-aza-2'-deoxycytidine, Zebu noactivity; larine, L-methionine, apicidine, hydralazine, procainamide, 1111 (b) use in a combinatorial regime as a chemo antisense oligonucleotides directed against mRNA for DNA therapeutic agent with at least one agent inducing mac methyltransferase, and histone deacetylase (HDAC) inhibi rophage activation; tOrS. 1112 (c) use in a combinatorial regime as a chemo 1096. When the improvement is made by use of bisantrene therapeutic agent with at least one cytokine; or a derivative or analog thereof to inhibit telomerase or 1113 (d) use in a combinatorial regime as a chemo induce telomere dysfunction, the use of bisantrene or a therapeutic agent with at least one agent inhibiting derivative or analog of bisantrene can be, but is not limited to, telomerase; a use selected from the group consisting of: 1114 (e) use in a combinatorial regime as a chemo 1097 (a) use to inhibit telomerase; and therapeutic agent with at least one agent inhibiting Sur 1098 (b) use to induce telomere dysfunction. vivin; 1099 Bisantrene and derivatives or analogs thereof can be 1115 (f) use in a combinatorial regime as a chemo used with telomerase inhibitors such as, but not limited to, therapeutic agent with at least one agent inducing dem BPPA (2,6-bis(3-piperidinopropionamido)anthraquinone), ethylation; (-)-epigallocatechin gallate, H-7 (2,6-bis(3-piperidinopropi 1116 (g) use in a combinatorial regime as a chemo onamido)anthraquinone), B-rubromycin, and BIBR1532 (2- therapeutic agent with at least one adjuvant; (2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl1-yl)aminoben 1117 (h) use in a combinatorial regime as a chemo Zoic acid). therapeutic agent with at least one antibody; 1100 When the improvement is made by use of bisantrene 1118 (i) use in a combinatorial regime as a chemothera or a derivative or analog thereof to activate macrophages or peutic agent with at least one innate or adaptive immune induce innate and/or adaptive immunity, the use of bisantrene stimulator; or a derivative or analog of bisantrene can be, but is not 1119 () use in a combinatorial regime as a chemothera limited to, a use selected from the group consisting of peutic agent with at least one checkpoint inhibitor, US 2016/0220537 A1 Aug. 4, 2016 68

1120 (k) use in a combinatorial regime as a chemo 1144 (a) use in a combinatorial regime as an agent therapeutic agent with at least one mTOR antagonist; inducing macrophage activation with taxane; and 1121 (1) use in a combinatorial regime as a chemothera 1145 (ak) use in a combinatorial regime as an agent peutic agent with at least one Akt inhibitor, inducing macrophage activation with taxol. 1122 (m) use in a combinatorial regime as a chemo 1146 Agents inducing demethylation include, but are not therapeutic agent with at least one notch inhibitor; limited to, 5-azacytidine, 5-aza-2'-deoxycytidine, Zebularine, 1123 (n) use in a combinatorial regime as a chemo L-methionine, apicidine, hydralazine, procainamide, and therapeutic agent with at least one HSP inhibitor; antisense oligonucleotides directed against mRNA for DNA 1124 (o) use in a combinatorial regime as a chemo methyltransferase. Additional drugs that inhibit DNA methy therapeutic agent with at least one phosphatidylinositide lation include inhibitors of histone deacetylase (HDAC). 3-kinase inhibitor; These compounds include, but are not limited to, compounds 1125 (p) use in a combinatorial regime as a chemo disclosed in PCT Patent Application Publication No. WO therapeutic agent with at least one kinase inhibitor, 02/22577 by Bair et al., incorporated herein by this reference, 1126 (q) use in a combinatorial regime as a chemo including, but not limited to, N-hydroxy-3-4-(2-hydroxy therapeutic agent with cytarabine; ethyl)2-(1H-indol-3-yl)ethyl-aminomethylphenyl-2E-2- 1127 (r) use in a combinatorial regime as a chemo propenamide, Suberoylanilide hydroxamic acid, 4-(2-amino therapeutic agent with taxane; phenylcarbamoyl)-benzyl-carbamic acid pyridine-3- 1128 (s) use in a combinatorial regime as a chemo ylmethyl ester and derivatives thereof, butyric acid, therapeutic agent with taxol; pyroxamide, trichostatin A, oxamflatin, apicidin, depsipep 1129 (t) use in a combinatorial regime as an agent tide, depudecin, trapoxin, HC toxin, and Sodium phenylbu inducing macrophage activation with at least one agent tyrate. inducing telomerase inhibition; 1147 Survivin is a regulator of apoptosis and acts to 1130 (u) use in a combinatorial regime as an agent counter apoptosis as described above. Inhibitors or modula inducing macrophage activation with at least one cytok tors of survivin activity or expression are described above. ine; 1148 Macrophage activators include, but are not limited 1131 (V) use in a combinatorial regime as an agent to: Bacillus Calmette-Guérin; Corynebacterium parvum; inducing macrophage activation with at least one agent endotoxins; muramyl dipeptide; pl.pC copolymer; pyran inhibiting Survivin; copolymer, lymphokines; Adriamycin; cyclophosphamide; 1132 (w) use in a combinatorial regime as an agent mitomycin C. mycoplasmal lipoproteins; bisacyloxypropyl inducing macrophage activation with at least one agent cysteine conjugates, as described in U.S. Pat. No. 8,119,689 inducing demethylation; to Ebenstein et al. incorporated herein by this reference; 1133 (X) use in a combinatorial regime as an agent glycolipopeptides as described in U.S. Pat. No. 7.820,797 to inducing macrophage activation with at least one adju Boons, incorporated herein by this reference; mineral oil; Vant, starch; polycarbophil; and bisantrene, as well as various 1134 (y) use in a combinatorial regime as an agent chemokines, lymphokines, and cancer vaccines described inducing macrophage activation with at least one anti previously herein. body; 1149 Checkpoint kinases are involved in the regulation of 1135 (Z) use in a combinatorial regime as an agent a number of cellular processes, including the cell cycle. inducing macrophage activation with at least one innate Eukaryotes have evolved elaborate sensory networks to or adaptive immune stimulator; detect and repair DNA damage and prevent alterations in their 1136 (aa) use in a combinatorial regime as an agent genetic material. In response to DNA damage, eukaryotic inducing macrophage activation with at least one check cells arrest either in G1 or S phase, to prevent replication of point inhibitor; damaged genes, or in G2 phase to avoid segregation of defec 1137 (ab) use in a combinatorial regime as an agent tive chromosomes. Checkpoint kinases, CHK1 and CHK2, inducing macrophage activation with at least one mTOR participate in various DNA-damage responses, including antagonist; cell-cycle checkpoints, genome maintenance, DNA repair, and apoptosis. They phosphorylate several key proteins 1138 (ac) use in a combinatorial regime as an agent involved in the cell cycle and block their activity. CHK1, an inducing macrophage activation with at least one Akt evolutionarily conserved protein kinase, is expressed in the S inhibitor; and G2 phases of cell cycle of proliferating cells. It is acti 1139 (ad) use in a combinatorial regime as an agent vated by phosphorylation on Ser7 and Ser' in response to inducing macrophage activation with at least one notch DNA damage. Once activated, CHK1 phosphorylates Ser' inhibitor; of Cdc25A, which targets it for ubiquitin-mediated degrada 1140 (ae) use in a combinatorial regime as an agent tion. The phosphorylated Cdc25A cannot dephosphorylate inducing macrophage activation with at least one HSP and activate Cdk1 and Cdk2, resulting in an arrest of cell cycle inhibitor; in the G1, S, and G2 phases. CHK1 also phosphorylates 1141 (af) use in a combinatorial regime as an agent Ser' (14-3-3 binding site) on Cdc25C and prevents its acti inducing macrophage activation with at least one phos vation in the G2 phase. Phosphorylated Cdc25C cannot phatidylinositide 3-kinase inhibitor; dephosphorylate and activate Cdk1. Recent research indi 1142 (ag) use in a combinatorial regime as an agent cates that CHK1 is an ideal chemosensitization target and its inducing macrophage activation with at least one kinase inhibition can sensitize tumors, particularly those with p53 inhibitor; deficiency, to various chemotherapeutic agents. CHK2 is 1143 (ah) use in a combinatorial regime as an agent structurally different from CHK1, but they share overlapping inducing macrophage activation with cytarabine; substrate specificities. CHK2 is activated following exposure US 2016/0220537 A1 Aug. 4, 2016 69 to infrared light or topotecan, whereas CHK1 is activated by Publication No. 2011/01 18230 by Chen et al.: United States agents that interfere with DNA replication. This observation Patent Application Publication No. 2011/0021498 by Stokes has led to the belief that CHK1 blocks cell-cycle progression et al.; United States Patent Application Publication No. 2011/ when replication is inhibited, whereas CHK2 acts when there 00094.15 by Wu: United States Patent Application Publica are double-strand breaks induced in DNA. CHK2 is activated tion No. 2010/0260868 by Humphries et al.: United States by DNA-strand-breaking agents such as ionizing radiation Patent Application Publication No. 2010/0226917 by Brown and topoisomerase inhibitors through the ATM-dependent et al.; United States Patent Application Publication No. 2010/ pathway. The role of CHK2 in checkpoints is not clearly 0143332 by Parry et al. (including pyrazolopyrimidines, imi understood. However, it is reported to phosphorylate Cdc25A and inhibitits activity. CHK2 also phosphorylates Ser' at the dazopyrazines, UCN-01, indolcarbazole compounds, amino-terminal activation domain of p53 and regulates levels Go6976, SB-218078, staurosporine, ICP-1, CEP-3891, of p53 in response to DNA double strand breaks. Phosphory isogranulatimide, debromohymenialdisine (DBH), pyri lation of Ser' is not the only important event for p53 response dopyrimidine derivatives, PD0166285, scytonemin, diary1 induced by UV light. CHK2 can also regulate p53 through ureas, benzimidazole quinolones, CHR 124, CHR 600, tricy targeting several other phosphorylation sites. Many current clic diazopinoindolones, PF-00394.691, furanopyrimidines, cancer treatments, including certain classes of chemothera pyrrolopyrimidines, indolinones, Substituted pyrazines, com peutic agents, induce cytotoxicity by damaging DNA. How pound XL844, pyrimidinylindazolyamines, aminopyrazoles, ever, many cancers become resistant to these therapies. Thus, 2-ureidothiophenes, pyrimidines, pyrrolopyrimidines, 3-ure modulating DNA-damage responses to selectively enhance idothiophenes, indenopyazoles, triazlones, dibenzodiazepi the sensitivity of cancer cells to these therapies is highly nones, macrocyclic ureas, pyrazoloquinoloines, and the pep desirable. Inhibitors of CHK1 and CHK2 have shown poten tidomimetic CBP501 as CHK1 inhibitors); United States tial to enhance the efficacy of DNA-damaging cancer thera Patent Application Publication No. 2010/0105683 by Keegan peutic agents by selectively increasing the sensitivity of et al.; United States Patent Application Publication No. 2010/ tumor cells. 0069423 by Pommier et al.; United States Patent Application Publication No. 2009/0312280 by Anderes et al. (including 1150 Checkpoint kinase inhibitors include, but are not (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1-methyl-1H-pyrazol limited to, AZD7762 (1-(2-((S)-piperidin-3-ylcarbamoyl)-5- 4-yl)-1-oxo-2,6-dihydro-1H-1.2diazepino 4.5,6-cd indol (3-fluorophenyl)thiophen-3-yl)urea), LY2603618 (S)-1-(5- 8-yl)acetamide); United States Patent Application Publica bromo-4-methyl-2-(morpholin-2-ylmethoxy)phenyl)-3-(5- tion No. 2009/0143357 by Diaz et al. (including 1-5-chloro methylpyrazin-2-yl)urea), CHIR-124 (S)-3-(1H-benzod 2-S-(1,4oxazepan-2-ylmethoxy)-phenyl-3-(5-methyl imidazol-2-yl)-6-chloro-4-(duinuclidin-3-ylamino)quinolin pyrazin-2-yl)-urea, 1-5-chloro-2-(1,4oxazepan-2- 2(1H)-one), SCH 900776 (6-bromo-3-(1-methyl-1H ylmethoxy)-phenyl)-3-(5-methyl-pyrazin-2-yl)-urea, 1-5- pyrazol-4-yl)-5-((R)-piperidin-3-yl)pyrazolo 1.5-a chloro-2-R-(1,4oxazepan-2-ylmethoxy)-phenyl-3-(5- pyrimidin-7-amine), and PF 477736. methyl-pyrazin-2-yl)-urea, 1-5-chloro-4-methyl-2-S-(1,4)- 1151. Additional inhibitors of checkpoint kinases are oxazepan-2-ylmethoxy)-phenyl-3-(5-methyl-pyrazin-2-yl)- described in the following United States patents and patent urea, 1-5-bromo-2-(1,4oxazepan-2-ylmethoxy)-phenyl applications, all of which are incorporated herein by this 3-(5-methyl-pyrazin-2-yl)-urea, 1-5-bromo-2-(4-methyl-1, reference: U.S. Pat. No. 8,455,471 to Wisdom et al.; U.S. Pat. 4oxazepan-2-ylmethoxy)-phenyl-3-(5-methyl-pyrazin-2- No. 8,435,970 to Curry et al.; U.S. Pat. No. 8,410,279 to yl)-urea, 1-2-(1,4-dimethyl-piperazin-2-ylmethoxy)-5- Gazzard et al.; U.S. Pat. No. 8,372,842 to Blake et al.; U.S. methyl-phenyl-3-(5-methyl-pyrazin-2-yl)-urea, 1-5- Pat. No. 8,324.226 to Collins et al.; U.S. Pat. No. 8,314,108 to methyl-2-(1-methyl-piperazin-2-ylmethoxy)-phenyl)-3-(5- Farouzet al.: U.S. Pat. No. 8.277,807 to Gallagher et al.; U.S. methyl-pyrazin-2-yl)-urea, 1-5-chloro-2-(1-methyl Pat. No. 8,178,131 to Le Huerou et al.; U.S. Pat. No. 8,093, piperazin-2-ylmethoxy)-phenyl-3-(5-methyl-pyrazin-2-yl)- 244 to Diaz et al.; U.S. Pat. No. 7,825,132 to Cai et al., U.S. urea, 1-5-chloro-2-S-(1-methyl-piperazin-2-ylmethoxy)- Pat. No. 7,781,580 to Lee et al.; U.S. Pat. No. 7,608,618 to phenyl-3-(5-methyl-pyrazin-2-yl)-urea, 1-(5-cyano Kesicki et al.; U.S. Pat. No. 7,560,462 to Gaudino et al.; U.S. pyrazin-2-yl)-3-5-methyl-2-(4-methyl-morpholin-2- Pat. No. 7,550,477 to Brnardic et al.; U.S. Pat. No. 7,501,435 ylmethoxy)-phenyl-urea, 1-5-bromo-2-S-(4-methyl to Arrington et al.; U.S. Pat. No. 7,485,649 to Brnardic et al.: morpholin-2-ylmethoxy)-phenyl-3-(5-methyl-pyrazin-2- U.S. Pat. No. 7,470,709 to Barsanti et al.; U.S. Pat. No. yl)-urea, 1-5-chloro-2-S-(4-cyanomethyl-morpholin-2- 7.462,713 to Benedictet al.; U.S. Pat. No. 7,202,244 to Boyle ylmethoxy)-phenyl)-3-(5-methyl-pyrazin-2-yl)-urea, 1-5- et al.; U.S. Pat. No. 7,132,533 to Benedictet al.; U.S. Pat. No. chloro-2-S-(4-methyl-morpholin-2-ylmethoxy)-phenyl-3- 7,094,798 to Booth et al.; U.S. Pat. No. 7,067,506 to Keegan (5-cyano-pyrazin-2-yl)-urea, 1-5-chloro-2-(S-4-methyl et al.; U.S. Pat. No. 6,967,198 to Benedictet al.; U.S. Pat. No. morpholin-2-ylmethoxy)-phenyl-3-(5-methyl-pyrazin-2- 6,670,167 to Chen et al.; United States Patent Application yl)-urea, 1-5-chloro-2-(R-morpholin-3-ylmethoxy)- Publication No. 2013/0045286 by Le Huerou et al.: United phenyl)-3-(5-methyl-pyrazin-2-yl)-urea, 1-4,5-dichloro-2- States Patent Application Publication No. 2012/0232082 by (S-morpholin-2-ylmethoxy)-phenyl-3-(5-methyl-pyrazin Wu: United States Patent Application Publication No. 2012/ 2-yl)-urea, 1-(5-cyano-pyrazin-2-yl)-3-5-methyl-2- 0184505 by Popovici-Muller et al.; United States Patent (morpholin-2-ylmethoxy)-phenyl-urea, 1-5-chloro-4- Application Publication No. 2012/0114765 by Cao et al.: methyl-2-(S-morpholin-2-ylmethoxy)phenyl)-3-(5-methyl United States Patent Application Publication No. 2011/ pyrazin-2-yl)-urea, 1-5-chloro-4-methyl-2-(R-morpholin 0201592 by Collins et al.; United States Patent Application 2-ylmethoxy)-phenyl-3-(5-methyl-pyrazin-2-yl)-urea, 1-4. Publication No. 2011/0183938 by Dyke et al.; United States 5-dichloro-2-(R-morpholin-2-ylmethoxy)-phenyl)-3-(5- Patent Application Publication No. 2011/0183933 by Guzi et methyl-pyrazin-2-yl)-urea, 1-4,5-dimethyl-2-(morpholin-2- al.; United States Patent Application Publication No. 2011/ ylmethoxy)-phenyl-3-(5-methyl-pyrazin-2-yl)-urea, 1-4- 0.124654 by Chen et al.; United States Patent Application chloro-5-methyl-2-(S-morpholin-2-ylmethoxy)-phenyl-3-

US 2016/0220537 A1 Aug. 4, 2016 77 tions, including differentiation, and cellular proliferation. Biochemicals), LY411575 (Eli Lilly and Co.), L-685,458 Mutations that increase Notch signaling have been associated (Sigma-Aldrich), BMS-289948 (4-chloro-N-(2,5-difluo with the development of leukemia and inhibitors of Notch are rophenyl)-N-((1R)-4-fluoro-2-3-(1H-imidazol-1-yl)pro being studied for their potential use in the treatment of neu pylphenylethyl)benzenesulfonamide hydrochloride) and rological diseases and cancer. The Notch pathway is activated BMS-299897 (4-2-((1R)-1-(4-chlorophenyl)sulfonyl-2, by four different transmembrane receptor subtypes (desig 5-difluoroanilino)ethyl)-5-fluorophenylbutanoic acid) nated as Notch-1-Notch-4) that rely upon regulated proteoly (Bristol Myers Squibb), MK0752 (Merck), and MRK-003 sis. Expression patterns of Notch depend on cell type. Fol (Merck); United States Patent Application Publication No. lowing ligand binding, the receptor undergoes sequential 2011/0059096 by Danget al. (antibodies that bind to epitopes cleavage by metalloproteases of the ADAM family and the selected from the group consisting of CFNTLGGHS (SEQID presenilin-dependent gamma-secretase. The final proteolytic NO: 14), CVCVNGWTGES (SEQ ID NO: 15), CATAV cleavage step permits the intracellular domain of the Notch (SEQID NO:16), CFHGAT (SEQIDNO:17), CVSNP (SEQ receptor to translocate to the cell nucleus where it interacts ID NO: 18) and CLNGGS (SEQID NO: 19)); United States with transcription factors to induce target gene expression. In Patent Application Publication No. 2010/0292.165 by Clevers the cell nucleus, the Notch intracellular domain undergoes et al. (gamma secretase inhibitors including DAPT ((N-N- ubiquitilation. Proteolytic processing of the Notch precursor (3,5-difluorophenylacetyl)-L-alanyl-S-phenylglycine t-bu protein by furin-protease and its trafficking to the cell mem tyl ester), dibenzazepine, and a benzodiazepine); United brane also determine turnover and availability of receptors, States Patent Application Publication No. 2010/0267801 by and, in turn, activation of this signaling pathway. Altered Lewis et al.; United States Patent Application Publication No. glycosylation of the Notch extracellular domain by Fringe 2010/0222283 by Susztak et al. (gamma secretase inhibitors protein family members may also modify efficiency of ligand including gamma Secretase inhibitor I, gamma Secretase binding. inhibitor II, gamma secretase inhibitor III, gamma Secretase 1159. Notch inhibitors include, but are not limited to, inhibitor IV. gamma secretase inhibitor V. gamma Secretase semagacestat, 7-(S)-N'(3,5-difluorophenylacetyl)-L-alani inhibitor VI, gamma Secretase inhibitor VII, gamma Secretase nyl)amino-5-methyl-5,7-dihydro-6H-dibenzb.dazepin-6- inhibitor IX, gamma secretase inhibitor X, gamma Secretase one (Y0-01027), and (2R,3S)-N-(3S)-1-Methyl-2-oxo-5- inhibitor XI, gamma secretase inhibitor XII, gamma Secretase phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3, inhibitor XIII, gamma secretase inhibitor XIV. gamma secre 3,3-trifluoropropyl)succinamide (BMS-906024). tase inhibitor XVI, gamma secretase inhibitor XVII, gamma 1160 Additional inhibitors of Notch are described in the secretase inhibitor XIX, gamma secretase inhibitor XX. following United States patents and patent applications, all of gamma secretase inhibitor XXI, gamma40 secretase inhibitor which are incorporated herein by this reference: U.S. Pat. No. I, gamma40 secretase inhibitor II, and isovaleryl-V V-Sta 8,377,886 to Susztak et al.; U.S. Pat. No. 8.362,075 Lewis et A-Sta-OCH); and PCT Patent Application Publication No. al.; U.S. Pat. No. 8,343,923 to Long et al. (DAPT (N-N-(3, WO 2012/129353 by Quesnelle et al. 5-difluorophenacetyl-L-alanyl)-S-phenylglycine t-butyl 1161 The 90kDaheat shock proteins (“Hsp90) belong to ester), 1-(S)-endo-N-(1,3,3)-Trimethylbicyclo[2.2.1]hept-2- a family of chaperones that regulate intracellular functions yl)-4-fluorophenyl sulfonamide, WPE-III31C, S-3-N'-(3.5- and are required for the refolding of denatured proteins fol difluorophenyl-alpha-hydroxyacetyl)-L-alaninylamino-2, lowing heat shock, as well as the conformational maturation 3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, of a large number of key proteins involved in cellular pro (N)—(S)-2-hydroxy-3-methyl-butyryl-1-(L-alaninyl)-(S)- cesses. The Hsp90 family of chaperones is comprised of four 1-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2- different isoforms. Hsp90-alpha and Hsp90-beta are found one): U.S. Pat. No. 8,242,103 to Lewis et al.; U.S. Pat. No. predominately in the cytosol, the 94-kDa glucose-regulated 8,133,857 to Aikawa; U.S. Pat. No. 8,119,366 to Stylianou: protein (“GRP94) is localized to the endoplasmic reticulum, U.S. Pat. No. 7,901,876 to Di Fiore et al.; U.S. Pat. No. and Hsp75/tumor necrosis factor receptor associated protein 7,837,993 to Conboy et al.; U.S. Pat. No. 7,807,630 to Dang 1 (“TRAP-1) resides mainly in the mitochondrial matrix. et al.; United States Patent Application Publication No. 2013/ These Hsp90s bind to client proteins in the presence of 0064832 by Aikawa et al.; United States Patent Application cochaperones, immunophilins, and partner proteins to make Publication No. 2013/0039930 by Alitalo et al.: United States the multiprotein complex responsible for conformational Patent Application Publication No. 2013/0029972 by Hips maturation of newly formed nascent peptides into biologi kind et al. (4,4,4-trifluoro-N-(1S)-2-(7S)-5-(2-hydroxy cally active three-dimensional structures. Hsp90 is an ATP ethyl)-6-oxo-7H-pyrido2.3-d3benzazepin-7-yl)amino dependent protein with an ATP binding site in the N-terminal 1-methyl-2-oxo-ethylbutanamide); United States Patent region of the active homodimer. Disruption of the ATPase Application Publication No. 2012/0328.608 by Siebel (an activity of Hsp90 results in the destabilization of multiprotein tagonist antibodies and anti-Notch3 NRR (negative regula complexes and Subsequent ubiquitination of the client pro tory region) antibodies); United States Patent Application tein, which undergoes proteasome-mediated hydrolysis. Publication No. 2011/0223183 by Kitajewski et al. (fusion More specifically, in an ATP-dependent fashion, Hsp70 binds proteins as decoy inhibitors); United States Patent Applica to newly synthesized proteins cotranslationally and/or post tion Publication No. 2011/0178046 by Ross et al. (gamma translationally to stabilize the nascent peptide by preventing secretase inhibitors, including Semagacestat (2S)-2-Hy aggregation. Stabilization of the Hsp70/polypeptide binary droxy-3-methyl-N-(1S)-1-methyl-2-oxo-2-(1S)-2,3,4,5- complex is dependent upon the binding of Hsp70 interacting tetrahydro-3-methyl-2-oxo-1H-3-benzazepin-1-yl)amino protein (“HIP”), which occurs after Hsp70 binds to the newly ethylbutanamide, also known as LY450139; Eli Lilly and formed peptide. Hsp70-Hsp90 organizing protein (“HOP) Co.), Compound E ((2S)-2-(3,5-difluorophenyl)acetyl contains highly conserved tetratricopeptide repeats (“TPRs) amino-N-(3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H that are recognized by both Hsp70 and Hsp90, promoting the 1,4-benzodiazepin-3-ylpropanamide, available from Alexis union of Hsp70/HIP and Hsp90, which results in a heteropro US 2016/0220537 A1 Aug. 4, 2016

tein complex. In the case of telomerase and steroid hormone 6.7-tetrahydroindazol-1-yl)phenylamino)cyclohexyl 2-ami receptors, the client protein is transferred from the Hsp70 noacetate; 2-amino-4-(2,4-dichloro-5-(2-(pyrrolidin-1-yl) system to the Hsp90 homodimer with concomitant release of ethoxy)phenyl)-N-ethylthieno 2,3-dipyrimidine-6- Hsp70, HIP, and HOP. Upon binding of ATP and an immu carboxamide: 6-chloro-9-(4-methoxy-3,5-dimethylpyridin nophilin with cis/trans peptidyl prolyl-isomerase activity 2-yl)methyl)-9H-purin-2-amine; MPC-3100 ((S)-1-(4-(2-(6- (FKBP51, FKBP52, or CyPA), the ensemble folds the client amino-8-((6-bromobenzod1.3dioxol-5-yl)thio)-9H protein into its three-dimensional structure. In a Subsequent purin-9-yl)ethyl)piperidin-1-yl)-2-hydroxypropan-1-one); event, p23 binds Hsp90 near the N-terminal region promoting CCT-018159 (4-4-(2,3-Dihydro-1,4-benzodioxin-6-yl)-5- the hydrolysis of ATP and release of the folded protein, Hsp90 methyl-1H-pyrazol-3-yl)-6-ethyl-1,3-benzenediol); partner proteins, and ADP, Hsp90 (heat shock protein 90) is a CCT-129397 (3-(5-chloro-2,4-dihydroxyphenyl)-N-ethyl-4- chaperone protein that has a number of functions, including (4-methoxyphenyl)-1H-pyrazole-5-carboxamide); PU-H71 assisting proteins to fold properly, stabilizing proteins against (6-amino-8-(6-iodo-1,3-benzodioxol-5-yl)thio-N-(1-me heat stress, and aiding in protein degradation. It also has the thylethyl)-9H-purine-9-propanamine); SNX-2112 (4-(6.6- effect of stabilizing a number of proteins required for tumor dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydroinda growth. Hsp90 has four structural domains: (i) a highly con Zol-1-yl)-2-((1r,4r)-4-hydroxycyclohexylamino)benzamide; served amino-terminal domain of about 25kDa; (ii) a charged STA-9090; AT-13387: XL-888; CU-0305; CNF-1010; linker region that connects the amino-terminal domain with macbecin I; macbecin II; 11-O-methyl derivatives of geldana the middle domain; (iii) a middle domain of about 40 kDa, mycin; 17-allylamino-17-demethoxygeldanamycin, 17 and (iv) a carboxy-terminal domain of about 12 kDa. Hsp90 (dimethylaminoethylamino)-17-demethoxygeldanamycin; typically forms homodimers. Functionally, Hsp90 contains 17-2-(pyrrolidin-1-yl)ethylamino-17-demethoxygeldana three domains, the ATP-binding, protein-binding, and dimer mycin; 17-(dimethylaminopropylamino)-17-demethox izing domains. Hsp90 also interacts with the glucocorticoid ygeldanamycin; KF58333 (E isomer); cycloproparadicicol; receptor (GR) and the functioning of GR in binding cortisol is pochonin D; B-zearalenol; celastrol: gedunin: LAQ824; or dependent on Hsp90. Hsp90 also binds immunophilins and FK228. Other inhibitors of Hsp90 are known, including: (i) other steroid receptors. In cancer cells, Hsp90 stabilizes agents that affect post-translational modification, such as EGFR and signal transduction proteins such as PI3K and Akt: acetylation orphosphorylation, of Hsp90; or (ii) recombinant inhibition of Hsp90 can therefore trigger apoptosis through antibodies such as efungumab. the inhibition of the PI3K/Akt pathway and various pathways 1163 Additional inhibitors of Hsp90 are described in the of growth factor signaling. Hsp90 may also stabilize mutant following United States patents and patent applications, all of proteins such as V-Src, the fusion oncogene Bcrl Abl, and which are incorporated herein by this reference: U.S. Pat. No. mutant forms of p53 that appear during cell transformation. 8,399,426 to Kim et al.; U.S. Pat. No. 8,343,913 to Cowen et Hsp90 also is important for the functioning of vascular endot al. (geldanamycin, 17-allylamino-17-demethoxygeldanamy helial growth factor (VEGF) and nitric oxide synthase (NOS) in malignant cells; the activities of these proteins are required cin (17-AAG), 17-(desmethoxy)-17-dimethylaminoethy to promote angiogenesis in tumor cells. Hsp90 also promotes lamino-geldanamycin (17-DMAG), radicicol); U.S. Pat. No. the spread of tumors by assisting matrix metalloproteinase 8.329,179 to Nietal. (17-aminogeldanamycin); U.S. Pat. No. MMP2. Another heat shock protein that acts as a chaperone is 8,158,638 to Ohsuki et al. (pyrazolopyrimidine derivatives); Hsp60. Hsp60 is implicated in mitochondrial protein import U.S. Pat. No. 7,129,244 to Kasibhatla et al.; U.S. Pat. No. 6,903,116 to Yokota et al. (benzo-1,3-dioxole); U.S. Pat. No. and macromolecular assembly. Under normal physiological 6,887,993 to Tian et al. (11-O-methylgeldanamycin com conditions, Hsp60 is a 60-kilodalton oligomer comprised of pounds); U.S. Pat. No. 6,875,863 to Tian et al.: U.S. Pat. No. monomers that form a complex arranged as two stacked hep 6.872,715 to Santi et al. (benzoquinone amsacrin analogs); tameric rings. This double ring structure forms a large central U.S. Pat. No. 5,392,566 to Schnur et al. (geldanamycin cavity in which the unfolded protein binds via hydrophobic derivatives); U.S. Pat. No. 5,387.584 to Schnur et al.; U.S. interactions. Hsp60 may also be found in the cytoplasm. Each Pat. No. 4,261,989 to Sasaki et al. (geldanamycin deriva subunit of Hsp60 has three domains: the apical domain, the tives); United States Patent Application Publication No. equatorial domain, and the intermediate domain. Hsp60 also 2012/0245186 by Blackman et al. (3-(2,4-dihydroxyphenyl)- functions in the replication of mitochondrial DNA. 4-(1-ethyl-indol-4-yl)-5-mercapto-1,2,4-triazole: 3-(2,4-di 1162 Hsp90 inhibitors include, but are not limited to, hydroxyphenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-1, IPI-493 (17-amino-17-demethoxygeldanamycin); IPI-504 2.4 triazole; 3-(2,4-dihydroxyphenyl)-4-(indol-4-yl)-5- (retaspimycin hydrochloride); 17-demethoxy-17-(2-propy mercapto-1,2,4-triazole; 3-(2,4-dihydroxyphenyl)-4-(1- lamino)-geldanamycin; AUY-922 (5-(2,4-dihydroxy-5-iso methoxyethyl-indol-4-yl)-5-mercapto-1,2,4-triazole: 3-(2, propylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl) 4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5- isoxazole-3-carboxamide); elesclomol; ganetispib; mercapto-1,2,4-triazole; 3-(2,4-dihydroxyphenyl)-4-(1- alvespimycin (17-demethoxy-17-2-(dimethylamino)ethyl dimethylcarbamoyl-indol-4-yl)-5-mercapto-1,2,4-triazole; aminol-geldanamycin hydrochloride); 5'-O-(4-cyanophe 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-indol-4-yl)- nyl)methyl-8-II(3,4-dichlorophenyl)methylamino-ad 5-mercapto-1,2,4-triazole; 3-(2,4-dihydroxy-5-ethyl-phe enosine; N1-(3-endo)-8-5-(cyclopropylcarbonyl)-2- nyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-1,2,4-triaz pyridinyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-5-II (1R)- ole; 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl 1-methylpropylamino-1,4-benzenedicarboxamide; (2,4- indol-5-yl)-5-mercapto-1,2,4-triazole: 3-(2,4-dihydroxy-5- dihydroxy-5-isopropylphenyl)(5-(4-methylpiperazin-1-yl) ethyl-phenyl)-4-(1-acetyl-2,3-dimethyl-indol-5-yl)-5- methyl)isoindolin-2-yl)methanone, 4-(6,6-dimethyl-4-oxo mercapto-1,2,4-triazole: 3-(2,4-dihydroxy-5-ethyl-phenyl)- 3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-1-yl)-2-((1 4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-1.2.4 r,4r)-4-hydroxycyclohexylamino)benzamide: (1 r,4r)-4-(2- triazole: 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-2,3- carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4.5, dimethyl-indol-5-yl)-5-mercapto-1,2,4-triazole; 3-(2,4- US 2016/0220537 A1 Aug. 4, 2016 79 dihydroxy-5-ethyl-phenyl)-4-(N-methyl-tetrahydrocarbo dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2- Zol-7-yl)-5-mercapto-1,2,4-triazole; 3-(2,4-dihydroxy-5- yloxy)guinolin-3-yl)-4-methoxy-3-(3-methoxyphenyl)- ethyl-phenyl)-4-(N-methyl-cyclononanaindol-5-yl)-5- benzamide: 3-(3',6-dimethoxybiphenyl-3-ylcarboxamido)- mercapto-1,2,4-triazole: 3-(2,4-dihydroxy-5-ethyl-phenyl)- 8-methyl-2-oxo-2H-chromen-7-yl propionate: 3-(3'.6- 4-(1-n-butyl-indol-4-yl)-5-mercapto-1,2,4-triazole: 3-(2,4- dimethoxybiphenyl-3-ylcarboxamido)-8-methyl-2-oxo-2H dihydroxy-5-ethyl-phenyl)-4-(1-n-pentyl-indol-4-yl)-5- chromen-7-yl cyclopropane carboxylate; and 3-(3',6- mercapto-1,2,4-triazole: 3-(2,4-dihydroxy-5-ethyl-phenyl)- dimethoxybiphenyl-3-ylcarboxamido)-6-methoxy-8- 4-(1-n-hexyl-indol-4-yl)-5-mercapto-1,2,4-triazole; 3-(2,4- methyl-2-oxo-2H-chromen-7-yl acetate). dihydroxy-5-cyclopropyl-phenyl)-4-(1-(1- 1164. The antibody used in a combinatorial regime can be, methylcyclopropyl)-indol-4-yl)-5-mercapto-1,2,4-triazole; but is not limited to, an antibody that specifically binds a 3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-isopropyl-7- Surface marker expressed on a tumor cell Such that the Surface methoxy-indol-4-yl)-5-mercapto-1,2,4-triazole; 3-(2,4-di marker is immunologically distinct from a Surface marker hydroxy-5-cyclopropyl-phenyl)-4-(1,2,3-trimethyl-indol-5- expressed on a non-tumor cell. Examples include, but are not yl)-5-mercapto-1,2,4-triazole; 3-(2,4-dihydroxy-5-ethyl limited to, Her2 (Herceptin). Additionally, many tumors phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto respond to anti-angiogenic antibodies Such as antibodies to 1.2.4 triazole disodium salt; 3-(2,4-dihydroxy-5-tert-butyl VEGF-2, antibodies to high molecular weight melanoma phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto associated antigen (HMW-MAA), antibodies to CD105 (en 1.2.4 triazole; 3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4- doglin), and other antibodies, and Such antibodies can be (1-propyl-7-methoxy-indol-4-yl)-5-mercapto-1.2.4 employed in a combinatorial regime according to the present triazole: 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3- invention. ethyl-indol-5-yl)-5-mercapto-1,2,4-triazole; 3-(2,4- 1165. When an adjuvant is used in a combinatorial regime, dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5- the adjuvant can be, but is not limited to, GM-CSF, poly mercapto-1.2.4 triazole; 3-(2,4-dihydroxy-5-isopropyl ICLC (carboxymethylcellulose, polyinosinic-polycytidylic phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto acid, and poly L-lysine), nanoparticles, microparticles, alu 1.2.4 triazole; 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1- minum salts, squalene, QS-21 (a plant extract from Ouillaia methyl-3-isopropyl-indol-5-yl)-5-mercapto-1,2,4-triazole, saponaria containing water-soluble triterpene glycosides), 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-ethyl-carbozol-7- Virosomes, IL-2, IL-7, IL-21, and type 1 interferons. yl)-5-mercapto-1,2,4-triazole; 3-(2,4-dihydroxy-5-ethyl 1166 Phosphatidylinositide 3-kinases (PI3K) area family phenyl)-4-(1-isopropyl-7-hydroxy-indol-4-yl)-5-mercapto of enzymes involved in a large number of cellular functions 1.2.4 triazole; 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1- including cell growth, proliferation, cellular differentiation, isopropyl-7-ethoxy-indol-4-yl)-5-mercapto-1,2,4-triazole; motility, survival, and intracellular trafficking. These func 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5- tions are also implicated in cancer, and PI3K has become an yl)-5-mercapto-1,2,4-triazole; 3-(2,4-dihydroxy-5-ethyl increasingly important target for the treatment of malignan phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-1,2,4-triaz cies. PI3Ks are a family of related intracellular signal trans ole: 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl ducer enzymes capable of phosphorylating the 3-position indol-5-yl)-5-mercapto-1,2,4-triazole: 3-(2,4-dihydroxy-5- hydroxyl group of the inositol ring of phosphatidylinositol. In cyclopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5- vivo, the PI3Ks interact with the insulin receptor substrate mercapto-1.2.4 triazole; 3-(2,4-dihydroxy-5-cyclopropyl (IRS) to regulate glucose uptake through a series of phospho phenyl)-4-(1-methyl-indol-5-yl)-5-mercapto-1,2,4-triazole; rylation events. The PI3K family is divided into three classes, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1H-indol-5-yl)-5- Class I, Class II, and Class III, based on primary structure, mercapto-1,2,4-triazole: 3-(2,4-dihydroxy-5-ethyl-phenyl)- regulation, and in vitro lipid Substrate specificity. Class I 4-(1,2-dimethyl-indol-5-yl)-5-mercapto-1,2,4-triazole; PI3Ks are responsible for the production of phosphatidyli 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-ethyl-indol-5- nositol 3-phosphate (PI(3)P), phosphatidylinositol 3,4-bis yl)-5-mercapto-1,2,4-triazole; and 3-(2,4-dihydroxy-5-iso phosphate (PI(3,4)P), and phosphatidylinositol 3,4,5-tris propyl-phenyl)-4-(1-propyl-indol-5-yl)-5-mercapto-1,2,4 phosphate (PI(3,4)P). These PI3Ks are activated by G triazole); United States Patent Application Publication No. protein-coupled receptors and tyrosine kinase receptors. 2012/0022026 by Krawczyk et al. (17-allylamino-17 They are heterodimeric molecules composed of a regulatory demethoxygeldanamycin hydroquinone hydrochloride, and a catalytic subunit; they are further divided between IA pochonin, radester, 8-arylsulfanyladenine derivatives, 3,4- and IB subsets on sequence similarity. Class IA PI3K is diarylpyrazoleresorcinol derivatives, sheperdin and deriva composed of a heterodimer between a p110 catalytic subunit tives thereof, retaspimycin hydrochloride, (-)epigallocat and a p85 regulatory subunit. There are five variants of the echin-3-gallate, and 4,5-diaryllisoxazole derivatives); United p85 regulatory subunit, designated p85C, p55C, p50C., p85 B. States Patent Application Publication No. 2011/01 18298 by and p85y. There are also three variants of the p110 catalytic Fritz et al.; United States Patent Application Publication No. subunit designated p110C., B, or 8 catalytic subunit. The first 2010/0093824 by Frydman et al.; United States Patent Appli three regulatory subunits are all splice variants of the same cation Publication No. 2010/0022635 by Rajewski (N-(7- gene (Pik3r1), the other two being expressed by other genes ((2R.3R,4S.5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl (Pik3r2 and Pik3r3, p85 B, and p55Y, respectively). The most tetrahydro-2H-pyran-2-yloxy)-2-oxo-2H-chromen-3-yl) highly expressed regulatory subunit is p85a, all three catalytic acetamide; N-(7-((2R,3R.4S.5R)-3,4-dihydroxy-5- Subunits are expressed by separate genes. Class II and III methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8- PI3Kare differentiated from the Class I by their structure and methyl-2-oxo-2H-chromen-3-yl)acetamide: N-(7-((2R,3R, function. Class II comprises three catalytic isoforms (C2C. 4S.5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro C2B, and C2Y), but, unlike Classes I and III, no regulatory 2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-1H proteins. Class II PI3Ks catalyze the production of PI(3)P and indole-2-carboxamide; N-(7-((2R,3R,4S.5R)-3,4- PI(3,4)P from PI; however, little is known about their role in US 2016/0220537 A1 Aug. 4, 2016

immune cells. The distinct feature of Class II PI3Ks is the TG-100713 (3-(2,4-diamino-6-pteridinyl)-phenol), PI3K/ C-terminal C2 domain. This domain lacks critical Asp resi HDAC Inhibitor I (N-hydroxy-2-(((2-(6-methoxypyridin-3- dues to coordinate binding of Ca", which suggests class II yl)-4-morpholinothieno3,2-dpyrimidin-6-yl)methyl)(me PI3Ks bind lipids in a Ca"-independent manner. Class III thyl)amino)pyrimidine-5-carboxamide), YM2O1636 produces only PI(3)P from PI but are more similar to Class I (6-amino-N-3-4-(4-morpholinyl)pyrido3'.2:4.5 furo3.2- in structure, as they exist as a heterodimers of a catalytic dpyrimidin-2-yl)phenyl-3-pyridinecarboxamide), NVP (Vps34) and a regulatory (Vps 15/p150) subunit. Class III BGT226 (8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-(piper seems to be primarily involved in the trafficking of proteins azin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c quinolin-2(3H)-one maleic acid), PF-04691502 (2-amino-8- and vesicles. There is, however, evidence to show that they are ((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-6-(6- able to contribute to the effectiveness of several processes methoxypyridin-3-yl)-4-methylpyrido2,3-dipyrimidin-7 important to immune cells, not least phagocytosis. PI3KS can (8H)-one), PKI-402 (1-(4-(3-ethyl-7-morpholino-3H-1.2.3 activate Akt, as in the PI3K/Akt/mTOR pathway. The various triazolo 4,5-dipyrimidin-5-yl)phenyl)-3-(4-(1- 3-phosphorylated inositides produced by the catalytic activ methylpiperazine-4-carbonyl)phenyl)urea), CH5132799 (5- ity of PI3Ks function in a mechanism by which various sig (7-(methylsulfonyl)-2-morpholino-6,7-dihydro-5H-pyrrolo naling proteins, containing the PX domain, pleckstrinhomol 2,3-dipyrimidin-4-yl)pyrimidin-2-amine), AS-252424 ((Z)- ogy domains (PH domains), FYVE domains, and other 5-((5-(4-fluoro-2-hydroxyphenyl)furan-2-yl)methylene) phosphoinositide-binding domains are recruited to cell mem thiazolidine-2,4-dione), AS-604850 ((Z)-5-((2.2- branes. In general. The pleckStrin homology domain of Akt difluorobenzod1.3dioxol-5-yl)methylene)thiazolidine-2, binds directly to PI(3,4)P and PI(3,4,5)P, which are pro 4-dione), CAY10505 ((E)-5-((5-(4-fluorophenyl)furan-2-yl) duced by activated PI 3-kinase. Since PI(3,4)P, and PI(3,4,5) methylene)thiazolidine-2,4-dione), GSK2126458 (2,4- Ps are restricted to the plasma membrane, this results in trans difluoro-N-(2-methoxy-5-(4-(pyridazin-4-yl)guinolin-6-yl) location of Akt to the plasma membrane. Likewise, the pyridin-3-yl)benzenesulfonamide), A66 ((2S)-N1-(5-(2- phosphoinositide-dependent kinase-1 also contains a pleck tert-butylthiazol-4-yl)-4-methylthiazol-2-yl)pyrrolidine-1,2- strin homology domain that binds directly to PI(3,4)P and dicarboxamide), PF-05212384 (1-(4-(4-(dimethylamino) PI(3,4,5)P, causing it to also translocate to the plasma mem piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3, brane upon activation of PI3K. The colocalization of acti 5-triazin-2-yl)phenyl)urea), PIK-294 (2-((4-amino-3-(3- vated phosphoinositide-dependent kinase-1 and Akt allows hydroxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) Akt to become phosphorylated by phosphoinositide-depen methyl)-5-methyl-3-o-tolylguinazolin-4(3H)-one), PIK-293 dent kinase-bon threonine 308, leading to partial activation of (2-((4-amino-1H-pyrazolo 3,4-dipyrimidin-1-yl)methyl)-5- Akt. Full activation of Akt occurs upon phosphorylation of methyl-3-o-tolylquinazolin-4(3H)-one), XL765 (N-4-3- serine 473 by the TORC2 complex of the mTOR protein (3,5-dimethoxyphenyl)amino-2-quinoxalinyl)aminosul kinase. This signaling pathway has been shown to be required fonylphenyl-3-methoxy-4-methyl-benzamide), PIK-93 (N- for an extremely diverse array of cellular activities, most 5-4-chloro-3-(2-hydroxyethyl)sulfamoylphenyl-4- notably cellular proliferation and survival. The phosphati methylthiazol-2-yl)acetamide), AZD6482 ((R)-2-(1-(7- dylinositol 3-kinase/protein kinase B pathway is stimulated methyl-2-morpholino-4-oxo-4H-pyrido 1,2-alpyrimidin-9- in protection of astrocytes from ceramide-induced apoptosis. yl)ethylamino)benzoic acid), AS-605240 ((Z)-5- Additionally, the Class IA PI3K p110C. is mutated in many (quinoxalin-6-ylmethylene)thiazolidine-2,4-dione), malignancies; many of these mutations cause the kinase to be GSK105.9615 ((Z)-5-(4-(pyridin-4-yl)guinolin-6-yl)meth more active. These mutations have been associated with a ylene)thiazolidine-2,4-dione), TG 100-115 (6.7-bis(3-hy number of types of cancer, including ovarian cancer, cervical droxyphenyl)pteridine-2,4-diamine), IC-87114 (2-((6- cancer, breast cancer, colorectal cancer, endometrial cancer, amino-9H-purin-9-yl)methyl)-5-methyl-3-O- gastric carcinomas, hepatocellular carcinoma, Small and non tolylcuinazolin-4(3H)-one), PIK-75 ((E)-N'-((6-bromoH Small cell lung cancer, thyroid carcinoma, acute myelogenous imidazo[1,2-alpyridin-3-yl)methylene)-N,2-dimethyl-5- leukemia (AML), chronic myelogenous leukemia (CML), and glioblastomas. Inhibitors of phosphatidylinositide 3-ki nitrobenzenesulfonohydrazide hydrochloride), PIK-90, nase (PI3K) include, but are not limited to, wortmannin, XL 147 (N-(3-(benzoc1,2,5thiadiazol-5-ylamino)qui LY294.002, BEZ-205 (2-methyl-2-(4-(3-methyl-2-oxo-8- noxalin-2-yl)-4-methylbenzenesulfonamide), ZSTK474 (2- (quinolin-3-yl)-2,3-dihydroimidazo 4.5-cquinolin-1-yl) (difluoromethyl)-1-(4,6-dimorpholino-1,3,5-triazin-2-yl)- phenyl)propanenitrile), GDC-0941 (2-(1H-indazol-4-yl)-6- 1H-benzodimidazole), and PI-103 (3-4-(4-morpholinyl) ((4-(methylsulfonyl)piperazin-1-yl)methyl)-4- pyrido 3',2:4.5 furo3,2-dpyrimidin-2-yl-phenol). morpholinothieno3,2-dipyrimidine), idelalisib, buparlisib, 1167. Additional inhibitors of PI3K are described in the GDC-0032 (4-5,6-dihydro-2-3-methyl-1-(1-methylethyl)- following United States patents and patent applications, all of 1H-1,2,4-triazol-5-yl)imidazo 1,2-d1.4benzoxazepin-9- which are incorporated herein by this reference: U.S. Pat. No. yl-O.C.-dimethyl-1H-pyrazole-1-acetamide), SF-1126 (N2 8.481,001 to Lamb et al. (quinoxalines); U.S. Pat. No. 8,476, 1,4-dioxo-4-4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl) 431 to Ren et al. (benzoxazoles); U.S. Pat. No. 8,476,282 to morpholinium-4-yl)methoxybutyl-L-arginylglycyl-L-O- Ren et al. (benzoxazoles); U.S. Pat. No. 8,476.268 to aspartyl-L-serine inner salt), NU7441 (8-(4-dibenzothienyl)- Fairhurst et al. (pyrrolidine-1,2-dicarboxamide derivatives, 2-(4-morpholinyl)-4H-1-benzopyran-4-one), BYL-719 including (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1 ((2S) N1-(4-methyl-5-2-(2.2.2-trifluoro-1,1-dimethyl 5-(2-cyclopropyl-pyridin-4-yl)-4-methyl-thiazol-2-yl)- ethyl)-4-pyridinyl-2-thiazolyl)-2-pyrrolidinedicarboxam amide} : (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide ide), IPI-145 (8-chloro-2-phenyl-3-(1S)-1-(9H-purin-6- 1-(5-2-(2-fluoro-phenyl)-pyridin-4-yl)-4-methyl-thiazol ylamino)ethyl-1(2H)-isoquinolinone), GSK2636771 2-yl)-amide); (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide (2-methyl-1-(2-methyl-3-(trifluoromethyl)phenyl)methyl 1-(5-(2-cyclobutyl-pyridin-4-yl)-4-methyl-thiazol-2-yl)- 6-(4-morpholinyl)-1H-Benzimidazole-4-carboxylic acid), amide} : (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide

US 2016/0220537 A1 Aug. 4, 2016

6-chloro-3-ethoxy-2-(2-oxo-1,3-oxazolidin-5-yl) diallylbenzene-1,2-diol, 4-allyl-5-propylbenzene-1,2-diol; benzonitrile; 6-3-1-(4-amino-3-methyl-1H-pyrazolo 3,4- 4.5-diallyl-1,2-phenylene diacetate, 4-allyl-1,2-phenylene dpyrimidin-1-yl)ethyl-5-chloro-2-methoxy-6- diacetate, 4-allyl-5-propyl-1,2-phenylene diacetate; (E)- methylphenylmorpholin-3-one: 5-3-1-(4-amino-3- ethyl 4-(3,4-dihydroxyphenyl)-4-methylpent-2-enoate; (E)- methyl-1H-pyrazolo 3,4-dpyrimidin-1-yl)ethyl-5-chloro 4-(5-ethoxy-2-methyl-5-oxopent-3-en-2-yl)-1,2-phenylene 2-methoxy-6-methylphenyl-1,3-oxazolidin-2-one: 4-3-1- diacetate; 3-allyl-benzene-1,2-diol; and 3-allyl-1,2-phe (4-amino-3-methyl-1H-pyrazolo 3,4-dpyrimidin-1-yl) nylene diacetate); United States Patent Application Publica ethyl-5-chloro-2-ethoxy-6-fluorophenylpyrrolidin-2-one; tion No. 2012/0178736 by Castanedo et al. (bicyclic pyrim 4-1-(4-amino-3-methyl-1H-pyrazolo 3,4-dpyrimidin-1-yl) idines); United States Patent Application Publication No. ethyl-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzoni 2012/0171199 by Dotsonetal. (tricyclic compounds); United States Patent Application Publication No. 2012/0165321 by trile, 4-3-1-(4-amino-3-methyl-1H-pyrazolo 3,4-dipyri Adams et al. (quinoline derivatives); United States Patent midin-1-yl)ethyl-5-chloro-2-ethoxy-6-fluorophenyl-1,3- Application Publication No. 2012/0157430 by Li et al. (N- oxazolidin-2-one; and 5-3-1-(4-amino-3-methyl-1H (1-(substituted-phenyl)ethyl)-9H-purin-6-amine deriva pyrazolo 3,4-dpyrimidin-1-yl)ethyl-5-chloro-2-ethoxy-6- tives); United States Patent Application Publication No. fluorophenyl-1,3-oxazolidin-2-one); United States Patent 2012/0129848 by Shuttleworth et al. (benzoE1.3oxazin Application Publication No. 2013/0029984 by Castro et al.: 4-one derivatives); United States Patent Application Publica United States Patent Application Publication No. 2013/ tion No. 2012/0108627 by Kumar et al. (imidazo[4,5-c. 0029982 by Castro et al.: United States Patent Application quinoline derivatives); United States Patent Application Publication No. 2013/0018057 by Burliet al. (quinoline and Publication No. 2012/0077815 by Allen et al. (amino-substi quinoxaline derivatives, substituted by a fused bicyclic pyri tuted fused pyridine and pyrazine derivatives); United States dine or pyrimidine moiety attached via an alkylene chain Patent Application Publication No. 2012/007 1475 by optionally linked to a heteroatom); United States Patent Taniyama et al. (urea derivatives); United States Patent Appli Application Publication No. 2013/0012517 by Allen et al. cation Publication No. 2012/0053167 by Allen et al. (substi (quinoline and quinoxaline derivatives, Substituted by an tuted 1.3.5 triazin-2-yl derivatives); United States Patent optionally Substituted bicyclic heteroaryl moiety consisting Application Publication No. 2012/0053166 by Hamblin et al. of two fused six-membered aromatic rings attached via an (4-oxadiazol-2-yl-indazoles); United States Patent Applica alkylene chain optionally linked to a heteroatom); United tion Publication No. 2012/0035208 by Dotson et al. (pyrazol States Patent Application Publication No. 2012/0263712 by opyridines); and United States Patent Application Publication Fairhurst et al. (pyrrolidine-1,2-dicarboxamide derivatives): No. 2012/0015964 by Fowler et al. (3-(2,6-difluoro-phenyl)- United States Patent Application Publication No. 2012/ 2-1-(9H-purin-6-ylamino)-ethyl-3H-quinazolin-4-one). 0252802 by Brown et al. ((alpha-substituted aralkylamino or heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benz 1168 Directed antibody conjugates, also known as anti imidazoles); United States Patent Application Publication body-drug conjugates, are well known in the art. Examples No. 2012/0245171 by Baldwin et al. (benzpyrazole deriva include brentuximab vedotin and trastuzumab emtansine. tives); United States Patent Application Publication No. Directed antibody conjugates (antibody-drug conjugates or 2012/0245144 by Heffron et al. (benzoxazepine com ADC) are described in U.S. Pat. No. 8,470,329 to Oflazoglu pounds); United States Patent Application Publication No. et al., U.S. Pat. No. 8,466,260 to Elkins et al., U.S. Pat. No. 2012/0238587 by Lee et al. (pyridopyrimidines); United 8,461,117 to Sufi et al., U.S. Pat. No. 8,436,147 to Dennis et States Patent Application Publication No. 2012/0238571 by al., U.S. Pat. No. 8,420,086 to Govindan et al., and U.S. Pat. Baldwin et al. (indazole derivatives); United States Patent No. 8.394.967 to Ebens, Jr. et al., all of which are incorpo Application Publication No. 2012/0232072 by Kumar et al. rated by this reference. In a directed antibody conjugate (an (imidazopyridine derivatives); United States Patent Applica tibody-drug conjugate), typically, the therapeutic agent and tion Publication No. 2012/0225859 by Burger et al. (pyrimi antibody are covalently joined by a cleavable linker. A num dine derivatives); United States Patent Application Publica ber of cleavable linkers are known in the art. tion No. 2012/0220587 by Emde et al. (pyridinylimidazolone 1169 Adjuvants are well known in the art and are derivatives); United States Patent Application Publication described above. No. 2012/02028.05 by Liang (6-(2-difluoromethyl-benzoimi 1170 Kinase inhibitors are well known in the art. Kinase dazol-1-yl)-9-2-(4-methanesulfonyl-piperazin-1-yl)-ethyl inhibitors block the phosphorylation of one or more serine, 2-morpholin-4-yl-9H-purine: 2-6-2-(difluoromethyl)ben threonine, tyrosine, or in Some cases, histidine residues in Zimidazol-1-yl)-2-morpholin-4-ylpurin-9-yl)ethan-1-ol; proteins that are the Substrates of kinases. Many kinases regu 6-(2-difluoromethyl-benzoimidazol-1-yl)-2-morpholin-4- late cell proliferation and represent targets for chemotherapy. y1-9-(tetrahydro-pyran-4-yl)-9H-purine; 9-sec-butyl-6-(2- Kinase inhibitors can be either Small molecules, monoclonal difluoromethyl-benzoimidazol-1-yl)-2-morpholin-4-yl-9H antibodies, or RNA aptamers. Small-molecule kinase inhibi purine; 2-6-(2-difluoromethyl-benzoimidazol-1-yl)-2- tors include, but are not limited to, afatinib, axitinib, bosu morpholin-4-yl-purin-9-yl-propan-1-ol; 2-6-(2- tinib, crizotinib, dasatinib, erlotinib, fostamatinib, gefitinib, difluoromethyl-benzoimidazol-1-yl)-2-(8-oxa-3-aza ibrutinib, lapatinib, lenvatinib, mulbritinib, nilotinib, pazo bicyclo[3.2.1]oct-3-yl)-purin-9-yl)-propan-1-ol: 4-1-(2H panib, ruxolitinib, Sorafenib, Sunitinib, SU6656 (3Z) N.N- 3,4,5,6-tetrahydropyran-4-yl)-4-2-(difluoromethyl) Dimethyl-2-oxo-3-(4,5,6,7-tetrahydro-1H-indol-2-ylmeth benzimidazolylpyrazolo5,4-dipyrimidin-6-yl)morpholine; ylidene)-2,3-dihydro-1H-indole-5-sulfonamide)), and 4-4-2-(difluoromethyl)benzimidazolyl-6-morpholin tofacitinib, Vandetanib, and Vemurafenib. Monoclonal anti 4-ylpyrazolo 5,4-dipyrimidinyl)piperidyl 4-methylpiperazi body kinase inhibitors include, but are not limited to, bevaci nylketone); United States Patent Application Publication No. Zumab, cetuximab, panitumumab, ranibizumab, and trastu 2012/0190738 by Bandyopadhyay et al. (4-allyl-benzene-1, Zumab. RNA aptamer kinase inhibitors include, but are not 2-diol (hydroxychavicol); 4.5-diallylbenzene-1,2-diol: 3,4- limited to, pegaptinib. US 2016/0220537 A1 Aug. 4, 2016

1171 Another aspect of the present invention is a compo derivative, analog, or prodrug of the therapeutic agent is sition to improve the efficacy and/or reduce the side effects of optimized for increasing an immunologic response; and Suboptimally administered drug therapy comprising an alter 1180 (vii) a composition comprising: native selected from the group consisting of 1181 (a) a therapeutically effective quantity of a 1172 (i) a therapeutically effective quantity of a modi therapeutic agent or a derivative, analog, or prodrug of fied therapeutic agent or a derivative, analog, or prodrug a therapeutic agent; and of a therapeutic agent or modified therapeutic agent, 1182 (b) at least one immune adjuvant for stimulat wherein the modified therapeutic agent or the derivative, ing an immune response; analog or prodrug of the therapeutic agent or modified wherein the therapeutic agent, the modified therapeutic agent, therapeutic agent possesses increased therapeutic effi or the derivative, analog, or prodrug of a therapeutic agent or cacy or reduced side effects as compared with an modified therapeutic agent Subject to the bulk drug product unmodified therapeutic agent; improvement possesses increased therapeutic efficacy or 1173 (ii) a composition comprising: reduced side effects as compared with an unmodified thera 1174 (a) a therapeutically effective quantity of a peutic agent; wherein the unmodified therapeutic agent is therapeutic agent, a modified therapeutic agent or a bisantrene or a derivative or analog of bisantrene, the modi derivative, analog, or prodrug. ofatherapeutic agent or fied therapeutic agent is a modification of bisantrene or a modified therapeutic agent; and derivative or analog of bisantrene, and the derivative, analog, or prodrug is a derivative, analog, or prodrug of bisantrene or 1175 (b) at least one additional therapeutic agent, of a derivative or analog of bisantrene. therapeutic agent Subject to chemosensitization, 1183. In one alternative, the composition comprises a therapeutic agent Subject to chemopotentiation, dilu composition to improve the efficacy and/or reduce the side ent, excipient, solvent system, drug delivery system, effects of Suboptimally administered drug therapy compris or agent for enhancing the activity or efficacy of the ing a therapeutically effective quantity of a therapeutic agent therapeutic agent, the modified therapeutic agent or or modified therapeutic agent or a derivative, analog, or pro the derivative, analog, or prodrug of a therapeutic drug of a therapeutic agent or modified therapeutic agent, agent or modified therapeutic agent of (a), wherein the wherein the therapeutic agent or modified therapeutic agent composition possesses increased therapeutic efficacy or the derivative, analog or prodrug of the therapeutic agent or or reduced side effects as compared with an unmodi modified therapeutic agent possesses increased therapeutic fied therapeutic agent; efficacy or reduced side effects, wherein the composition: 1176 (iii) atherapeutically effective quantity ofathera 1184 (a) includes at least one bulk drug product peutic agent, a modified therapeutic agent, or a deriva improvement; tive, analog, or prodrug of a therapeutic agent or modi fied therapeutic agent that is incorporated into a dosage 1185 (b) is produced in a specified dosage form; form, wherein the therapeutic agent, the modified thera 1186 (c) includes a drug conjugate form; peutic agent, or the derivative, analog, or prodrug of a 1187 (d) includes a compound analog; or therapeutic agent or modified therapeutic agent incorpo 1188 (e) includes a prodrug; rated into the dosage form possesses increased therapeu wherein the therapeutic agent, the modified therapeutic agent, tic efficacy or reduced side effects as compared with an or the derivative, analog, or prodrug of a therapeutic agent or unmodified therapeutic agent; modified therapeutic agent Subject to the bulk drug product 1177 (iv) a therapeutically effective quantity of a thera improvement possesses increased therapeutic efficacy or peutic agent, a modified therapeutic agent, or a deriva reduced side effects as compared with an unmodified thera tive, analog, or prodrug of a therapeutic agent or modi peutic agent; wherein the unmodified therapeutic agent is fied therapeutic agent that is incorporated into a dosage bisantrene or a derivative or analog of bisantrene, the modi kit and packaging, wherein the therapeutic agent, the fied therapeutic agent is a modification of bisantrene or a modified therapeutic agent, or the derivative, analog, or derivative or analog of bisantrene, and the derivative, analog, prodrug of a therapeutic agent or modified therapeutic or prodrug is a derivative, analog, or prodrug of bisantrene or agent incorporated into the dosage kit and packaging of a derivative or analog of bisantrene. possesses increased therapeutic efficacy or reduced side 1189. In another alternative, the composition comprises a effects as compared with an unmodified therapeutic composition to improve the efficacy and/or reduce the side agent; and effects of Suboptimally administered drug therapy compris 1178 (V) a therapeutically effective quantity of a thera ing a therapeutically effective quantity of a therapeutic agent peutic agent, a modified therapeutic agent, or a deriva or modified therapeutic agent, wherein the composition: tive, analog, or prodrug of a therapeutic agent or modi 1190 (a) is formulated for use in a program of dose fied therapeutic agent that is Subjected to a bulk drug modification; product improvement, wherein the therapeutic agent, 1191 (b) is formulated for use in a program of alteration the modified therapeutic agent, or the derivative, analog, or modification of route of administration; or prodrug. ofatherapeutic agent or modified therapeutic 1192 (c) is formulated for use in a program of alteration agent Subject to the bulk drug product improvement or modification of schedule of administration; possesses increased therapeutic efficacy or reduced side 1193 (d) is formulated for use in a program of selecting effects as compared with an unmodified therapeutic appropriate indications for use: agent, 1194 (e) is formulated for use in a program of selecting 1179 (vi) a therapeutically effective quantity of a thera appropriate disease stages for use: peutic agent or a derivative, analog, or prodrug of a 1195 (f) is formulated for use in a program of selecting therapeutic agent, wherein the therapeutic agent or the appropriate additional indications for use: US 2016/0220537 A1 Aug. 4, 2016

1196 (g) is formulated for use in a program of selecting 1225 (i) at least one adjuvant; or appropriate patients for use of the composition; 1226 (j) an additional therapeutic agent suitable for use 1197 (h) is formulated for use in a program of selecting with the therapeutic agent in a combinatorial regime, appropriate patient or disease phenotypes for use of the wherein the quantities of the therapeutic agent and the composition; additional therapeutic agent are chosen to provide effec 1198 (i) is formulated for use in a program of selecting tive activity of both the therapeutic agent and the addi appropriate patient or disease genotypes for use of the tional therapeutic agent, wherein the therapeutic agent composition; or the modified therapeutic agent in the composition 1199 () is formulated for use in a program of prefpost possesses increased therapeutic efficacy or reduced side treatment preparation; effects as compared with the therapeutic agent or 1200 (k) is formulated for use in a program of alterna unmodified therapeutic agent as administered individu tive medicine/therapeutic Support; ally and not in the composition, wherein the unmodified 1201 (1) is formulated for use in a program of biothera therapeutic agent is bisantrene or a derivative or analog peutic enhancement; of bisantrene, and the modified therapeutic agent is a 1202 (m) is formulated for use in a program of bio modification of bisantrene or a derivative or analog of therapeutic resistance modulation; bisantrene. 1203 (n) is formulated for use in a program of radiation therapy enhancement; 1227. When the composition is formulated for use in a 1204 (o) is formulated for use to employ novel mecha program of dose modification or in a program of alteration or nisms of action in its therapeutic activity; modification of schedule of administration, one of ordinary 1205 (p) is formulated for use in a program of selective skill in the art would be able to formulate the composition target cell population therapeutics; according to the intended dosage or range of dosages or the 1206 (q) is formulated for use in a program of modu intended schedule of administration, taking into account Such lating DNA methylation: variables as the status or progress of the disease or condition 1207 (r) is formulated for use in a program of inhibiting for which the composition is to be used, other therapeutic telomerase or inducing telomere dysfunction; agents the sex, age, and weight of the patient, and pharmaco 1208 (s) is formulated for use in a program of inhibiting kinetic considerations such as liver or kidney function. When survivin; the composition is formulated for use in a program of alter 1209 (t) further comprises a diluent; ation or modification of route of administration, one of ordi 1210 (u) further comprises a solvent system; nary skill in the art would be able to formulate the composi 1211 (v) further comprises an excipient; tion according to the physical properties of the composition, 1212 (w) is incorporated into a dosage kit and packag such as physical form, flowability, and compatibility of the 1ng composition with the intended route of administration. When 1213 (X) comprises a drug delivery system; or the composition is formulated for use in a program of select ing appropriate indications for use, appropriate disease stages 1214 (y) is formulated to optimize an immunological for use, appropriate additional indications for use, or appro response; priate patients for use of the composition, one of ordinary wherein the therapeutic agent or the modified therapeutic skill in the art would be able to formulate the composition agent in the composition possesses increased therapeutic effi according to the intended requirements, including the targets cacy or reduced side effects as compared with the therapeutic of therapeutic treatment, the possibility of side effects or agent or unmodified therapeutic agent as administered indi toxicity, and the severity or stage of disease intended to be vidually and not in the composition, wherein the unmodified treated. When the composition is formulated for use in a therapeutic agent is bisantrene or a derivative or analog of program of selecting appropriate patient or disease pheno bisantrene, and the modified therapeutic agent is a modifica types or genotypes for use of the composition, one of ordinary tion of bisantrene or a derivative or analog of bisantrene. skill in the art would be able to formulate the composition 1215. In yet another alternative, the composition com according to the intended requirements, including the par prises a composition to improve the efficacy and/or reduce the ticular phenotypes or genotypes involved, the possibility of side effects of Suboptimally administered drug therapy com Somatic mutation in target cells, and the potential for the prising a therapeutically effective quantity of a therapeutic occurrence of drug resistance in target cells. When the com agent or modified therapeutic agent, wherein the composition position is formulated for use in a program of prefpost-treat further comprises: ment preparation or a program of alternative medicine/thera 1216 (a) an additional therapeutic agent; peutic support, one of ordinary skill in the art would be able to 1217 (b) a therapeutic agent subject to chemosensitiza formulate the composition according to the intended require tion; ments, including compatibility and lack of deleterious inter 1218 (c) a therapeutic agent Subject to chemopotentia actions with additional agents being administered or methods tion; being used. When the composition is formulated for use in a 1219 (d) a second therapeutic agent that forms a mul program of biotherapeutic enhancement or biotherapeutic tiple drug system; resistance modulation, one of ordinary skill in the art would 1220 (e)anagent that enhances the activity of the thera be able to formulate the composition according to the peutic agent or intended requirements, including the compatibility with the 1221 modified therapeutic agent; biotherapeutic agents and the lack of side effects or deleteri 1222 (f) at least one survivin modulator or inhibitor; ous interactions. When the composition is formulated for use 1223 (g) at least one multidrug resistance reversal in a program of radiation therapy enhancement, one of ordi agent, nary skill in the art would be able to formulate the composi 1224 (h) at least one directed antibody conjugate; tion according to the intended requirements, including com US 2016/0220537 A1 Aug. 4, 2016

patibility with the means of administering radiation and the tion Publication No. 2014/0186339 by Sabbadini et al. (for lack of side effects or deleterious interactions. When the mulations for ocular administration); and United States composition is formulated for use to employ novel mecha Patent Application Publication No. 2014/0183786 by Bittorf nisms of action in its therapeutic activity, one of ordinary skill et al. (spray-drying methods for preparation of pharmaceuti in the art would be able to formulate the composition accord cal compositions), all of which are incorporated herein by this ing to the intended requirements, including the scope of the reference. novel mechanisms of action, the targets of the novel mecha 1229 Methods of manufacture of pharmaceutical compo nism of action, including cells, tissues, or receptors, and the sitions is further described in S. K. Niazi, “Handbook of lack of side effects or deleterious interactions. When the Pharmaceutical Manufacturing Formulations” (2" ed., composition is formulated for use in a program of selective Informa Healthcare USA, NewYork, N.Y., 2009). Volume 1 is target cell population therapeutics, one of ordinary skill in the Compressed Solid Products; Volume 2 is Uncompressed art would be able to formulate the composition according to Solid Products; Volume 3 is Liquid Products: Volume 4 is the intended requirements, including the properties of the Semisolid Products; Volume 5 is Over-the-Counter Products; intended target cells, the ability of the therapeutic agent or and Volume 6 is Sterile Products. agents in the composition to be delivered to the target cells in 1230 Co-precipitation for use in the preparation of phar active form, and the lack of side effects or deleterious inter maceutical compositions is disclosed in U.S. Pat. No. 5,985, actions. When the composition is formulated for use in a 326 to Butler, incorporated herein by this reference. program of modulating DNA methylation, one of ordinary 1231. Use of alternative salts in the preparation of phar skill in the art would be able to formulate the composition maceutical compositions is disclosed in S. L. Morissette, according to the intended requirements, including the dosage “High-Throughput Crystallization: Polymorphs, Salts, Co required to modulate DNA methylation, the ability of the Crystals and Solvates of Pharmaceutical Solids.” Adv. Drug therapeutic agent or agents to be delivered to cells requiring Deliv Rev. 56: 275-300 (2004). When atherapeutically active modulation of DNA methylation, and the lack of side effects component present in a composition or used in a method or deleterious interactions. When the composition is formu according to the present invention exists in crystalline form, lated for use in a program of inhibiting telomerase or inducing one or more polymorphic forms of the crystalline component telomere dysfunction, one of ordinary skill in the art would be may exist or be prepared. These polymorphic forms may able to formulate the composition according to the intended differ in bioavailability or other properties and may result requirements, including the dosage required to inhibit telom from, for example, differences in the solvent used for crys erase or induce telomere dysfunction, the ability of the thera tallization, the temperature or rate of cooling, or other factors peutic agent or agents to be delivered to cells requiring inhi in the crystallization process. bition of telomerase or inducing telomere dysfunction, and 1232 Typically, the composition possesses increased effi the lack of side effects or deleterious interactions. When the cacy or reduced side effects for cancer therapy. Typically, the composition is formulated for use in a program of inhibiting unmodified therapeutic agent is bisantrene or a derivative or surviving, one of ordinary skill in the art would be able to analog orbisantrene, as described above, the modified thera formulate the composition according to the intended require peutic agent is a modification of bisantrene or a derivative or ments, including the dosage required to inhibit Survivin, the analog of bisantrene, and the derivative, analog, or prodrug is ability of the therapeutic agent or agents to be delivered to a derivative, analog, or prodrug of bisantrene or of a derivative cells requiring inhibition of survivin, and the lack of side or analog of bisantrene. effects or deleterious interactions. Other factors or variables 1233. In one alternative, the composition comprises a drug involved in the preparation of pharmaceutical compositions combination comprising: according to the present invention would be taken into 1234 (i) bisantrene or a derivative or analog of bisant account by one of ordinary skill in the art. rene; and 1235 (ii) an additional therapeutic agent selected from 1228 Manufacturing methods for compositions are well the group consisting of known in the art. Such manufacturing methods are disclosed 1236 (a) fraudulent nucleosides; in United States Patent Application Publication No. 2014/ 1237 (b) fraudulent nucleotides; 0179749 by Lorenz et al.; United States Patent Application 1238 (c) thymidylate synthetase inhibitors; Publication No. 2014/01797.12 by Baker et al. (tablets): U.S. 1239 (d) signal transduction inhibitors; Pat. No. 7,094.545 to Lomryd et al. (solid dosage forms): 1240 (e) cisplatin or platinum analogs; United States Patent Application Publication No. 2014/ 1241 (f) alkylating agents; 0179768 by Bettencourt (emulsions); PCT Patent Applica 1242 (g) anti-tubulin agents; tion Publication No. WO 2007/136219 by Kim et al. (doc etaxel for injection); United States Patent Application 1243 (h) antimetabolites: Publication No. 2014/0179738 by Singh et al. (formulations 1244 (i) berberine; for oral administration); United States Patent Application 1245 () apigenin: Publication No. 2014/0179732 by Jaroskova et al.; United 1246 (k) colchicine or an analog thereof; States Patent Application Publication No. 2014/0179624 by 1247 (1) genistein; Gutterman et al., PCT Patent Application Publication No. 1248 (m) etoposide; WO 2008/107452 by German et al.: United States Patent 1249 (n) cytarabine; Application Publication No. 2014/0186447 by Desai (nano 1250 (o) camptothecins; particulate compositions); United States Patent Application 1251 (p) vinca alkaloids; Publication No. 2014/0186430 by Gould-Fougerite etal. (co 1252 (q) topoisomerase inhibitors; chleate pharmaceutical compositions); United States Patent 1253 (r) 5-fluorouracil; Application Publication No. 2014/0186361 by Manning et al. 1254 (s) curcumin; (stable aqueous formulations); United States Patent Applica 1255 (t) rosmarinic acid; US 2016/0220537 A1 Aug. 4, 2016 89

1256 (u) mitoguaZone; 1300 (bm) GPBP-1 inhibitors, optionally together 1257 (v) meisoindigo; with a p21 inhibitor; and 1258 (w) imatinib; 1301 (bn) PGE inhibitors. 1259 (x) dasatinib; 1302 Typically, in this composition, the bisantrene or a 1260 (y) nilotinib; derivative or analog of bisantrene is bisantrene. 1261 (Z) epigenetic modulators; 1303. In another alternative, the composition comprises: 1262 (aa) transcription factor inhibitors; 1304 (i) bisantrene or a derivative or analog of bisant 1263 (ab) taxol; rene and 1264 (ac) homoharringtonine; 1305 (ii) a therapeutic agent subject to chemosensiti 1265 (ad) pyridoxal; Zation selected from the group consisting of 1266 (ae) spirogermanium; 1306 (a) topoisomerase inhibitors: 1267 (af) caffeine; 1307 (b) fraudulent nucleosides: 1268 (ag) nicotinamide: 1308 (c) fraudulent nucleotides; 1269 (ah) methylglyoxalbisguanylhydrazone: 1309 (d) thymidylate synthetase inhibitors; 1270 (ai) PARP inhibitors: 1310 (e) signal transduction inhibitors; 1271 (a) EGFR inhibitors: 1311 (f) cisplatin or platinum analogs; 1272 (ak) Bruton's tyrosine kinase (BTK) inhibi 1312 (g) alkylating agents; tors; 1313 (h) anti-tubulin agents: 1273 (al) bis-thio-hydrazideamides; 1314 (i) antimetabolites; 1274 (am) succinimide or maleimide derivatives as 1315 (i) berberine; inhibitors of topoisomerase II; 1316 (k) apigenin: 1275 (an) histone deacetylase (HDAC) inhibitors; 1317 (1) colchicine or an analog of colchicine; 1276 (ao) immunostimulants; 1318 (m) genistein; 1277 (ap) telomerase inhibitors; 1319 (n) etoposide; 1278 (aq) inhibitors of the expression or activity of 1320 (o) cytarabine; Her2: 1321 (p) camptothecin: 1279 (at) inhibitors of the expression of activity of 1322 (c) Vinca alkaloids; estrogen receptors; 1323 (r) 5-fluorouracil; 1280 (as) inhibitors of the expression or activity of 1324 (s) curcumin; an antigen associated with a specific tumor targets; 1325 (t) rosmarinic acid; and 1281 (at) G-quadruplex ligands; 1326 (u) mitoguaZone. 1282 (au) polycyclic lysophosphatidic receptor 1327 Typically, in this composition, the bisantrene or a antagonists; derivative or analog of bisantrene is bisantrene. 1283 (av) anti-CTGF agents; 1328. In another alternative, the composition comprises: 1284 (aw) myeloid differentiation inducing agents; 1329 (i) bisantrene or a derivative or analog of bisant 1285 (ax) covalent diabodies binding to a tumor rene and associated antigen; 1330 (ii) a therapeutic agent subject to chemopotentia 1286 (ay) bispecific antibodies that have a cell-pen tion selected from the group consisting of: etrating determinant and an intracellular target-bind 1331 (a) topoisomerase inhibitors: ing determinant; 1332 (b) fraudulent nucleosides: 1287 (az) multidomain molecules that comprise a 1333 (c) fraudulent nucleotides; cell binding ligand that binds to cells in the tumor 1334 (d) thymidylate synthetase inhibitors; stroma such as endothelial cells, fibroblasts, or 1335 (e) signal transduction inhibitors; immune cells and an oligonucleotide that inhibits the 1336 (f) cisplatin or platinum analogs; nonsense-mediated decay pathway; 1337 (g) alkylating agents; 1288 (ba) tumor-specificantibodies binding to a por 1338 (h) anti-tubulin agents: tion of the CD44 protein or a binding protein derived 1339 (i) antimetabolites: from the light-chain or heavy-chain complementary 1340 () berberine; determining regions of Such antibodies; 1341 (k) apigenin; 1289 (bb) inhibitors of CXCR4; 1342 (1) colchicine or an analog of colchicine; 1290 (bc) pyruvate dehydrogenase kinase (PDK1) 1343 (m) genistein; inhibitors; 1344 (n) etoposide; 1291 (bd) epherin receptor targeting agents; 1345 (o) cytarabine; 1292 (be) binding proteins for Axl; 1346 (p) camptothecin: 1293 (bf) Wnt pathway inhibitors together with 1347 (q) Vinca alkaloids; MAPK pathway inhibitors; 1348 (r) 5-fluorouracil; 1294 (bg) TEC family kinase inhibitors; 1349 (s) curcumin; 1295 (bh) substituted macrocyclic compounds with 1350 (t) rosmarinic acid; and proteasome activity; 1351 (u) mitoguaZone. 1296 (bi) peptide-based PACE4 inhibitors: 1352 Typically, in this composition, the bisantrene or a 1297 (b) azaindole derivatives as JAK3 inhibitors: derivative or analog of bisantrene is bisantrene. 1298 (bk) inhibitors of Myc: 1353. In yet another alternative, the therapeutic agent is 1299 (bl) inhibitors of furin and other pro-protein bisantrene or a derivative or analog of bisantrene, and the convertases; amonafide orderivative oranalog of bisantrene is Subjected to US 2016/0220537 A1 Aug. 4, 2016 90 a bulk drug product improvement, wherein the bulk drug 1400 (k) vitamin E: product improvement is selected from the group consisting 1401 (1) esterase inhibitors; of: 1402 (m) cytochrome P450 inhibitors; 1354 (a) preparation as a free base form: 1403 (n) multi-drug resistance (MDR) inhibitors; 1355 (b) salt formation: 1404 (o) organic resins; and 1356 (c) preparation as a homogeneous crystalline 1405 (p) detergents. Structure: 1406 Typically, in this composition, the bisantrene or 1357 (d) amorphous structure; derivative or analog of bisantrene is bisantrene. 1358 (e) preparation as a pure isomer; 1407. In yet another alternative, the therapeutic agent is 1359 (f) increased purity; bisantrene or a derivative or analog of bisantrene, and the 1360 (g) preparation with lower residual solvent con bisantrene or derivative or analog of bisantrene is incorpo tent; and rated into a dosage form selected from the group consisting 1361 (h) preparation with lower residual heavy metal of: COntent. 1408 (a) tablets; 1362 Typically, in this composition, the bisantrene or a 1409 (b) capsules; derivative or analog of bisantrene is bisantrene. 1410 (c) topical gels: 1363. In still another alternative, the therapeutic agent is 1411 (d) topical creams: bisantrene or a derivative or analog of bisantrene and the 1412 (e) patches: composition comprises a diluent, wherein the diluent is 1413 (f) suppositories: selected from the group consisting of: 1414 (g) lyophilized dosage fills; 1364 (a) an emulsion; 1415 (h) immediate-release formulations; 1365 (b) dimethylsulfoxide (DMSO); 1416 (i) slow-release formulations: 1366 (c) N-methylformamide (NMF) 1417 (j) controlled-release formulations: 1367 (d) dimethylformamide (DMF) 1418 (k) liquid in capsules; and 1368 (e) dimethylacetamide (DMA); 1419 (1) liposomal formulations. 1369 (f)ethanol: 1420 Typically, in this composition, the bisantrene or 1370 (g) benzyl alcohol: derivative or analog of bisantrene is bisantrene. 1371 (h) dextrose-containing water for injection; 1421. In yet another alternative, the therapeutic agent is 1372 (i) Cremophor; bisantrene or a derivative or analog of bisantrene and the 1373 () cyclodextrins; and bisantrene or derivative or analog of bisantrene is incorpo 1374 (k) PEG. rated into a dosage kit and packaging selected from the group 1375 Typically, in this composition, the bisantrene or a consisting of amber vials to protect from light and stoppers derivative or analog of bisantrene is bisantrene. with specialized coatings to improve shelf-life stability. 1376. In still another alternative, the therapeutic agent is 1422 Typically, in this composition, the bisantrene or bisantrene or a derivative or analog of bisantrene and the derivative or analog of bisantrene is bisantrene. composition comprises a solvent system, wherein the solvent 1423. In still another alternative, the therapeutic agent is system is selected from the group consisting of: bisantrene or a derivative or analog of bisantrene and the 1377 (a) an emulsion; composition comprises a drug delivery system selected from 1378 (b) DMSO, the group consisting of 1379 (c) NMF; 1424 (a) oral dosage forms; 1380 (d) DMF; 1425 (b) nanocrystals: 1381 (e) DMA; 1426 (c) nanoparticles; 1382 (f)ethanol: 1427 (d) cosolvents: 1383 (g) benzyl alcohol; 1428 (e) slurries: 1384 (h) dextrose-containing water for injection; 1429 (f) syrups: 1385 (i) Cremophor; 1430 (g) bioerodible polymers: 1386 (i) PEG; and 1431 (h) liposomes; 1387 (k) salt systems. 1432 (i) slow-release injectable gels: 1388 Typically, in this composition, the bisantrene or a 1433 () microspheres; derivative or analog of bisantrene is bisantrene. 1434 (k) amphiphilic block copolymer systems; 1389. In yet another alternative, the therapeutic agent is 1435 (1) emulsion vehicles comprising an emulsion of bisantrene or a derivative or analog of bisantrene and the C-tocopherol stabilized by biocompatible surfactants; composition comprises an excipient, wherein the excipient is 1436 (m) biodegradable polymer compositions con selected from the group consisting of: taining phosphorus and desaminotyrosyl L-tyrosine 1390 (a) mannitol; linkages in the polymer backbone; 1391 (b) albumin; 1437 (n) substantially anhydrous injectable semi-solid 1392 (c) EDTA; compositions comprising a water immiscible fatty acid 1393 (d) sodium bisulfite: matrix and a cytostatic agent; 1394 (e) benzyl alcohol: 1438 (o) lipophilic vehicles; 1395 (f) carbonate buffers: 1439 (p) pH-dependent carriers that include a com 1396 (g) phosphate buffers; pound that includes at least one ionizable group; 1397 (h) PEG: 1440 (q) pH-dependent carriers that include a mono 1398 (i) vitamin A; carboxylic acid having at least 8 carbons and less than 1399 () vitamin D; about 10% by weight of Zwitterionic phospholipids; and US 2016/0220537 A1 Aug. 4, 2016

1441 (r) liposomes comprising the bisantrene or the 1474 Typically, in this composition, the modified bisant derivative or analog thereof followed, in use of the com rene or modified derivative or analog of bisantrene is a modi position, by administration of a lipid nanoparticle com fied bisantrene. prising a triggering agent. 1475. In still another alternative of a composition accord 1442 Typically, in this composition, the bisantrene or ing to the present invention, the therapeutic agent is bisant derivative or analog of bisantrene is bisantrene. rene or a derivative or analog of bisantrene and the bisantrene 1443. In yet another alternative, the therapeutic agent is or derivative or analog of bisantrene is in the form of a bisantrene or a derivative or analog of bisantrene and the prodrug system, wherein the prodrug system is selected from bisantrene or derivative or analog of bisantrene is present in the group consisting of the composition in a drug conjugate form selected from the 1476 (a) enzyme sensitive esters; group consisting of 1477) (b) dimers: 1444 (a) a polymer System; 1478 (c) Schiffbases: 1445 (b) polylactides; 1479 (d) pyridoxal complexes: 1446 (c) polyglycolides; 1480 (e) caffeine complexes; 1447 (d) amino acids; 1481 (f) plasmin-activated prodrugs; and 1448 (e) peptides; 1482 (g) drug targeting complexes comprising a target 1449 (f) multivalent linkers: ing carrier molecule that is selectively distributed to a 1450 (g) conjugates to fatty acids; specific cell type or tissue containing the specific cell 1451 (h) conjugates to fatty alcohols; type; a linker which is acted upon by a molecule that is 1452 (i) conjugates to elastin-like peptide; present at an effective concentration in the environs of 1453 () conjugates with polyclonal or monoclonal the specific cell type; and a therapeutically active agent antibodies, proteins, or peptides; to be delivered to the specific cell type; and 1454 (k) conjugates with cell-binding agents through a 1483 (h) a prodrug molecule comprising a conjugate of charged or pro-charged cross-linker, bisantrene or a derivative or analog of bisantrene, a 1455 (1) conjugates to antibodies targeted to tumor protease-specific cleavable peptide, and optionally, a markers; targeting peptide, with the prodrug molecule being Sub 1456 (m) biodegradable polymer-bioactive moiety stantially inactive prior to degradation of the protease conjugates: specific cleavable peptide by a proteolytic enzyme within or in close proximity to the cancer cell. 1457 (n) conjugates with 2-nitroimidazole compounds 1484 Typically, in this composition, the bisantrene or with a secondary basic nitrogen atom and a linker; derivative or analog of bisantrene is bisantrene. 1458 (o) conjugates with ladder frame polyether com 1485. In yet another alternative, the therapeutic agent is pounds, including those derived from brevenal, brevisin, bisantrene or a derivative or analog of bisantrene and the tamulamide, brevetoxins, hemibrevetoxins, gambierols, composition further comprises at least one additional thera and gambieric acids; peutic agent to form a multiple drug system, wherein the at 1459 (p) conjugates to antibodies having one or more least one additional therapeutic agent is selected from the non-natural amino acid residues at specific positions in group consisting of: the heavy or light chains; 1486 (a) inhibitors of multi-drug resistance: 1460 (q) conjugates to a sialoadhesin binding moiety; 1487 (b) specific drug resistance inhibitors; 1461 (r) pheophorbide-C. conjugates; 1488 (c) specific inhibitors of selective enzymes; 1462 (s) conjugates to multi-component nanochains: 1489 (d) signal transduction inhibitors; 1463 (t) conjugates to activatable antibodies that 1490 (e) meiso indigo; include a masking moiety, a cleavable moiety, and an 1491 (f) imatinib: antibody binding specifically to interleukin-6: 1492 (g) hydroxyurea; 1464 (u) conjugates including hydrophilic linkers; 1493 (h) dasatinib: 1465 (v) conjugates to antibodies specific for p97; 1494 (i) capecitabine; 1466 (w) conjugates including a modified amino acid 1495 () nilotinib: incorporating an azido group; 1496 (k) repair inhibition agents: 1467 (X) conjugates to albumin; and 1497 (1) topoisomerase inhibitors with non-overlap 1468 (y) conjugates to folate. ping side effects; 1469. Typically, in this composition, the bisantrene or 1498 (m) PARP inhibitors: derivative or analog of bisantrene is bisantrene. 1499 (n) EGFR inhibitors; and 1470. In yet another alternative, the therapeutic agent is a 1500 (o) HDAC inhibitors. modified bisantrene or a modified derivative or analog of 1501 Typically, in this composition, the bisantrene or bisantrene and the modification is selected from the group derivative or analog of bisantrene is bisantrene. consisting of: 1502. In still another alternative, the therapeutic agent is 1471 (a) alteration of side chains to increase or bisantrene or a derivative or analog of bisantrene and the decrease lipophilicity; composition further comprises at least one agent for enhanc 1472 (b) addition of an additional chemical function ing the activity or efficacy of the bisantrene or derivative or ality to alter a property selected from the group consist analog of bisantrene, wherein the at least one agent for ing of reactivity, electron affinity, and binding capacity; enhancing the activity or efficacy of the bisantrene or deriva and tive or analog of bisantrene is selected from the group con 1473 (c) alteration of salt form. sisting of: US 2016/0220537 A1 Aug. 4, 2016 92

1503 (i) nicotinamide: 1531 (g) an adjuvant, wherein the bisantrene or deriva 1504 (ii) caffeine: tive or analog thereofacts as a chemotherapeutic agent; 1505 (iii) tetandrine; and 1532 (h) an antibody, wherein the bisantrene or deriva 1506 (iv) berberine. tive or analog thereofacts as a chemotherapeutic agent; 1507 Typically, in this composition, the bisantrene or 1533 (i) an innate or adaptive immune stimulator, derivative or analog of bisantrene is bisantrene. wherein the bisantrene or derivative or analog thereof 1508. In still another alternative, the composition com acts as a chemotherapeutic agent; prises a therapeutically effective quantity of bisantrene or a 1534 () a checkpoint inhibitor, wherein the bisantrene derivative, analog, or prodrug of bisantrene, wherein the or derivative or analog thereofacts as a chemotherapeu bisantrene or the derivative, analog, or prodrug of bisantrene tic agent; is optimized for increasing an immunologic response. 1535 (k) an mTOR antagonist, wherein the bisantrene 1509 Typically, in this composition, the bisantrene or or derivative or analog thereofacts as a chemotherapeu derivative or analog of bisantrene is bisantrene. tic agent; 1510. In still another alternative, the composition com 1536 (1) an Akt inhibitor, wherein the bisantrene or prises: derivative or analog thereofacts as a chemotherapeutic 1511 (a) a therapeutically effective quantity of bisant agent, rene or a derivative, analog, or prodrug of bisantrene; 1537 (m) a notch inhibitor, wherein the bisantrene or and derivative or analog thereofacts as a chemotherapeutic 1512 (b) at least one immune adjuvant for stimulating agent, an immune response. 1538 (n) an HSP inhibitor, wherein the bisantrene or 1513 Suitable immune adjuvants are as described above. derivative or analog thereofacts as a chemotherapeutic 1514 Typically, in this composition, the bisantrene or agent, derivative or analog of bisantrene is bisantrene. 1539 (o) a phosphatidylinositide 3-kinase inhibitor, 1515. In still another alternative, the composition com wherein the bisantrene or derivative or analog thereof prises: acts as a chemotherapeutic agent; 1516 (a) a therapeutically effective quantity of bisant 1540 (p) a kinase inhibitor, wherein the bisantrene or rene or a derivative or analog of bisantrene; and derivative or analog thereofacts as a chemotherapeutic 1517 (b) a multidrug resistance reversal agent. agent, 1518. Typically, the multidrug resistance reversal agent is 1541 (q) an agent inducing telomerase inhibition, Verapamil. wherein the bisantrene or derivative or analog thereof 1519 Typically, in this composition, the bisantrene or acts as an agent inducing macrophage activation; derivative or analog of bisantrene is bisantrene. 1520. In yet another alternative, the composition com 1542 (r) a cytokine, wherein the bisantrene or deriva prises: tive or analog thereofacts as an agent inducing macroph 1521 (a) a therapeutically effective quantity of bisant age activation; rene or a derivative or analog of bisantrene; and 1543 (s) an agent inhibiting survivin, wherein the 1522 (b) an additional therapeutic agent suitable for bisantrene or derivative or analog thereof acts as an use with the bisantrene or the derivative or analog of agent inducing macrophage activation; bisantrene in a combinatorial regime; 1544 (t) an agent inducing demethylation, wherein the wherein the quantities of the bisantrene or the derivative or bisantrene or derivative or analog thereof acts as an analog of bisantrene and the additional therapeutic agent are agent inducing macrophage activation; chosen to provide effective activity of both the bisantrene or 1545 (u) an adjuvant, wherein the bisantrene or deriva the derivative or analog of bisantrene and the additional thera tive or analog thereofacts as an agent inducing macroph peutic agent. age activation; 1523 Typically, in this composition, the bisantrene or 1546 (v) an antibody, wherein the bisantrene or deriva derivative or analog of bisantrene is bisantrene. tive or analog thereofacts as an agent inducing macroph 1524 Typically, in this composition, the additional thera age activation; peutic agent is selected from the group consisting of 1547 (w) an innate or adaptive immune stimulator, 1525 (a) an agent inducing immunoactivity, wherein wherein the bisantrene or derivative or analog thereof the bisantrene or derivative or analog thereof acts as a acts as an agent inducing macrophage activation; chemotherapeutic agent; 1548 (x) a checkpoint inhibitor, wherein the bisantrene 1526 (b) an agent inducing macrophage activation, or derivative or analog thereofacts as an agent inducing wherein the bisantrene or derivative or analog thereof macrophage activation; acts as a chemotherapeutic agent; 1549 (y) an mTOR antagonist, wherein the bisantrene 1527 (c) a cytokine, wherein the bisantrene or deriva or derivative or analog thereofacts as an agent inducing tive or analog thereofacts as a chemotherapeutic agent; macrophage activation; 1528 (d) an agent inhibiting telomerase, wherein the 1550 (z) an Akt inhibitor, wherein the bisantrene or bisantrene or derivative or analog thereofacts as a che derivative or analog thereof acts as an agent inducing motherapeutic agent; macrophage activation; 1529 (e) an agent inhibiting surviving, wherein the 1551 (aa) a notch inhibitor, wherein the bisantrene or bisantrene or derivative or analog thereofacts as a che derivative or analog thereof acts as an agent inducing motherapeutic agent; macrophage activation; 1530 (f) an agent inducing demethylation, wherein the 1552 (ab) an HSP inhibitor; wherein the bisantrene or bisantrene or derivative or analog thereofacts as a che derivative or analog thereof acts as an agent inducing motherapeutic agent; macrophage activation; US 2016/0220537 A1 Aug. 4, 2016 93

1553 (ac) a phosphatidylinositide 3-kinase inhibitor, acid, Such as acetic acid, maleic acid, Succinic acid, mandelic wherein the bisantrene or derivative or analog thereof acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, acts as an agent inducing macrophage activation; and glycolic acid, Salicylic acid, a pyranosidyl acid, such as glu 1554 (ad) a kinase inhibitor, wherein the bisantrene or curonic acid or galacturonic acid, an alpha-hydroxy acid, derivative or analog thereof acts as an agent inducing Such as citric acid or tartaric acid, an amino acid, Such as macrophage activation. aspartic acid or glutamic acid, an aromatic acid. Such as 1555 Typically, the composition is optimized to treat a benzoic acid or cinnamic acid, a Sulfonic acid, Such as p-tolu hyperproliferative disease. Typically, the hyperproliferative enesulfonic acid or ethanesulfonic acid, or the like. If the disease is cancer. Typically, the cancer is a form of cancer pharmacologically active compound has one or more acidic selected from the group consisting of breast cancer, (includ functional groups, the desired pharmaceutically acceptable ing refractory and triple-negative breast cancer), acute salt may be prepared by any suitable method available in the myelocytic leukemia, acute leukemias of childhood, lym art, for example, treatment of the free acid with an inorganic phoma and ovarian cancer. or organic base. Such as an amine (primary, secondary or 1556. In one alternative, the composition is formulated for tertiary), an alkali metal hydroxide or alkaline earth metal intravenous, intraperitoneal, or Subcutaneous administration. The composition can alternatively be formulated for other hydroxide, or the like. Illustrative examples of suitable salts routes of administration, Such as, but not limited to, central or include organic salts derived from amino acids, such as gly peripheral venous administration, intravesicular administra cine and arginine, ammonia, primary, secondary, and tertiary tion (particularly for use in treating bladder cancer), intrath amines, and cyclic amines, such as piperidine, morpholine ecal administration, and intra-arterial administration. and piperazine, and inorganic salts derived from Sodium, 1557. When a pharmaceutical composition according to calcium, potassium, magnesium, manganese, iron, copper, the present invention includes a prodrug, prodrugs and active Zinc, aluminum and lithium. metabolites of a compound may be identified using routine 1559. In the case of agents that are solids, it is understood techniques known in the art. See, e.g., Bertolini et al., J. Med. by those skilled in the art that the inventive compounds and Chem., 40, 2011-2016 (1997); Shan et al., J. Pharm. Sci., 86 salts may exist in different crystal or polymorphic forms, all (7), 765-767: Bagshawe, Drug Dev. Res., 34,220-230 (1995); of which are intended to be within the scope of the present Bodor, Advances in Drug Res., 13, 224-331 (1984); Bund invention and specified formulas. gaard, Design of Prodrugs (Elsevier Press 1985); Larsen, Design and Application of Prodrugs, Drug Design and Devel 1560. The amount of a given pharmacologically active opment (Krogsgaard-Larsen et al., eds., Harwood Academic agent that is included in a unit dose of a pharmaceutical Publishers, 1991); Dearet al., J. Chromatogr. B, 748,281-293 composition according to the present invention will vary (2000); Spraulet al., J. Pharmaceutical & Biomedical Analy depending upon factors such as the particular compound, sis, 10, 601-605 (1992); and Proxet al., Xenobiol. 3, 103-112 disease condition and its severity, the identity (e.g., weight or (1992), all incorporated herein by this reference. Surface area) of the Subject in need of treatment, but can 1558. When the pharmacologically active compound in a nevertheless be routinely determined by one skilled in the art. pharmaceutical composition according to the present inven Typically, such pharmaceutical compositions include athera tion possesses a Sufficiently acidic, a Sufficiently basic, or peutically effective quantity of the pharmacologically active both a sufficiently acidic and a sufficiently basic functional agent and an inert pharmaceutically acceptable carrier or group, these group or groups can accordingly react with any diluent. Typically, these compositions are prepared in unit of a number of inorganic or organic bases, and inorganic and dosage form appropriate for the chosen route of administra organic acids, to form a pharmaceutically acceptable salt. tion, Such as oral administration or parenteral administration. Exemplary pharmaceutically acceptable salts include those A pharmacologically active agent as described above can be salts prepared by reaction of the pharmacologically active administered in conventional dosage form prepared by com compound with a mineral or organic acid or an inorganic bining a therapeutically effective amount of Such a pharma base. Such as salts including Sulfates, pyrosulfates, bisulfates, cologically active agent as an active ingredient with appro Sulfites, bisulfites, phosphates, monohydrogenphosphates, priate pharmaceutical carriers or diluents according to dihydrogenphosphates, metaphosphates, pyrophosphates, conventional procedures. These procedures may involve mix chlorides, bromides, iodides, acetates, propionates, ing, granulating and compressing or dissolving the ingredi decanoates, caprylates, acrylates, formates, isobutyrates, ents as appropriate to the desired preparation. The pharma caproates, heptanoates, propiolates, oxalates, malonates, suc ceutical carrier employed may be either a solid or liquid. cinates, Suberates, sebacates, fumarates, maleates, butyne-1, Exemplary of Solid carriers are lactose. Sucrose, talc, gelatin, 4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, agar, pectin, acacia, magnesium Stearate, Stearic acid and the methyl benzoates, dinitrobenzoates, hydroxybenzoates, like. Exemplary of liquid carriers are syrup, peanut oil, olive methoxybenzoates, phthalates, Sulfonates, Xylenesulfonates, oil, water and the like. Similarly, the carrier or diluent may phenylacetates, phenylpropionates, phenylbutyrates, citrates, include time-delay or time-release material known in the art, lactates, B-hydroxybutyrates, glycolates, tartrates, methane Such as glyceryl monostearate or glyceryl distearate alone or Sulfonates, propanesulfonates, naphthalene-1-sulfonates, with a wax, ethylcellulose, hydroxypropylmethylcellulose, naphthalene-2-sulfonates, and mandelates. If the pharmaco methylmethacrylate and the like. logically active compound has one or more basic functional 1561. A variety of pharmaceutical forms can be employed. groups, the desired pharmaceutically acceptable salt may be Thus, if a solid carrier is used, the preparation can be tableted, prepared by any suitable method available in the art, for placed in a hard gelatin capsule in powder or pellet form or in example, treatment of the free base with an inorganic acid, the form of a troche or lozenge. The amount of solid carrier Such as hydrochloric acid, hydrobromic acid, Sulfuric acid, may vary, but generally will be from about 25 mg to about 1 nitric acid, phosphoric acid and the like, or with an organic g. If a liquid carrier is used, the preparation will be in the form US 2016/0220537 A1 Aug. 4, 2016 94 of syrup, emulsion, Soft gelatin capsule, sterile injectable lar, for bisantrene or derivatives or analogs thereof, suitable Solution or Suspension in an ampoule or vial or non-aqueous doses typically are from about 50 mg/m to about 500 mg/m liquid Suspension. or from about 0.1 mg/kg to about 10 mg/kg. These doses are 1562. To obtain a stable water-soluble dose form, a phar particularly suitable for bisantrene. maceutically acceptable salt of a pharmacologically active 1566 Plasma concentrations in the subjects may be agent as described above is dissolved in an aqueous solution between about 1 uM to about 1000 uM. In some embodi of an organic or inorganic acid, Such as 0.3 M solution of ments, the plasma concentration may be between about 200 Succinic acid or citric acid. If a soluble salt form is not avail uM to about 800 uM. In other embodiments, the concentra able, the agent may be dissolved in a suitable cosolvent or tion is about 300 uM to about 600 uM. In still other embodi combinations of cosolvents. Examples of suitable cosolvents ments the plasma concentration may be between about 400 to include, but are not limited to, alcohol, propylene glycol, about 800 uM. In one typical alternative, dosages of bisant polyethylene glycol 300, polysorbate 80, glycerin and the like rene or a derivative or analog of bisantrene are from about 1 in concentrations ranging from 0-60% of the total volume. In mg/m/day to about 600 mg/m/day. Administration of pro an exemplary embodiment, a compound of Formula I is dis drugs is typically dosed at weight levels which are chemically solved in DMSO and diluted with water. The composition equivalent to the weight levels of the fully active form. may also be in the form of a solution of a salt form of the active 1567 Pharmaceutical formulations for parenteral admin ingredient in an appropriate aqueous vehicle Such as water or istration can include aqueous Solutions or Suspensions. Suit isotonic saline or dextrose Solution. able lipophilic solvents or vehicles include fatty oils such as 1563. It will be appreciated that the actual dosages of the sesame oil or synthetic fatty acid esters, such as ethyl oleate or agents used in the compositions of this invention will vary triglycerides. Aqueous injection Suspensions may contain according to the particular complex being used, the particular Substances which increase the viscosity of the Suspension, composition formulated, the mode of administration and the Such as Sodium carboxymethyl cellulose, Sorbitol, or dextran. particular site, host and disease and/or condition being Optionally, the Suspension may also contain Suitable stabiliz treated. Actual dosage levels of the active ingredients in the ers or modulators which increase the solubility or dispersibil pharmaceutical compositions of the present invention can be ity of the composition to allow for the preparation of highly varied so as to obtainanamount of the active ingredient which concentrated Solutions, or can contain Suspending or dispers is effective to achieve the desired therapeutic response for a ing agents. Pharmaceutical preparations for oral use can be particular subject, composition, and mode of administration, obtained by combining the pharmacologically active agent without being toxic to the subject. The selected dosage level with solid excipients, optionally grinding a resulting mixture, depends upon a variety of pharmacokinetic factors including and processing the mixture of granules, after adding Suitable the activity of the particular therapeutic agent, the route of auxiliaries, if desired, to obtain tablets or dragee cores. Suit administration, the time of administration, the rate of excre able excipients are, in particular, fillers such as Sugars, includ tion of the particular compound being employed, the severity ing lactose, Sucrose, mannitol, or Sorbitol; cellulose prepara of the condition, other health considerations affecting the tions such as, for example, maize starch, wheat starch, rice subject, and the status of liver and kidney function of the starch, potato starch, gelatin, gum tragacanth, methyl cellu subject. It also depends on the duration of the treatment, other lose, hydroxypropylmethyl-cellulose, sodium carboxymeth drugs, compounds and/or materials used in combination with ylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, the particular therapeutic agent employed, as well as the age, disintegrating modulators may be added, such as the cross weight, condition, general health and prior medical history of linked polyvinyl pyrrolidone, agar, or alginic acid or a salt the subject being treated, and like factors. Methods for deter thereof Such as Sodium alginate. mining optimal dosages are described in the art, e.g., Rem 1568. Other ingredients such as stabilizers, for example, ington: The Science and Practice of Pharmacy, Mack Pub antioxidants such as sodium citrate, ascorbyl palmitate, pro lishing Co., 20" ed., 2000. Optimal dosages for a given set of pyl gallate, reducing agents, ascorbic acid, vitamin E, sodium conditions can be ascertained by those skilled in the art using bisulfite, butylated hydroxytoluene, BHA, acetylcysteine, conventional dosage-determination tests in view of the monothioglycerol, phenyl-O-naphthylamine, or lecithin can experimental data for an agent. For oral administration, an be used. Also, chelators such as EDTA can be used. Other exemplary daily dose generally employed is from about 0.001 ingredients that are conventional in the area of pharmaceuti to about 3000 mg/kg of body weight, with courses of treat cal compositions and formulations, such as lubricants in tab ment repeated at appropriate intervals. In some embodiments, lets or pills, coloring agents, or flavoring agents, can be used. the daily dose is from about 1 to 3000 mg/kg of body weight. Also, conventional pharmaceutical excipients or carriers can 1564 Methods and compositions according to the present be used. The pharmaceutical excipients can include, but are invention are Suitable for use in treating diseases and condi not necessarily limited to, calcium carbonate, calcium phos tions of both humans and non-humans, including treatment of phate, various Sugars or types of starch, cellulose derivatives, Socially and economically important animals such as dogs, gelatin, vegetable oils, polyethylene glycols and physiologi cats, cows, horses, sheep, pigs, goats, and other species. cally compatible solvents. Other pharmaceutical excipients Unless specified, methods and compositions according to the are well known in the art. Exemplary pharmaceutically present invention are not limited to treatment of humans. acceptable carriers include, but are not limited to, any and/or 1565 Typical daily doses in a patient may be anywhere all of solvents, including aqueous and non-aqueous solvents, between about 500 mg to about 3000 mg, given once or twice dispersion media, coatings, antibacterial and/or antifungal daily, e.g., 3000 mg can be given twice daily for a total dose agents, isotonic and/or absorption delaying agents, and/or the of 6000 mg. In one embodiment, the dose is between about like. The use of Such media and/or agents for pharmaceuti 1000 to about 3000 mg. In another embodiment, the dose is cally active substances is well known in the art. Exceptinsofar between about 1500 to about 2800 mg. In other embodiments, as any conventional medium, carrier, or agent is incompatible the dose is between about 2000 to about 3000 mg. In particu with the active ingredient or ingredients, its use in a compo US 2016/0220537 A1 Aug. 4, 2016

sition according to the present invention is contemplated. tained-release materials have been established and are known Supplementary active ingredients can also be incorporated by those skilled in the art. Sustained-release capsules may, into the compositions, particularly as described above. For depending on their chemical nature, release the compounds administration of any of the compounds used in the present for a few weeks up to over 100 days. Depending on the invention, preparations should meet sterility, pyrogenicity, chemical nature and the biological stability of the therapeutic general safety, and purity standards as required by the FDA reagent, additional strategies for protein stabilization may be Office of Biologics Standards or by other regulatory organi employed. Zations regulating drugs. 1574. The pharmaceutical compositions also may com 1569. The compounds may be formulated for parenteral prise Suitable Solid- or gel-phase carriers or excipients. administration by injection, e.g., by bolus injection or con Examples of Such carriers or excipients include calcium car tinuous infusion. Formulations for injection may be presented bonate, calcium phosphate, Sugars, starches, cellulose deriva in unit-dosage form, e.g., in ampoules or in multi-dose con tives, gelatin, and polymers such as polyethylene glycols. tainers, with an added preservative. The compositions may 1575. A pharmaceutical composition can be administered take Such forms as Suspensions, solutions or emulsions in oily by a variety of methods known in the art. The routes and/or or aqueous vehicles, and may contain formulatory agents modes of administration vary depending upon the desired Such as Suspending, stabilizing and/or dispersing agents. results. Depending on the route of administration, the phar 1570 Pharmaceutical formulations for parenteral admin macologically active agent may be coated in a material to istration include aqueous solutions of the active compounds protect the targeting composition or other therapeutic agent in water-soluble form. Additionally, suspensions of the active from the action of acids and other compounds that may inac agents may be prepared as appropriate oily injection Suspen tivate the agent. Conventional pharmaceutical practice can be sions. Suitable lipophilic solvents or vehicles include fatty employed to provide Suitable formulations or compositions oils such as sesame oil, or synthetic fatty acid esters. Such as for the administration of Such pharmaceutical compositions ethyl oleate or triglycerides, or liposomes. Aqueous injection to Subjects. Any appropriate route of administration can be Suspensions may contain Substances that increase the viscos employed, for example, but not limited to, peripheral intra ity of the Suspension, such as sodium carboxymethyl cellu venous, central intravenous, parenteral, intraperitoneal, tran lose, Sorbitol, or dextran. Optionally, the Suspension may also Scutaneous, Subcutaneous, intramuscular, intra-urethral, or contain Suitable stabilizers or agents, which increase the solu oral administration. Depending on the severity of the malig bility of the compounds to allow for the preparation of highly nancy or other disease, disorder, or condition to be treated, as concentrated Solutions. well as other conditions affecting the subject to be treated, 1571 Alternatively, the active ingredient may be in pow either systemic or localized delivery of the pharmaceutical der form for constitution with a suitable vehicle, e.g., sterile composition can be used in the course of treatment. The pyrogen-free water, before use. The compounds may also be pharmaceutical composition as described above can be formulated in rectal compositions such as Suppositories or administered together with additional therapeutic agents retention enemas, e.g., containing conventional Suppository intended to treat a particular disease or condition, which may bases such as cocoa butter or other glycerides. be the same disease or condition that the pharmaceutical 1572 An exemplary pharmaceutical carrier for hydropho composition is intended to treat, which may be a related bic compounds is a cosolvent system comprising benzyl alco disease or condition, or which even may be an unrelated hol, a nonpolar Surfactant, a water-miscible organic polymer, disease or condition. and an aqueous phase. The cosolvent system may be a VPD 1576 Pharmaceutical compositions according to the co-solvent system. VPD is a solution of 3% w/v benzyl alco present invention can be prepared in accordance with meth hol, 8% w/v of the nonpolar surfactant polysorbate 80, and ods well known and routinely practiced in the art. See, e.g., 65% w/v polyethylene glycol 300, made up to volume in Remington: The Science and Practice of Pharmacy, Mack absolute ethanol. The VPD co-solvent system (VPD:5W) Publishing Co., 20" ed., 2000; and Sustained and Controlled contains VPD diluted 1:1 with a 5% dextrose in water solu Release Drug Delivery Systems, J. R. Robinson, ed., Marcel tion. This co-solvent system dissolves hydrophobic com Dekker, Inc., New York, 1978. Pharmaceutical compositions pounds well, and itself produces low toxicity upon systemic are preferably manufactured under GMP conditions. Formu administration. Naturally, the proportions of a co-solvent sys lations for parenteral administration may, for example, con tem may be varied considerably without destroying its solu tain excipients, Sterile water, or saline, polyalkylene glycols bility and toxicity characteristics. Furthermore, the identity of Such as polyethylene glycol, oils of vegetable origin, or the co-solvent components may be varied: for example, other hydrogenated naphthalenes. Biocompatible, biodegradable low-toxicity nonpolar surfactants may be used instead of lactide polymers, lactide/glycolide copolymers, or polyoxy polysorbate 80; the fraction size of polyethylene glycol may ethylene-polyoxypropylene copolymers may be used to con be varied; other biocompatible polymers may replace poly trol the release of the compounds. Other potentially useful ethylene glycol, e.g. polyvinyl pyrrolidone; and other Sugars parenteral delivery systems for molecules of the invention or polysaccharides may be substituted for dextrose. include ethylene-vinyl acetate copolymer particles, osmotic 1573 Alternatively, other delivery systems for hydropho pumps, and implantable infusion systems. Formulations for bic pharmaceutical compounds may be employed. Lipo inhalation may contain excipients, for example, lactose, or Somes and emulsions are known examples of delivery may be acqueous solutions containing, e.g., polyoxyethylene vehicles or carriers for hydrophobic drugs. Certain organic 9-lauryl ether, glycocholate and deoxycholate, or can be oily Solvents such as dimethylsulfoxide also may be employed, Solutions for administration or gels. although usually at the cost of greater toxicity. Additionally, 1577 Pharmaceutical compositions according to the the compounds may be delivered using a Sustained-release present invention are usually administered to the Subjects on system, Such as semipermeable matrices of Solid hydropho multiple occasions. Intervals between single dosages can be bic polymers containing the therapeutic agent. Various Sus weekly, monthly or yearly. Intervals can also be irregular as US 2016/0220537 A1 Aug. 4, 2016 96 indicated by therapeutic response or other parameters well logically active agents and pharmaceutical compositions, are known in the art. Alternatively, the pharmaceutical composi all incorporated herein by this reference. tion can be administered as a Sustained release formulation, in which case less frequent administration is required. Dosage Advantages of the Invention and frequency vary depending on the half-life in the Subject of the pharmacologically active agent included in a pharmaceu 1583. The present invention provides more effective and tical composition. The dosage and frequency of administra efficient methods of using therapeutic drugs that have previ tion can vary depending on whether the treatment is prophy ously been evaluated for treatment of a number of diseases lactic ortherapeutic. In prophylactic applications, a relatively and conditions, especially hyperproliferative disorders, but low dosage is administered at relatively infrequent intervals whose evaluations resulted in a premature conclusion of lack over a long period of time. Some Subjects may continue to of sufficient efficacy or of occurrence of side effects sufficient receive treatment for the rest of their lives. In therapeutic to prevent the use of the therapeutic drug. Such more effective applications, a relatively high dosage at relatively short inter and efficient methods of therapeutic drugs will improve effi vals is sometimes required until progression of the disease is cacy, prevent or reduce the occurrence of significant side reduced or terminated, and preferably until the subject shows effects, and will identify categories of patients and situations partial or complete amelioration of symptoms of disease. in which Such drugs can be effectively employed. Such drugs Thereafter, the subject can be administered a prophylactic particularly include bisantrene and derivatives and analogs regime. thereof. 1584 Methods according to the present invention possess 1578. For the purposes of the present application, treat industrial applicability for the preparation of a medicament ment can be monitored by observing adverse events or one or for the treatment of a number of diseases and conditions, more of the improving symptoms associated with the disease, especially hyperproliferative diseases, and compositions disorder, or condition being treated, or by observing one or according to the present invention possess industrial applica more of the improving clinical parameters associated with the bility as pharmaceutical compositions. disease, disorder, or condition being treated, as described 1585 Where methods are referred to, the methods of the above. present invention provide specific method steps that are more 1579 Sustained-release formulations or controlled-re than general applications of laws of nature and require that lease formulations are well-known in the art. those practicing the method steps employ steps other than 1580. The pharmacokinetic principles of controlled drug those conventionally known in the art, in addition to the delivery are described, for example, in B. M. Silber et al., specific applications of laws of nature recited or implied in the "Pharmacokinetic/Pharmacodynamic Basis of Controlled claims, and thus confine the scope of the claims to the specific Drug Delivery” in Controlled Drug Delivery: Fundamentals applications recited therein. In some contexts, these claims and Applications (J. R. Robinson & V. H. L. Lee, eds, 2d ed., are directed to new ways of using an existing drug. Marcel Dekker, New York, 1987), ch.5, pp. 213-251, incor 1586. The inventions illustratively described herein can porated herein by this reference. suitably be practiced in the absence of any element or ele 1581. One of ordinary skill in the art can readily prepare ments, limitation or limitations, not specifically disclosed formulations for controlled release or Sustained release com herein. Thus, for example, the terms “comprising.” “includ prising a pharmacologically active agent according to the ing.” “containing, etc. shall be read expansively and without present invention by modifying the formulations described limitation. Additionally, the terms and expressions employed above, such as according to principles disclosed in V. H. K. Li herein have been used as terms of description and not of et al., “Influence of Drug Properties and Routes of Drug limitation, and there is no intention in the use of Such terms Administration on the Design of Sustained and Controlled and expressions of excluding any equivalents of the future Release Systems” in Controlled Drug Delivery. Fundamen shown and described or any portion thereof, and it is recog tals and Applications (J. R. Robinson & V. H. L. Lee, eds. 2d ed., Marcel Dekker, New York, 1987), ch. 1, pp. 3-94, incor nized that various modifications are possible within the scope porated herein by this reference. This process of preparation of the invention claimed. Thus, it should be understood that typically takes into account physicochemical properties of although the present invention has been specifically disclosed the pharmacologically active agent, such as aqueous solubil by preferred embodiments and optional features, modifica ity, partition coefficient, molecular size, stability, and nonspe tion and variation of the inventions herein disclosed can be cific binding to proteins and other biological macromol resorted by those skilled in the art, and that such modifica ecules. This process of preparation also takes into account tions and variations are considered to be within the scope of biological factors, such as absorption, distribution, metabo the inventions disclosed herein. The inventions have been lism, duration of action, the possible existence of side effects, described broadly and generically herein. Each of the nar and margin of safety, for the pharmacologically active agent. rower species and Subgeneric groupings falling within the Accordingly, one of ordinary skill in the art could modify the Scope of the generic disclosure also form part of these inven formulations into a formulation having the desirable proper tions. This includes the generic description of each invention ties described above for a particular application. with a proviso or negative limitation removing any subject 1582 U.S. Pat. No. 6,573.292 by Nardella, U.S. Pat. No. matter from the genus, regardless of whether or not the 6,921,722 by Nardella, U.S. Pat. No. 7,314,886 to Chao et al., and U.S. Pat. No. 7,446,122 by Chao et al., which disclose excised materials specifically resided therein. methods of use of various pharmacologically active agents 1587. In addition, where features or aspects of an inven and pharmaceutical compositions in treating a number of tion are described in terms of the Markush group, those diseases and conditions, including cancer, and methods of schooled in the art will recognize that the invention is also determining the therapeutic effectiveness of such pharmaco thereby described in terms of any individual member or sub US 2016/0220537 A1 Aug. 4, 2016 97 group of members of the Markush group. It is also to be (b) the bisantrene analog of Formula (III) understood that the above description is intended to be illus trative and not restrictive. Many embodiments will be appar ent to those of in the art upon reviewing the above description. The scope of the invention should therefore, be determined not with reference to the above description, but should instead (III) H be determined with reference to the appended claims, along N with the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, includ NH ing patent publications, are incorporated herein by reference. N (DN n 1. A composition to improve the efficacy and/or reduce the side effects of Suboptimally administered drug therapy com prising a therapeutically effective quantity of a therapeutic agent or modified therapeutic agent or a derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent, wherein the therapeutic agent or modified therapeutic agent N or the derivative, analog or prodrug of the therapeutic agent or modified therapeutic agent possesses increased therapeutic HN efficacy or reduced side effects, wherein the composition: (a) includes at least one bulk drug product improvement; (b) is produced in a specified dosage form; (c) includes a drug conjugate form; (d) includes a compound analog; or (c) the bisantrene analog of Formula (IV) (e) includes a prodrug; wherein the therapeutic agent, the modified therapeutic agent, or the derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent Subject to the bulk drug product improvement possesses increased therapeutic efficacy or (IV) reduced side effects as compared with an unmodified thera HN N peutic agent; wherein the unmodified therapeutic agent is bisantrene or a derivative or analog of bisantrene, the modi Y fied therapeutic agent is a modification of bisantrene or a derivative or analog of bisantrene, and the derivative, analog, t -K D or prodrug is a derivative, analog, or prodrug of bisantrene or N n of a derivative or analog of bisantrene. 2. The composition of claim 1 wherein the composition comprises bisantrene. 3. The composition of claim 1 wherein the composition comprises a derivative or analog of bisantrene. 4. The composition of claim 3 wherein the derivative or (d) the bisantrene analog of Formula (V) analog of bisantrene is selected from the group consisting of (a) the analog of Formula (II)

(V) (II) H N N N-(DN N HN n NN US 2016/0220537 A1 Aug. 4, 2016 98

(e) the bisantrene analog of Formula (VI) (j) the bisantrene analog of Formula (XI)

(VI) (XI)

NHNN N 0

N&

(f) the bisantrene analog of Formula (VII) (k) the bisantrene analog of Formula (XII) (VII)

(XII) NH N N -k N D is

(g) the bisantrene analog of Formula (VIII)

(VIII)

(XIII) (h) the bisantrene analog anthracen-9-ylmethylene-2- methoxyethoxymethylsulfanyl-5-pyridin-3-yl-1,2,4 triazol-4-amine; (i) the bisantrene analog of Formula (X) O) (X) -HN N US 2016/0220537 A1 Aug. 4, 2016 99

(m) bisantrene analogs of Formula (XIV) D-CH-. R R2 N ClC CH , or R.OCHCH , where R, is hydrogen or C-C alkyl, hydrogen, or a pharmaceutically acceptable cat sh=N-N- ion or R' and R" are linked to form a —CHCH group or N a

R3 N

hi-N--R. N group, and n is an integer representing the number of primary or secondary basic nitrogenatoms in the compound such that wherein RandR are the same or different and are hydrogen, at least one Q is A: C-C alkyl, —C(O)—Rs, wherein Rs is hydrogen, C-C, (n) the bisantrene analog 9,10-bis(2-hydroxyethyl)imi alkyl, phenyl, mono-substituted phenyl (wherein the substitu nomethyllanthracene; ent can be ortho, meta, or para and is fluoro, nitro, C-C alkyl, (o) the bisantrene analog 9,10-bis(2-(-2-hydroxyethyl C-C alkoxy, or cyano), pentafluorophenyl, naphthyl, fura amino)ethyliminomethyl)anthracene; nyl, (p) the bisantrene analog 9,10-bis(2-(-2-hydroxyethyl amino)ethyliminomethyl)anthracene; (q) the bisantrene analog 9,10-bis(2-(morpholin-4-yl) ethyliminomethyl)anthracene: t t (r) the bisantrene analog 9,10-bis(2-hydroxyethyl)ami -CHNHCOOC(CH), -CHNH, -CHCHCOOH, nomethyllanthracene; -OC(CH3)3, -CHOCH, -(CH2)3COOH, (s) the bisantrene analog 9,10-bis(2-(2-hydroxyethyl COOH amino)ethylaminomethyl)anthracene tetrahydrochlo ride; (t) the bisantrene analog 9,10-bis(2-(piperazin-1-yl) , -(CH2)2SOH or ethylaminomethyl)anthracene hexahydrochloride; (u) the bisantrene analog 9,10-bis(2-(morpholin-4-yl) ethylaminomethyl)anthracene tetrahydrochloride; -CHNG)-(CH3)3CIG)); -P(OH), -P(OCH3), (v) N,N'-bis(2-(dimethylamino)ethyl-9,10-anthracene bis(methylamine); (w) N,N'-bis(1-ethyl-3-piperidinyl)-9,10-anthracene-bis (methylamine); and --( ). -o-( )—cil O (X) derivatives and salt forms of the compounds of (a)-(w). 5. The composition of claim 1 wherein the therapeutic agentis bisantrene or a derivative or analog of bisantrene, and SOH; wherein only one of R and R may be hydrogen or the bisantrene or derivative or analog of bisantrene is sub C-C alkyl, R and Ra are the same or different and are: jected to a bulk drug product improvement, wherein the bulk hydrogen, C-C alkyl or—C(O)—R, where R is hydrogen, drug product improvement is selected from the group con C-C alkyl, phenyl, mono-Substituted phenyl (wherein the sisting of: Substituent may be in the ortho, meta, or para position and is (a) preparation as a free base form; fluoro, nitro, C-C alkyl, C-C alkoxy, or cyano), pentafluo (b) salt formation; rophenyl, naphthyl, furanyl, or —CHOCH. The com (c) preparation as a homogeneous crystalline structure; pounds can have the schematic structure B(O), wherein B is (d) amorphous structure; the residue formed by removal of a hydrogen atom from one (e) preparation as a pure isomer, or more basic nitrogen atoms of an amine, amidine, guani (f) increased purity; dine, isourea, isothiourea, or biguanide-containing pharma (g) preparation with lower residual solvent content; and ceutically active compound, and Q is hydrogen or A, wherein (h) preparation with lower residual heavy metal content. A is 6. The composition of claim 5 wherein the bisantrene or the derivative or analog of bisantrene is bisantrene. 7. The composition of claim 5 wherein the bisantrene or the derivative or analog of bisantrene is a derivative or analog of RO bisantrene. D 8. The composition of claim 1 wherein the therapeutic agentis bisantrene or a derivative or analog of bisantrene, and the bisantrene or derivative or analog of bisantrene is incor such that RandR" are the same or different and are R (where porated into a dosage form selected from the group consisting R is C-C alkyl, aryl, aralkyl, heteroalkyl, NC CHCH . of: