US 2016O166546A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0166546A1 GARNER et al. (43) Pub. Date: Jun. 16, 2016

(54) COMBINATORIAL METHODS TO IMPROVE Related U.S. Application Data THE THERAPEUTIC BENEFIT OF (60) Provisional application No. 61/858,729, filed on Jul. BSANTRENE AND ANALOGS AND 26, 2013. DERVATIVES THEREOF Publication Classification (71) Applicant: UPDATE PHARMA INC., Lebanon, NJ (US) (51) Int. Cl. A613 L/478 (2006.01) (72) Inventors: William J. GARNER, San Francisco, A613 L/468 (2006.01) CA (US); Amie FRANKLIN, Mountain (52) U.S. Cl. View, CA (US); John ROTHMAN, CPC ...... A61K 31/4178 (2013.01); A61 K31/4168 Lebanon, NJ (US) (2013.01) (57) ABSTRACT (21) Appl. No.: 14/907,729 The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutic agents (22) PCT Filed: Jul. 25, 2014 previously limited by suboptimal therapeutic performance by PCT/US1.4/48137 either improving efficacy as monotherapy or reducing side (86). PCT No.: effects. Such methods and compositions are particularly S371 (c)(1), applicable to bisantrene or derivatives, analogs, or prodrugs (2) Date: Jan. 26, 2016 thereof. US 2016/0166546 A1 Jun. 16, 2016

COMBINATORIAL METHODS TO IMPROVE biological Screening systems that have been Successfully THE THERAPEUTIC BENEFIT OF used. However, from the tens of billions of dollars spent over BSANTRENE AND ANALOGS AND the past thirty years Supporting these programs both preclini DERVATIVES 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 2016/0166546 A1 Jun. 16, 2016

an approximate 4% increase predicted for 2003 in the United side-effects are severe enough to limit wide utility. More States by the American Cancer Society such that over 1.3 specifically, the inventive methods and compositions also million new cancer cases are estimated. In addition, with focus on improvements for bisantrene and derivatives orana advances in diagnosis such as mammography for breast can logs thereof, including, but not limited to, the derivatives and cer and PSA tests for prostate cancer, more patients are being analogs described below. diagnosed at a younger age. For difficult to treat cancers, a patient’s treatment options are often exhausted quickly 0013. One aspect of the present invention is a method to resulting in a desperate need for additional treatment regi improve the efficacy and/or reduce the side effects of subop mens. Even for the most limited of patient populations, any timally administered drug therapy comprising the steps of: additional treatment opportunities would be of considerable 0014 (1) identifying at least one factor or parameter asso value. This invention focuses on inventive compositions and methods for improving the therapeutic benefit of sub-opti ciated with the efficacy and/or occurrence of side effects of mally administered chemical compounds including Substi the drug therapy; and tuted hexitols such as bisantrene and analogs and derivatives 00.15 (2) modifying the factor or parameter to improve the thereof. efficacy and/or reduce the side effects of the drug therapy: 0009 Relevant literature includes Foye, W. O., “Cancer wherein the drug therapy comprises administration of bisant Chemotherapeutic Agents. American Chemical Society, rene or a derivative or analog thereof. 1995, and Dorr, R.T., and Von Hoff, D.D., “Cancer Chemo therapy Handbook. Appleton and Lange, 1994. 0016. In one alternative, the drug therapy comprises 0010. Therefore, there is a need for compositions and administration of bisantrene. In another alternative, the drug methods including bisantrene or analogs or derivatives therapy comprises a derivative or analog of bisantrene. thereof that improve the therapeutic benefit of these com 0017. The derivative or analog of bisantrene can be pounds, particularly for the treatment of malignancies. There selected from the group consisting of: is a particular need for combinatorial methods to improve the therapeutic benefit of these compounds. 0018 (a) the bisantrene analog of Formula (II) SUMMARY OF THE INVENTION (II) 0011. This invention relates to novel compositions and H methods to improve the utility of chemical agents with sub N optimal performance in patients suffering with immunologi cal disease, metabolic disease, infection, or hyperprolifera N i-CN tive diseases including cancer. The invention describes novel improvements, pharmaceutical ingredients, dosage forms, n excipients, solvents, diluents, drug delivery systems, preser Vatives, more accurate drug administration, improved dose 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 of drug delivery systems, novel prodrugs, polymer conju 0019 (b) the bisantrene analog of Formula (III) gates, novel routes of administration, other agents to poten tiate the activity of the compounds or inhibit the repair of (III) suboptimal cellular effects or sublethal damage or to “push' H the cell into more destructive cellular phases Such as apopto N sis. In some case, the use of these Suboptimal therapeutics in conjunction with radiation or other conventional chemothera N i-CN peutic agents or biotherapeutic agents such as antibodies, N 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 precluded further human clinical evaluation. It also includes those agents from Phase II trials where limited or no signifi 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 approval by government agencies for commercialization or commercialized agents whose clinical performance (i.e. response rates) as a monotherapy are less than 25%, or whose US 2016/0166546 A1 Jun. 16, 2016

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

HN 2 N i-CN H N N NH NH-(| N. D N •2HCl; 0025 (h) the bisantrene analog anthracen-9-ylmethylene 2-methoxyethoxymethylsulfanyl-5-pyridin-3-yl-1,2,4 triazol-4-amine; 0026 (i) the bisantrene analog of Formula (X) (X) 0021 (d) the bisantrene analog of Formula (V) O) (V) I N N 2 N HN YN .2HCl;

0027 (i) the bisantrene analog of Formula (XI) (XI)

0022 (e) the bisantrene analog of Formula (VI) I O)N 2 N (VI)

N 2 HNN OCCN N h 0028 (k) the bisantrene analog of Formula (XII) NS OC (XII) 0023 (f) the bisantrene analog of Formula (VII)

(VII)

NH N NH & D HN NN US 2016/0166546 A1 Jun. 16, 2016

0029 (1) the bisantrene analog of Formula (XIII) —SOH; wherein only one of R and R may be hydrogen or 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, (XIII) C-C alkyl, phenyl, mono-substituted phenyl (wherein the 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 s pounds can have the schematic structure B(O), wherein B is 2N 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

21 ROD N NH s such that RandR" are the same or different and are R (where K. R is C-C alkyl, aryl, aralkyl, heteroalkyl, NC CHCH . 0030 (m) bisantrene analogs of Formula (XIV) D-CH-. R ClC C , or ROCH2CH2—, where R, is hydrogen or R2 N C-C alkyl, hydrogen, or a pharmaceutically acceptable cat ion or Rand R" are linked to forma —CH-CH group or ---K a R3 COO N CHN-N R4 KN group, and n is an integer representing the number of primary or secondary basic nitrogenatoms in the compound such that 0031 wherein RandR are the same or different and are at least one Q is A: hydrogen, C-C alkyl, —C(O)—Rs, wherein Rs is hydro 0032 (n) the bisantrene analog 9,10-bis(2-hydroxyethyl) gen, C-C alkyl, phenyl, mono-Substituted phenyl (wherein iminomethylanthracene; the Substituent can be ortho, meta, or para and is fluoro, nitro, 0033 (o) the bisantrene analog 9,10-bis(2-(2-hydroxy C-C alkyl, C-C alkoxy, or cyano), pentafluorophenyl, ethylamino)ethyliminomethyl)anthracene; naphthyl, furanyl, 0034 (p) the bisantrene analog 9,10-bis(2-(-2-hydroxy ethylamino)ethyliminomethyl)anthracene; 0035 (q) the bisantrene analog 9,10-bis(2-(morpholin-4- t t yl)ethyliminomethyl)anthracene; -CHNHCOOC(CH3)3, -CHNH2, -CH2CHCOOH, 0036 (r) the bisantrene analog 9,10-bis(2-hydroxyethyl) -OC(CH), -CHOCH, -(CH2)COOH, aminomethylanthracene; 0037 (s) the bisantrene analog 9,10-bis(2-(2-hydroxy COOH ethylamino)ethylaminomethyl)anthracene tetrahydrochlo ride; 0038 (t) the bisantrene analog 9,10-bis(2-(piperazin-1- yl)ethylaminomethyl)anthracene hexahydrochloride; 0039 (u)the bisantrene analog 9,10-bis(2-(morpholin-4- yl)ethylaminomethyl)anthracene tetrahydrochloride; -CH.N2-(CH3)4C1); -P(OH), -P(OCH3), 0040 (v) N,N'-bis(2-(dimethylamino)ethyl-9,10-an O thracene-bis(methylamine); -P(O ), -SO CH3 or 0041) (w) N,N'-bis(1-ethyl-3-piperidinyl)-9,10-an thracene-bis(methylamine); and 0042 (x) derivatives and salt forms of the compounds of (a)-(u). US 2016/0166546 A1 Jun. 16, 2016

0043. Typically, the factor or parameter is selected from 0090 (ii) at least one additional therapeutic agent, the group consisting of therapeutic agent Subject to chemosensitization, thera 0044 (1) dose modification; peutic agent Subject to chemopotentiation, diluent, 0045 (2) route of administration: excipient, Solvent system, drug delivery system, or agent 0046 (3) schedule of administration; for enhancing the activity or efficacy of the therapeutic 0047 (4) indications for use: agent, the modified therapeutic agent or the derivative, 0048 (5) selection of disease stage; analog, or prodrug of a therapeutic agent or modified 0049 (6) other indications: therapeutic agent of (a), wherein the composition pos 0050 (7) patient selection: sesses increased therapeutic efficacy or reduced side 0051 (8) patient/disease phenotype: effects as compared with an unmodified therapeutic 0052 (9) patient/disease genotype: agent, 0053 (10) prefpost-treatment preparation; 0091 (c) a therapeutically effective quantity of atherapeu 0054 (11) toxicity management; tic agent, a modified therapeutic agent, or a derivative, analog, 0055 (12) pharmacokinetic/pharmacodynamic monitor or prodrug of a therapeutic agent or modified therapeutic 1ng agent that is incorporated into a dosage form, wherein the 0056 (13) drug combinations: therapeutic agent, the modified therapeutic agent, or the 0057 (14) chemosensitization; derivative, analog, or prodrug of a therapeutic agent or modi 0058 (15) chemopotentiation: fied therapeutic agent incorporated into the dosage form pos 0059 (16) post-treatment patient management; sesses increased therapeutic efficacy or reduced side effects 0060 (17) alternative medicine/therapeutic support; as compared with an unmodified therapeutic agent; 0061 (18) bulk drug product improvements: 0092 (d) a therapeutically effective quantity of a thera 0062 (19) diluent systems: peutic agent, a modified therapeutic agent, or a derivative, 0063 (20) solvent systems; analog, or prodrug of a therapeutic agent or modified thera 0064 (21) excipients; peutic agent that is incorporated into a dosage kit and pack 0065 (22) dosage forms: aging, wherein the therapeutic agent, the modified therapeu 0.066 (23) dosage kits and packaging; tic agent, or the derivative, analog, or prodrug. ofatherapeutic 0067 (24) drug delivery systems: agent or modified therapeutic agent incorporated into the 0068 (25) drug conjugate forms: dosage kit and packaging possesses increased therapeutic 0069 (26) compound analogs; efficacy or reduced side effects as compared with an unmodi 0070 (27) prodrugs: fied therapeutic agent; 0071 (28) multiple drug systems; 0093 (e)atherapeutically effective quantity of atherapeu 0072 (29) biotherapeutic enhancement; tic agent, a modified therapeutic agent, or a derivative, analog, 0073 (30) biotherapeutic resistance modulation; or prodrug of a therapeutic agent or modified therapeutic 0074 (31) radiation therapy enhancement; agent that is subjected to a bulk drug product improvement; 0075 (32) novel mechanisms of action; 0094 (f) a therapeutically effective quantity of a therapeu 0076 (33) selective target cell population therapeutics; tic agent or a derivative, analog, or prodrug of a therapeutic 0077 (34) use with an agent enhancing its activity; agent, wherein the therapeutic agent or the derivative, analog, 0078 (35) use to modulate DNA methylation: or prodrug of the therapeutic agent is optimized for increasing 0079 (36) use to inhibit telomerase or induce telomere an immunologic response; and dysfunction; 0.095 (g) a composition comprising: 0080 (37) use to activate macrophages or innate immu 0.096 (i) a therapeutically effective quantity of a thera nity; peutic agent or a derivative, analog, or prodrug of a 0081 (38) use to inhibit expression of survivin or with therapeutic agent; and survivin inhibitors or modulators; 0097 (ii) at least one immune adjuvant for stimulating 0082 (39) use with multidrug resistance reversal agents: an immune response; 0083 (40) use in combinatorial regimes: wherein the therapeutic agent, the modified therapeutic agent, 0084 (41) use with directed antibody conjugates; and or the derivative, analog, or prodrug of a therapeutic agent or 0085 (42) use with adjuvants. modified therapeutic agent Subject to the bulk drug product I0086. Another aspect of the invention is a composition to improvement possesses increased therapeutic efficacy or improve the efficacy and/or reduce the side effects of subop reduced side effects as compared with an unmodified thera timally administered drug therapy comprising an alternative peutic agent; wherein the unmodified therapeutic agent is selected from the group consisting of: bisantrene or a derivative or analog of bisantrene, the modi 0087 (a) a therapeutically effective quantity of a modified fied therapeutic agent is a modification of bisantrene or a therapeutic agent or a derivative, analog, or prodrug of a derivative or analog of bisantrene, and the derivative, analog, therapeutic agent or modified therapeutic agent, wherein the or prodrug is a derivative, analog, or prodrug of bisantrene or modified therapeutic agent or the derivative, analog or pro of a derivative or analog of bisantrene. drug of the therapeutic agent or modified therapeutic agent 0098. Accordingly, as described in further detail below, possesses increased therapeutic efficacy or reduced side one aspect of the present invention is a method to improve the effects as compared with an unmodified therapeutic agent; efficacy and/or reduce the side effects of suboptimally admin 0088 (b) a composition comprising: istered drug therapy comprising the steps of I0089 (i) a therapeutically effective quantity of a thera 0099 (a) identifying at least one factor or parameter asso peutic agent, a modified therapeutic agent or a deriva ciated with the efficacy and/or occurrence of side effects of tive, analog, or prodrug of a therapeutic agent or modi the drug therapy, wherein the factor or parameter is addition fied therapeutic agent; and ally associated with at least one of: (i) the specific disease or US 2016/0166546 A1 Jun. 16, 2016

condition being treated; (ii) the stage of the disease or condi intravenously (i.v.), intraperitoneally (i.p.), or Subcutane tion being treated; (iii) selection of an appropriate patient for ously (s.c.), the drug was effective in cancer models using treatment; (iv) selection of an appropriate phenotype of the colon 26, Lewis lung, Ridgway osteosarcoma, B16, Lieber patient or the disease or condition being treated; and (v) man plasma cell, P388 or L1210 cancer cells. Activity in selection of an appropriate phenotype of the patient or the clonogenic assays from 684 patients was seen in breast, Small disease or condition being treated; and cell lung, large cell lung, squamous cell lung, ovarian, pan 0100 (b) modifying the factor or parameter to improve the creatic, renal, adrenal, head and neck, sarcoma, gastric, lym efficacy and/or reduce the side effects of the drug therapy: phoma and melanoma tumor cells, but not in colorectal can wherein the drug therapy comprises administration of bisant cer. Importantly, a lack of cross resistance with adriamycin rene or a derivative or analog thereof. and mitoxantrone was found. 0101. As described in further detail below, another aspect 0.108 Toxicity studies in in dogs and monkeys revealed of the present invention is a method to improve the efficacy that at high doses leukopenia, anorexia, diarrhea, injection and/or reduce the side effects of suboptimally administered site necrosis, enterocolitis, muscle degeneration, and pulmo drug therapy comprising the steps of nary edema were observed. Although anthracyclines, despite 0102 (a) identifying at least one factor or parameter asso their clinical utility, are known to be cardiotoxic, the toxicity ciated with the efficacy and/or occurrence of side effects of of bisantrene was observed to be less than that of the anthra the drug therapy, wherein the factor or parameter is addition cycline doxorubicin. ally associated with at least one of: (i) the chemical compo sition of the drug being administered; (ii) the physical form of 0109 Because of its lack of aqueous solubility at physi the drug being administered or a pharmaceutical composition ologic pH bisantrene precipitates in the body have been including the drug being administered; (iii) the makeup of a observed in studies of rabbits and calves. Deposition of drug pharmaceutical composition including the drug being admin into the tissues has been associated with phlebitis, and depo istered; (iv) the specific use of the drug being administered; sition has also been explored as a mechanism for the delivery (v) the target cell, organ, or receptor targeted by the drug of high tissue concentrations of the drug. being administered; or (vi) additional agents administered 0110 Bisantrene may have immunologic and/or genomic with the drug being administered; and properties that might be responsible for some of its activities, 0103 (b) modifying the factor or parameter to improve the and which may make this agent a useful tool in the combina efficacy and/or reduce the side effects of the drug therapy: torial treatment of cancer in conjunction with newer immu wherein the drug therapy comprises administration of bisant notherapeutic agents. Subsequent to treatment with bisant rene or a derivative or analog thereof. rene, treated with bisantrene, and for 4 weeks thereafter, 0104. As described in further detail below, yet another macrophages could be isolated from peritoneal exudate that aspect of the present invention is a method to improve the had cytostatic anti-proliferative functionality in cultures of efficacy and/or reduce the side effects of suboptimally admin P815 (mastocytoma) tumor cells. Moreover, the supernatants istered drug therapy comprising the steps of from bisantrene activated macrophages also had a protective 0105 (a) identifying at least one factor or parameter asso cytostatic effect in the tumor cell cultures. Further work ciated with the efficacy and/or occurrence of side effects of revealed that macrophages activated with bisantrene and the drug therapy; and adoptively transferred to mice with EL-4 lymphomas more 0106 (b) modifying the factor or parameter to improve the than doubled their median survival time, with 7 of 10 mice in efficacy and/or reduce the side effects of the drug therapy: the group being cured. Multiple administrations of activated wherein the drug therapy comprises administration of bisant macrophages were more effective than a single administra rene or a derivative or analog thereof; tion. and wherein the factor or parameter is use of bisantrene or a 0111. There is also evidence that the survivin inhibitors derivative or analog thereof in a combinatorial regime. research that looked at the effect of bisantrene on survivin reported an interaction; one paper did find that the Survivin DETAILED DESCRIPTION OF THE INVENTION inhibitors NSC80467 and YM155 acted in a manner that 0107 Bisantrene is an unusual agent with direct cytotoxic correlated with the known mechanism of DNA expression action as well as genomic and immunologic methods of inhibition of bisantrene. action. The chemical name forbisantrene is 9, 10-anthracene 0112 Bisantrene has also been found to have non-immu dicarboxaldehyde-bis (4, 5-dihydro-1H-imidazole-2-yl) nologic telomeric effects. Bisantrene binds to DNA at a site hydrazine dihydrochloride, and it was originally classed as called a G-quadraplex, in which 4 guanines are associated by an anthracycline chemotherapeutic agent. These are drugs folding. Stabilization of the G-quadraplex can interfere with with planar structures based around a resonant aromatic ring telomere-telomerase interaction and thus inhibit the activity structure that intercalates within the helices of DNA and of telomerase in various ways, including the displacement of disrupt various functions, including replication, presumably telomerase binding proteins. Since the level oftopoisomerase due to a strong inhibitory effect on the enzyme topoisomerase II inhibition does not always correlate with cytotoxic efficacy, II. It was found that, like other anthracyclines, it could kill alternative mechanisms may play a role in the actions of tumor cells in clonogenic assays and intercalate with DNA, bisantrene. Analogs of bisantrene have been made in an where it inhibits both DNA and RNA synthesis. The primary attempt to improve upon the anti-telomerase activity; these chemo-therapeutic mechanism for bisantrene is its preferen analogs are described further below. Human melanoma (SK tial binding to A-T rich regions where it effects changes to Mel5) and colon cancer (LoVo) tumor cells were observed to Supercoiling and initiates Strand breaks in association with lose their proliferative ability in the presence of these agents. DNA associated proteins. This results from the inhibition of Apoptosis was not observed, however a loss of immortality the enzyme topoisomerase II, which relaxes DNA coiling was seen, with treated cells reacquiring the ability to become during replication. It was found that while inactive orally, Senescent, age, and die. US 2016/0166546 A1 Jun. 16, 2016

0113. Several clinical trials have investigated the pharma predicated on the RECIST scale (Response Evaluation Cri cokinetics of bisantrene in humans. In one trial of patients teria In Solid Tumors), but not survival, performance status, given a 90 mininfusion at 260 mg/m a biphasic elimination or other measures of response. The methodology of Such with an initial half-life of 65+15 min, a terminal half-life of trials was derived from agents having a chemotherapeutic 1142+226 min, and a steady state volume of distribution mechanism of action exclusively, not best Suited for agents (Vdss) of 1845 L/m. Plasma clearance in this trial was 735 with immunological or genomic effects Such as bisantrene, as ml/min/m, with 11.3% of the administered dose excreted it is now known that immune therapies can have salutary unchanged in the urine in 24 hr. In another trial, doses of effects on Survival independent of tumor responses, and that 80-250 mg/m were assessed, and the initial and terminal even minor responses of the type not reported in the older half-lives were 0.6 hr and 24.7 hr, respectively, with a clear studies can be attended by a favorable overall outcome in ance of 1045.5+51.0 ml/kg/hr and a calculated volume of terms of performance status and Survival. distribution of 42.1+5.9 L/kg. In this study only 3.4+1.1% of 0116 Cancer drug development in the 1980s, especially the administered dose was found in the urine over 96 hr. In anthracycline development, was predicated upon a maximum three other single dose studies triphasic elimination was tolerated dose (MTD) model. That is, since the drug is a toxin reported, one with t/2C, B, 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 0114. 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 0117 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, 0118. 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) H were similar to that observed in phase I. In a phase III trial, it N 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 i-n-N-(D oHC. tion was used that toxicity was noted to be considerably less than with peripheral venous administration. 0115 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 0119 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)hydrazine dihydrochloride. trials typically reported objective response rates, usually The molecular formula is CHNs.2HCl and the molecular US 2016/0166546 A1 Jun. 16, 2016

weight, 471.4. The alkylimidazole side chains are very basic Associated DNA Strand Breaks Under Hypoxic Condition.” and, at physiologic pH, are positively charged. This is Cancer Treat. Rep. 68: 367-372 (1984)). The noncovalent believed to facilitate electrostatic attractions to negatively binding of bisantrene to DNA appears to comprise two types charged ribose phosphate groups in DNA. of interactions: (1) intercalation of the planaranthracene moi 0120 Bisantrene has shown antitumor activity in murine ety between DNA base pairs, and (2) electrostatic binding tumor models including P-388 leukemia and B-16 melanoma between negatively charged ribose phosphates of DNA and (R. V. Citarella et al., “Anti-Tumor Activity of CL-216942: positively charged basic nitrogens on the alkyl side chains of 9,10-Anthracenedicarboxaldehyde bis (4,5-dihydro-1H the drug. This is reflected in the biphasic DNA dissociation imidazol-2-yl)hydrazone) dihydrochloride (Abstract #23) in curves forbisantrene in calfthymus DNA in vitro (W.O. Foye Abstracts of the 20' Interscience Conference on Antimicro et al., “DNA-Binding Abilities of Bisguanylhydrazones of bial Agents and Chemotherapy (Bethesda, Md., American anthracene-9,10-dicarboxaldehyde. Anti-Cancer Drug Society for Microbiology 1980)). Human tumor cells that Design 1:65-71 (1986)). were sensitive to bisantrene as assessed by in vitro colony (0123. In one alternative, bisantrene vials have been recon forming assays include breast cancer, ovarian cancer, renal stituted with 2 to 5 mL of Sterile Waterfor Injection, USP, and cancer, Small cell and non-Small cell lung cancer, lymphoma, then diluted with approximately 0.1 to 0.5 mg/mL in D5W acute myelogenous leukemia, melanoma, gastric cancer, (5% dextrose in water). Bisantrene is incompatible with adrenal cancer, and head and neck cancer (D. D. Von Hoffet saline and unstable in light (G. Powis et al., “Pharmacokinetic al, “Activity of 9,10-Anthracenedicarboxaldehyde bis(4,5- Study of ADAH in Humans and Sensitivity of ADAH to dihydro-1H-imidazol-2-yl)hydrazinedihydrochloride Light” (Abstract #C-74).” ASCO Proc. 1: 19 (1982). (CL216,942) in a human tumor cloning system. Cancer 0.124 Because of severe local venous toxicity, bisantrene Chemother: Pharmacol. 6: 141-144 (1981) (“Von Hoffet al. doses have been infused via central venous access devices (1981a)”). In phase I clinical trials bisantrene showed activity over 1 hour (Van Hoff et al., 1981b). Bisantrene has been in hepatocellular cancer and hypernephroma (one patient infused through peripheral veins over 2 hours, and has been each) (D.D. Von Hoffet al., Phase I Clinical Investigation of "piggybacked' into a running dextrose infusion in an attempt 10-Anthracenedicarboxaldehyde bis(4,5-dihydro-1H-imi to lessen delayed Swelling in the arm used for infusion. dazol-2-yl)hydrazinedihydrochloride (CL216,942). Can 0.125 To reduce venous irritation, hyperpigmentation, cer Res. 31 18-3121 (1981) (“Von Hoffetal. (1981b)') and in drug extravasation, and anaphylactoid reactions, patients lymphoma, myeloma, melanoma, renal cancer, and tumors of have been given hydrocortisone (50 mg IV) and the antihis the bladder and lung (D. S. Alberts et al., “Phase I Clinical tamine diphenhydramine (50 mg 1M) immediately prior to Investigation of 9,10-Anthracenedicarboxaldehyde bis(4,5- bisantrene (Alberts et al. (1982)), supra). Bisantrene is known dihydro-1H-imidazol-2-yl)hydrazone Dihydrochloride with to stain the skin orange. Correlative in Vitro Human Tumor Clonogenic Assay. Can 0.126 Maximally tolerated doses in several bisantrene cer Res. 42: 1170-1175 (1982)). Phase I activity was also phase I schedules include: (1) 200 mg/m weeklyx3 (150 observed in two other hypernephroma patients (R. J. Spiegel mg/mg for patients with poor bone marrow reserve (e.g., et al., “Phase I Clinical Trial of 9,10-Anthracene Dicarbox those patients who have received radiotherapy or extensive aldehyde (Bisantrene) Administered in a Five-Day Schedule, chemotherapy regimens) (Alberts et al. (1982), supra); (2) “Cancer Res. 42: 354-358 (1982)). Bisantrene was inactive in 150 mg/m weeklyx3 (repeat every 4-5 week) (B.-S. Yap et human colon cancer tested in vitro or in vivo (M. C. Perry et al., “Phase I Clinical Evaluation of 9,10-Anthracenedicar al. "Phase II trial of bisantrene inadvanced colorectal cancer: boxaldehydebis(4,5-dihydro-1H-imidazol-2-yl)hydrazone A cancer and leukemia group B study. Cancer Treat. Rep. 66: dihydrochloride (Bisantrene). Cancer Treat. Rep. 66: 1517 1997-1998 (1982); Von Hoffet al. (1981a); Von Hoff et al. 1520 (1982)) (3) 260 mg/m monthly (every 3-4 week) (240 (1981 b). It was also inactive in refractory malignant mela mg/mg for patients with poor bone marrow reserve (e.g., noma (D. S. Alberts et al., “Phase II Evaluation of Bisantrene those patients who have received radiotherapy or extensive Hydrochloride in Refractory Malignant Melanoma.” Invest. chemotherapy regimens) (Von Hoffet al., 1981 b); and (4) 80 New Drugs 5: 289-292 (1987)). mg/m dailyx5 (repeat every 4 week) (R. J. Spiegel et al. 0121. In Phase II clinical trials, bisantrene was active in (1982), supra). patients with metastatic breast cancer (H.-Y. Yap et al., I0127. More than 95% of bisantrene is bound to plasma “Bisantrene, an Active New Drug in the Treatment of Meta proteins and the drug has a long terminal plasma half-life. static Breast Cancer.” Cancer Res. 43: 1402-1404 (1983)). There appeared to be three phases of elimination: an initial Partial response rates were observed in heavily pretreated distributive phase of 6 minutes, a betaphase of approximately patients with metastatic breast cancer. However, the study 1.5 hours, and a final gamma elimination phase of 23 to 54 was terminated because of significant local toxicity observed. hours (Alberts et al. (1983), supra). Typical areas under the 0122 The mechanism of action for bisantrene has been plasma concentration X time curve are 4.4 to 5.7 mgh/mL studied. Bisantrene has been shown to induce altered DNA following intravenous doses of 260 to 340 mg/m, respec supercoiling indicative of DNA intercalation (G. T. Bowden tively (Alberts et al. 1983, supra). Less than 7% of a bisant et al., “Comparative Molecular Pharmacology in Leukemic rene dose is excreted in the urine and the majority of the drug L1210 cells of the Anthracene Anticancer Drugs Mitox is eliminated by the hepatobiliary route. The drug may be antrone and Bisantrene, Cancer Res. 45: 4915-4920 (1985)). metabolized to some extent in vivo. In vitro bisantrene is a In L-1210 leukemia cells bisantrene was also shownto induce Substrate for hepatic microsomal enzymes but specific protein-associated DNA strand breaks typical of drug-in metabolites have not been identified. Preclinical drug distri duced inhibition of DNA topoisomerase II enzymes (Bowden bution studies showed that the tissues with the highest con et al., 1985). Both cytotoxicity and the DNA strand breaks centration (in descending order) are kidney, liver, gallbladder, appear to be reduced in hypoxic conditions (C. U. Ludwig et spleen, lung, and heart. Brain levels were extremely low. The al., “Reduced Bisantrene-Induced Cytotoxicity and Protein drug did distribute to lymph nodes and bone marrow (W. H. US 2016/0166546 A1 Jun. 16, 2016

Wu & G. Nicolau, “Disposition and Metabolic Profile of a of bisantrene had been halted. However, the results suggest a New Antitumor Agent, CL 216,942 (Bisantrene) in Labora reevaluation of the use of bisantrene for antineoplastic use tory Animals.” Cancer Treat Rep. 66: 1173-1185 (1982)). and for other indications, despite the prior halt of develop 0128. The major dose-limiting toxic effect of bisantrene is ment. leukopenia (Von Hoffetal. 1981 b: Alberts et al. 1982, supra; 0.133 Various formulations suitable for use in the admin Spiegel et al. 1982, supra; Yap et al 1982, supra)). On a istration of bisantrene or derivatives or analogs thereof are schedule of every 3 to 4 weeks, the nadir for myelosuppres known in the art. U.S. Pat. No. 4,784,845 to Desai et al., sion was 9 days with recovery by 19 days (Von Hoff et al. incorporated herein by this reference, discloses a composi 1981 b). Thrombocytopenia was mild although bisantrene tion of matter for delivery of a hydrophobic drug (i.e., bisant can also inhibit platelet aggregation (M. E. Rybak et al., “The rene or a derivative or analog thereof) comprising: (i) the Effects of Bisantrene on Human Platelets.” Invest. New Drugs hydrophobic drug; (ii) an oleaginous vehicle or oil phase that 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 0129. 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 Lawter et al. 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 0130 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 0131 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 I0134. 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. I0135. As detailed above, in addition to directantineoplas (1982), supra). tic effects related to the activity of bisantrene as a DNA 0132) 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 US 2016/0166546 A1 Jun. 16, 2016

Lymphocytes Predict Response to Anthracycline-Based Che this reference. The minimal effective in vivo dose of bisant motherapy in Estrogen-Resistant Breast Cancer. Breast rene appeared to be 25 mg/kg, with peak activation being Canc. Res. 13: R126 (2011), which concludes that the level of achieved at doses of 50 to 100 mg/kg. A number of macroph tumor-infiltrating lymphocytes is correlated with a response age activators are known, including Bacillus Calmette to the administration of anthracycline-based agents; the Guerin, Corynebacterium parvum, endotoxins, muramyl markers associated with tumor-infiltrating lymphocytes dipeptide, pI:pC copolymer, pyran copolymer, lymphokines, (TIL) include CD19, CD3D, CD48, GZMB, LCK, MS4A1, Adriamycin, cyclophosphamide, and mitomycin C. The effi PRF1, and SELL; (ii) L. Zitvogel et al., “Immunological cacy of bisantrene in allogeneic macrophage transplants and Aspects of Cancer Chemotherapy.” Nature Rev. Immunol. 8: with Supernatants of macrophages activated by bisantrene has 59-73 (2008), which states that DNA damage, such as that been shown in B. S. Wang et al., “Immunotherapy of a Murine produced by intercalating agents such as bisantrene, induces Lymphoma by Adoptive Transfer of Syngeneic Macrophages the expression of NKG2D ligands on tumor cells in an ATM Activated by Bisantrene.” Cancer Res. 46: 503-506 (1986), dependent and CHK1-dependent (but p53-independent) incorporated herein by this reference. Specifically, the active manner; NKG2D is an activating receptor that is involved in cells were obtained from peritoneal exudate. Bisantrene-ac tumor immunosurveillance by NK cells, NKT cells, Yö T cells tivated macrophages were shown to be highly cytostatic to and resting (in mice) and/or activated (in humans) CD8" T tumor cells. Repeated treatments with activated macrophages cells, and also states that anthracycline-based agents may act were shown to be more effective in protecting animals inocu as immunostimulators, particularly in combination with lated with tumors. This represents immunotherapy by adop IL-12; such agents also promote HMGB1 release and activate tive transfer of immunocompetent cells. Culture Supernatants T cells; (iii) D.V. Krysko et al., “TLR2 and TLR9 Are Sensors of activated macrophages were also found to have antiprolif of Apoptosis in a Mouse Model of Doxorubicin-Induced erative effects on tumor cells, indicating that a cytostatic Acute Inflammation.” Cell Death Different. 18: 1316-1325 factor or factors were produced by these macrophages. (B.S. (2011), which states that anthracycline-based antibiotics Wang et al., “Activation of Tumor-Cytostatic Macrophages induce an immunogenic form of apoptosis that has immuno with the Antitumor Agent 9,10-Anthracenedicarboxaldehyde stimulatory properties mediated by MyD88, TLR2, and Bis(4,5-dihydro-1H-imidazole-2-yl)hydrazine Dihydro TLR9; (iv) C. Ferraro et al., “Anthracyclines Trigger Apop chloride (Bisantrene).” Cancer Res. 44: 2363-2367 (1984)). tosis of Both GO-G1 and Cycling Peripheral Blood Lympho 0.138 Bisantrene and analogs thereof have been reported cytes and Induce Massive Deletion of Mature T and B Cells.” as inhibiting telomerase activity, especially by stabilizing Cancer Res. 60: 1901-1907 (2000), which stated that anthra G-quadruplex DNA structures as disclosed in M. Folini et al., cyclines induce apoptosis and ceramide production, as well as “Remarkable Interference with Telomeric Function by a activate caspase-3 in resting and cycling cells; the apoptosis G-Quadruplex Selective Bisantrene Regioisomer. Biochem. induced is independent from CD95-L/CD95 and TNF/TNF Pharmacol. 79: 1781-1790 (2010). The bisantrene analogs R; and (v) K. Lee et al., “Anthracycline Chemotherapy Inhib used are those of Formulas (II), (III), (IV), (V), (VI), (VII), its HIF-1 Transcriptional Activity and Tumor-Induced Mobi and (VIII): lization of Circulating Angiogenic Cells. Proc. Natl. Acad. Sci USA 106: 2353-2358 (2009), which provides another antineoplastic mechanism for anthracycline-based antibiot (II) ics, namely inhibition of HIF-1 mediated gene transcription, which, in turn, inhibits transcription of VEGF required for angiogenesis; HIF-1 also activates transcription of genes 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 cancer cells, and pyruvate dehydrogenase kinase 1 (PDK1), which shunts pyruvate away from the mitochondria, thereby increasing lactate production; patients with HIF-1C. overex pression based on immunohistochemical results were Sug gested to be good candidates for treatment with anthracy cline-based antibiotics. 0.136 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). 0.137 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 US 2016/0166546 A1 Jun. 16, 2016 11

-continued machinery inhibitors have been evaluated as potential anti (IV) cancer agents, including nucleotide analogs such as 7-deaza 2'-deoxyguanosine, BIBR1532, antisense oligonucleotides, GRN163L, and other agents. For such agents, a number of different pathways are involved in inhibition of telomerase activity. Generally, inhibition of telomerase activity results in cellular senescence or apoptosis in a time-dependent manner that correlates with the initial telomere length in the cells in which telomerase is inhibited. When telomere architecture collapses or is disrupted, a signaling cascade comparable to that produced by DNA damage is activated and cell cycle arrest (accelerated Senescence) or cell death through apopto sis is induced. 0140 Telomerase substrates are the telomeres, double (V) stranded DNA portions with a 3' protruding overhang (100 200 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 lapping planar regions were identified by four Hoogsteen 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 (VI) interaction thus interfering with the telomere elongation step 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 pounds able to interact with and stabilize G-quadruplex struc tures formed by G-rich single-stranded overhangs of telom eres have been identified, including anthraquinones, fluorenones, acridines, triazine, cationic porphyrins, and perylenes, as well as other compounds. These compounds share ageneral consensus structural motif based on a large flat 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 0.141 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 NH tification of effective G-quadruplex binders such as the tri in N D substituted acridine BRACO 19 and the 2.6 or 2.7 bis N 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. 0142. 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 0139 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 US 2016/0166546 A1 Jun. 16, 2016

druplex binders are substituted on two distinct aromatic rings Cytotoxic Properties of Novel Topoisomerase II-Directed with side chains pointing in opposite directions with refer Bisantrene Analogues. Bioorg. Med. Chem. Lett. 20: 121 ence to the long axis of the aromatic system likely suggests 126 (1998).T. L. Fields et al., “The Synthesis of Heterocyclic formation of additional specific interactions between the 4.5- Analogs of Bisantrene.” J. Heterocyclic Chem. 25: 1917 dihydro-1H-imidazol-2-yl hydrazone groups and the G-qua 1918 (1988) discloses bisguanylhydrazones of anthracene-9, druplex structure. 10-dicarboxaldehyde as bisantrene analogs. Bisantrene 0143. At least one of the bisantrene analogs. Formula (III), amsacrine hybrids are also disclosed in G. Capranico et al., has the ability to act both at the telomerase level, by interfer "Mapping Drug Interactions at the Covalent Topoisomerase ing with Substrate recognition (hence Suppressing its catalytic II-DNA Complex by Bisantrene/Amsacrine Congeners. J. activity), and at the telomere level, by modifying its structural Biol. Chem. 273: 12732-12739 (1998). These compounds are organization. This compound affects telomere function not only in telomerase-expressing cells but also in ALT-positive depicted below as Formulas (X), (XI), (XII), and (XIII): cell lines, since it consistently provokes a DNA damage response, as evidenced by the formation of YH2AX foci that partially co-localize at the telomere, in agreement with results (X) 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 O) arrest), Suggest a drug-mediated activation of a senescence I N pathway. 2N s 0144. Additional bisantrene analogs have been described in T. P. Wunz et al., “New Antitumor Agents Containing the Anthracene Nucleus,” J. Med. Chem. 30: 1313-1321 (1987), including N,N'-bis(2-(dimethylamino)ethyl-9,10-an thracene-bis(methylamine) and N,N'-bis(1-ethyl-3-piperidi nyl)-9,10-anthracene-bis(methylamine). 0145 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), (XI) incorporated herein by this reference. HL-37 is anthracen-9- ylmethylene-2-methoxyethoxymethylsulfanyl-5-pyridin 3-yl-1,2,4-triazol-4-amine and has the structure shown O) below as Formula (IX): I N 21 N s

(IX) N

2 N

(XII)

0146. 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 Topoisomerase II Poisoning. Mol. Pharmacol. 54: 1036 NH 1045 (1998) discloses additional analogs, including an aza bioisostere that can be considered a bisantrene-amsacrine hybrid. Still other bisantrene analogs and derivatives are dis closed in G. Zagotto et al., “Synthesis, DNA-Damaging and US 2016/0166546 A1 Jun. 16, 2016 13

-continued Substituent may be in the ortho, meta, or para position and is (XIII) 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 P 0147 Additional derivatives and analogs of bisantrene R"O include the diphosphoramidic and monophosphoramidic derivatives of bisantrene, disclosed in U.S. Pat. No. 4,900,838 such that RandR" are the same or different and are R (where to Murdock and U.S. Pat. No. 5,212,191 to Murdock et al., R is C-C alkyl, aryl, aralkyl, heteroalkyl, NC CHCH . both of which are incorporated herein by this reference. These compounds are compounds of Formula (XIV): D-CH,- (XIV) R ClC C , or ROCH2CH2—, where R, is hydrogen or C-C alkyl, hydrogen, or a pharmaceutically acceptable cat CHEN-N ion or R' and R" are linked to form a —CHCH group or -K a li=n-i-KN R4 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, 0.148. Additional bisantrene analogs are disclosed in M. alkyl, phenyl, mono-substituted phenyl (wherein the substitu Kozurková et al., “DNA Binding Properties and Evaluation of ent can be ortho, meta, or para and is fluoro, nitro, C-C alkyl, Cytotoxic Activity of 9,10-Bis-N-Substituted (Aminomethy C-C alkoxy, or cyano), pentafluorophenyl, naphthyl, fura l)anthracenes.” Int. J. Biol. Macromol. 41: 415-422 (2007). nyl, These compounds include 9,10-bis(2-hydroxyethyl)imi nomethyl)anthracene: 9,10-bis(2-(-2-hydroxyethylamino) ethyliminomethyl)anthracene: 9,10-bis(2-(morpholin-4- t th yl)ethyliminomethyl)anthracene; 9,10-bis(2- -CHNHCOOC(CH), -CHNH2, -CH2CHCOOH, hydroxyethyl)aminomethyllanthracene; 9,10-bis(2-(2- -OC(CH), -CHOCH, -(CH2)COOH, hydroxyethylamino)ethylaminomethyl)anthracene tetrahydrochloride; 9,10-bis(2-(piperazin-1-yl)ethyl COOH aminomethyl)anthracene hexahydrochloride; and 9,10-bis: -(CH2)2SOH 2-(morpholin-4-yl)ethylaminomethyl)anthracene tetrahy s O drochloride. 0149 Other analogs and derivatives are known in the art, including derivatives and salt forms of the compounds described above. 0150. This invention relates to novel compositions and methods to improve the utility of chemical agents including bisantrene and derivatives and analogs thereof, as described above, with Suboptimal performance for patients with cancer --(). --( )—cit O and with other diseases and conditions, including metabolic diseases, immunological diseases, and infectious diseases. —SOH; wherein only one of R and R may be hydrogen or The invention describes the novel development of improved C-C alkyl, R and Ra are the same or different and are: pharmaceutical ingredients, dosage forms, excipients, Sol hydrogen, C-C alkyl or—C(O)—R, where R is hydrogen, vents, diluents, drug delivery systems, preservatives, more C-C alkyl, phenyl, mono-Substituted phenyl (wherein the accurate drug administrations, improved dose determination US 2016/0166546 A1 Jun. 16, 2016

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 0157 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 0158. 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 0151. 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 0159. 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, 0152 The activity of bisantrene has been described above. branched or cyclic hydrocarbyl residue having one or more 0153. 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. 0154 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 aromatic nucleus but has one or more Substituents as a monocyclic or fused bicyclic moiety having the well-known described below that replace at least one hydrogen present in characteristics of aromaticity; examples include phenyl and bisantrene with another moiety. As used herein, the term naphthyl, which can be optionally Substituted. As used herein, “analog as applied to bisantrene applies to a compound the term “hydroxyaryl” refers to an aryl group including one related structurally to bisantrene but alters one or more of the or more hydroxyl groups as Substituents; as further detailed tricyclic aromatic nucleus or one or more of the side chains, below, further substituents can be optionally included. As for example, by replacing one or more carbons in the tricyclic used herein, the term "heteroaryl refers to monocyclic or aromatic nucleus with nitrogens or by removing or moving fused bicyclic ring systems that have the characteristics of one or both of the side chains. Some analogs are described aromaticity and include one or more heteroatoms selected above; others are known to one of skill in the art. from O, S, and N. The inclusion of a heteroatom permits 0155. In summary, bisantrene and its derivatives or ana aromaticity in 5-membered rings as well as in 6-membered logs can be expected to have antineoplastic activity against rings. Typical heteroaromatic systems include monocyclic the following cancers: acute myelogenous leukemia (AML, Cs-C heteroaromatic groups such as pyridyl, pyrimidyl, also called acute non-lymphocytic leukemia, ANLL), lym pyrazinyl, thienyl, furanyl, pyrrolyl pyrazolyl, thiazolyl, phoma, ovarian cancer, and breast cancer, especially refrac oxazolyl, triazolyl, triazinyl, tetrazolyl, tetrazinyl, and imida tory AML or breast cancer. Zolyl, as well as the fused bicyclic moieties formed by fusing 0156 Derivatives of bisantrene include, but are not limited one of these monocyclic heteroaromatic groups with a phenyl to: (1) derivatives of bisantrene in which at least one of the ring or with any of the heteroaromatic monocyclic groups to hydrogen atoms bound to the carbon atoms that are directly form a Cs-Co. bicyclic group Such as indolyl, benzimida US 2016/0166546 A1 Jun. 16, 2016

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 CN, 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(Oz)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) definition. This definition also includes bicyclic groups where Z, C(O)C, C(O)OZ, 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, NZC(S)Z, delocalized electron distribution that is characteristic of aro NZ°C(O)O, NZ'C(O)OZ’, NZ'C(S)OZ, NZ'C maticity. Typically the ring systems contain 5 to 12 ring (O)NZZ, NZC(NZ)Z, NZPC(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 “haloaryl' and “haloheteroaryl refer to aryl and heteroaryl to 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 0162 Similarly, substituent groups useful for substituting stituents can be optionally included. As used herein, the terms unsaturated carbon atoms in the specified group, moiety, or “haloalkyl,” “haloalkenyl, and “haloalkynyl refer to alkyl, radical include, but are not limited to, —Z', halo, —O, alkenyl, and alkynyl groups, respectively, Substituted with at —OZ, -SZ, -S, NZZ, trihalomethyl, -CF, CN, least one halo group, where "halo' refers to a halogen 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 C(O)Z, C(S)Z, C(NZ)Z, C(O)O, C(O)OZ’, below, further substituents can be optionally included. C(S)OZ, C(O)NZZ, C(NZ)NZZ, OC(O)Z, 0160. As used herein, the term “optionally substituted OC(S)Z, OC(O)C, OC(O)OZ, OC(S)OZ’, indicates that the particular group or groups referred to as NZ°C(O)OZ’, NZ'C(S)OZ, NZ'C(O)NZZ, optionally Substituted may have no non-hydrogen Substitu NZ°C(NZ)Z, and NZ'C(NZ)NZZ, wherein Z, Z”, ents, or the group or groups may have one or more non and Z are as defined above. hydrogen Substituents consistent with the chemistry and 0163 Similarly, substituent groups useful for substituting pharmacological activity of the resulting molecule. If not nitrogen atoms in heteroalkyl and cycloheteroalkyl groups otherwise specified, the total number of such substituents that include, but are not limited to, —Z", halo, —O, OZ’, may be present is equal to the total number of hydrogenatoms —SZ, -S, NZZ, trihalomethyl, -CF, —CN, present on the unsubstituted form of the group being OCN, -SCN, NO, NO, S(O)Z, -S(O)O, described; fewer than the maximum number of such substitu —S(O)OZ’, —OS(O)OZ’, —OS(O)O, -P(O)(O), ents may be present. Where an optional substituent is attached - P(O)(OZ)(O), P(O)(OZ)(OZ), C(O)Z, C(S)Z, via a double bond, Such as a carbonyl oxygen (C=O), the C(NZ)Z, C(O)OZ, C(S)OZ, C(O)NZZ, group takes up two available Valences on the carbon atom to C(NZ)NZZ, OC(O)Z, OC(S)Z, OC(O)OZ’, which the optional substituent is attached, so the total number OC(S)OZ, NZC(O)Z, NZPC(S)Z, NZPC(O) of Substituents that may be included is reduced according to OZ, NZC(S)OZ, NZPC(O)NZZ, NZ'C(NZ)Z, the number of available valences. As used herein, the term and - NZ'C(NZ)NZZ, wherein Z, Z, and Z are as “substituted, whether used as part of “optionally substituted defined above. or otherwise, when used to modify a specific group, moiety, 0164. The compounds described herein may contain one or radical, means that one or more hydrogenatoms are, each, or more chiral centers and/or double bonds and therefore, independently of each other, replaced with the same or dif may exist as stereoisomers, such as double-bond isomers ferent substituent or substituents. (i.e., geometric isomers such as E and Z), enantiomers or 0161 Substituent groups useful for substituting saturated diastereomers. The invention includes each of the isolated carbon atoms in the specified group, moiety, or radical Stereoisomeric forms (such as the enantiomerically pure iso US 2016/0166546 A1 Jun. 16, 2016

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. the atom or atoms in the Substituent groups to which they are Accordingly, the chemical structures depicted herein encom attached to form Such a ring. pass all possible enantiomers and stereoisomers of the illus (0169) “Heteroalkyl,” “heteroalkenyl,” and “heteroalky trated compounds including the stereoisomerically pure form nyl' and the like are defined similarly to the corresponding (e.g., geometrically pure, enantiomerically pure or diastereo hydrocarbyl (alkyl, alkenyl and alkynyl) groups, but the het merically pure) and enantiomeric and stereoisomeric mix ero terms refer to groups that contain 1-3 O.S or N heteroa tures. Enantiomeric and stereoisomeric mixtures can be toms or combinations thereof within the backbone residue; resolved into their component enantiomers or stereoisomers thus at least one carbon atom of a corresponding alkyl, alk using separation techniques or chiral synthesis techniques enyl, or alkynyl group is replaced by one of the specified well known to the skilled artisan. The invention includes each heteroatoms to form, respectively, a heteroalkyl, heteroalk of the isolated stereoisomeric forms as well as mixtures of enyl, or heteroalkynyl group. For reasons of chemical stabil Stereoisomers in varying degrees of chiral purity, including ity, it is also understood that, unless otherwise specified. Such racemic mixtures. It also encompasses the various diastere groups do not include more than two contiguous heteroatoms omers. Other structures may appear to depict a specific iso except where an oxo group is present on NorSas in a nitro or mer, but that is merely for convenience, and is not intended to Sulfonyl group. limit the invention to the depicted isomer. When the chemical (0170 While “alkyl as used herein includes cycloalkyl name does not specify the isomeric form of the compound, it and cycloalkylalkyl groups, the term "cycloalkyl may be denotes any one of the possible isomeric forms or mixtures of used hereinto describe a carbocyclic non-aromatic group that those isomeric forms of the compound. is connected via a ring carbon atom, and “cycloalkylalkyl 0.165. The compounds may also exist in several tautomeric may be used to describe a carbocyclic non-aromatic group forms, and the depiction herein of one tautomer is for conve that is connected to the molecule through an alkyl linker. nience only, and is also understood to encompass other tau 0171 Similarly, "heterocyclyl may be used to describe a tomers of the form shown. Accordingly, the chemical struc non-aromatic cyclic group that contains at least one heteroa tures depicted herein encompass all possible tautomeric tom (typically selected from N, O and S) as a ring member and forms of the illustrated compounds. The term “tautomer as that is connected to the molecule via a ring atom, which may used herein refers to isomers that change into one another be C (carbon-linked) or N (nitrogen-linked); and "heterocy with great ease so that they can exist together in equilibrium. clylalkyl may be used to describe Such a group that is con For example, ketone and enol are two tautomeric forms of one nected to another molecule through a linker. The heterocyclyl compound. can be fully saturated or partially saturated, but non-aromatic. 0166 As used herein, the term “solvate” means a com The sizes and substituents that are suitable for the cycloalkyl, pound formed by solvation (the combination of solvent mol cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl groups ecules with molecules or ions of the Solute), or an aggregate are the same as those described above for alkyl groups. The that consists of a solute ion or molecule, i.e., a compound of heterocyclyl groups typically contain 1, 2 or 3 heteroatoms, the invention, with one or more solvent molecules. When selected from N, O and S as ring members; and the Nor S can water is the solvent, the corresponding solvate is a “hydrate.” be substituted with the groups commonly found on these Examples of hydrates include, but are not limited to, hemi atoms in heterocyclic systems. As used herein, these terms hydrate, monohydrate, dihydrate, trihydrate, hexahydrate, also include rings that contain a double bond or two double and other hydrated forms. It should be understood by one of bonds, as long as the ring that is attached is not aromatic. The ordinary skill in the art that the pharmaceutically acceptable Substituted cycloalkyl and heterocyclyl groups also include salt and/or prodrug of the present compound may also exist in cycloalkyl or heterocyclic rings fused to an aromatic ring or a solvate form. The solvate is typically formed via hydration heteroaromatic ring, provided the point of attachment of the which is either part of the preparation of the present com group is to the cycloalkyl or heterocyclyl ring rather than to pound or through natural absorption of moisture by the anhy the aromatic/heteroaromatic ring. drous compound of the present invention. 0172 AS used herein, “acyl encompasses groups com 0167 As used herein, the term “ester” means any ester of prising an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical a present compound in which any of the COON functions attached at one of the two available valence positions of a of the molecule is replaced by a COOR function, in which carbonyl carbon atom, and heteroacyl refers to the corre the R moiety of the ester is any carbon-containing group sponding groups wherein at least one carbon other than the which forms a stable ester moiety, including but not limited to carbonyl carbon has been replaced by a heteroatom chosen alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, ary from N, O and S. lalkyl, heterocyclyl, heterocyclylalkyl and substituted deriva 0173 Acyl and heteroacyl groups are bonded to any group tives thereof. The hydrolyzable esters of the present com or molecule to which they are attached through the open pounds are the compounds whose carboxyls are present in the valence of the carbonyl carbon atom. Typically, they are form of hydrolyzable ester groups. That is, these esters are C-Cs acyl groups, which include formyl, acetyl, pivaloyl, pharmaceutically acceptable and can be hydrolyzed to the and benzoyl, and C-Cs heteroacyl groups, which include corresponding carboxyl acid in vivo. methoxyacetyl, ethoxycarbonyl, and 4-pyridinoyl. 0168. In addition to the substituents described above, (0174 Similarly, “arylalkyl and “heteroarylalkyl” refer to alkyl, alkenyl and alkynyl groups can alternatively or in addi aromatic and heteroaromatic ring systems which are bonded tion be substituted by C-Cs acyl, C-Cs heteroacyl, Co-Co to their attachment point through a linking group Such as an aryl, C-Cs cycloalkyl, C-Cs heterocyclyl, or Cs-Co het alkylene, including Substituted or unsubstituted, Saturated or eroaryl, each of which can be optionally substituted. Also, in unsaturated, cyclic or acyclic linkers. Typically the linker is US 2016/0166546 A1 Jun. 16, 2016

C-Cs alkyl. These linkers may also include a carbonyl group, regard to the primary substituents themselves if the substitu thus making them able to provide Substituents as an acyl or ents are not otherwise described. heteroacyl moiety. An aryl or heteroaryl ring in an arylalkyl or 0180 Amino” as used herein refers to —NH, but where heteroarylalkyl group may be substituted with the same sub an amino is described as “substituted' or “optionally substi stituents described above for aryl groups. Preferably, an ary tuted’, the term includes NR'R'" wherein each R' and R" is lalkyl group includes a phenyl ring optionally Substituted independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or with the groups defined above for aryl groups and a C-C, arylalkyl group, and each of the alkyl, alkenyl, alkynyl, acyl, alkylene that is unsubstituted or is substituted with one or two aryl, or arylalkyl groups is optionally substituted with the C-C alkyl groups or heteroalkyl groups, where the alkyl or substituents described herein as suitable for the correspond heteroalkyl groups can optionally cyclize to form a ring Such ing group; the R' and R" groups and the nitrogen atom to as cyclopropane, dioxolane, or oxacyclopentane. Similarly, a which they are attached can optionally form a 3- to 8-mem heteroarylalkyl group preferably includes a C-C monocy bered ring which may be saturated, unsaturated or aromatic clic heteroaryl group that is optionally substituted with the and which contains 1-3 heteroatoms independently selected groups described above as Substituents typical on aryl groups from N, O and S as ring members, and which is optionally and a C-C alkylene that is unsubstituted or is Substituted substituted with the substituents described as suitable for 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 0181. 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 0175 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. 0182. As used herein, the term "heteroatom” refers to any 0176 "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 (0177) “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 0183. 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 linked through a hydrocarbyl linker Such as an alkylene; and “alkynylcarbonyl refer to an alkenyl or alkynyl group, heteroaryl groups linked through a heteroalkyl linker. Thus, respectively, linked to a carbonyl group. for example, C7-heteroarylalkyl would include pyridylm 0.184 As used herein, the term “alkoxy' refers to an alkyl ethyl, phenoxy, and N-pyrrolylmethoxy. group covalently linked to an oxygen atom; the alkyl group 0.178 “Alkylene' as used herein refers to a divalent hydro can be considered as replacing the hydrogen atom of a carbyl group; because it is divalent, it can link two other hydroxyl group. The term “lower alkoxy' refers to an alkoxy groups together. Typically it refers to —(CH), where n is group in which the alkyl portion of the alkoxy group is C-C. 1-8 and preferably n is 1-4, though where specified, an alky The alkyl portion of the alkoxy group can be optionally Sub lene can also be substituted by other groups, and can be of stituted as described above. As used herein, the term other lengths, and the open Valences need not be at opposite “haloalkoxy' refers to an alkoxy group in which the alkyl ends of a chain. The general term “alkylene' encompasses portion is Substituted with one or more halo groups. more specific examples such as “ethylene, wherein n is 2. 0185. As used herein, the term "sulfo’ refers to a sulfonic “propylene, wherein n is 3, and “butylene, wherein n is 4. acid ( -SOH) substituent. The hydrocarbyl groups of the alkylene can be optionally 0186. As used herein, the term "sulfamoyl refers to a substituted as described above. substituent with the structure—S(O)NH2, wherein the nitro 0179. In general, any alkyl, alkenyl, alkynyl, acyl, or aryl gen of the NH2 portion of the group can be optionally Substi orarylalkyl group that is contained in a Substituent may itself tuted as described above. optionally be substituted by additional substituents. The 0187. As used herein, the term “carboxyl refers to a group nature of these substituents is similar to those recited with of the structure —C(O)H. US 2016/0166546 A1 Jun. 16, 2016

0188 As used herein, the term “carbamyl refers to a Structure Determination and Methodological Implications.” group of the structure —C(O)NH, wherein the nitrogen of Nucl. Acids. Res. 32(12): e103 (2004), incorporated herein by the NH portion of the group can be optionally substituted as this reference. described above. 0194 Accordingly, as described in further detail below, one aspect of the present invention is a method to improve the 0189 As used herein, the terms “monoalkylaminoalkyl efficacy and/or reduce the side effects of suboptimally admin and “dialkylaminoalkyl refer to groups of the structure istered drug therapy comprising the steps of -Alk-NH-Alk, and -Alk-N(Alk)(Alk3), wherein Alk, 0.195 (a) identifying at least one factor or parameter asso Alk, and Alks refer to alkyl groups as described above. ciated with the efficacy and/or occurrence of side effects of 0190. As used herein, the term “alkylsulfonyl refers to a the drug therapy, wherein the factor or parameter is addition group of the structure —S(O)-Alk wherein Alk refers to an ally associated with at least one of: (i) the specific disease or alkyl group as described above. The terms “alkenylsulfonyl condition being treated; (ii) the stage of the disease or condi and “alkynylsulfonyl refer analogously to Sulfonyl groups tion being treated; (iii) selection of an appropriate patient for covalently bound to alkenyl and alkynyl groups, respectively. treatment; (iv) selection of an appropriate phenotype of the The term “arylsulfonyl refers to a group of the structure patient or the disease or condition being treated; and (v) —S(O), Ar wherein Ar refers to an aryl group as described selection of an appropriate phenotype of the patient or the above. The term “aryloxyalkylsulfonyl refers to a group of disease or condition being treated; and the structure —S(O)-Alk-O Ar, where Alk is an alkyl 0.196 (b) modifying the factor or parameter to improve the group as described above and Aris an aryl group as described efficacy and/or reduce the side effects of the drug therapy: above. The term “arylalkylsulfonyl refers to a group of the wherein the drug therapy comprises administration of bisant structure —S(O)-AlkAr, where Alk is an alkyl group as rene or a derivative or analog thereof. described above and Ar is an aryl group as described above. 0.197 As described in further detail below, another aspect 0191 As used herein, the term “alkyloxycarbonyl refers of the present invention is a method to improve the efficacy to an ester Substituent including an alkyl group wherein the and/or reduce the side effects of suboptimally administered carbonyl carbon is the point of attachment to the molecule. An drug therapy comprising the steps of example is ethoxycarbonyl, which is CHCHOC(O)—. 0198 (a) identifying at least one factor or parameter asso Similarly, the terms “alkenyloxycarbonyl.” “alkynyloxycar ciated with the efficacy and/or occurrence of side effects of the drug therapy, wherein the factor or parameter is addition bonyl, and “cycloalkylcarbonyl refer to similar ester sub ally associated with at least one of: (i) the chemical compo stituents including an alkenyl group, alkenyl group, or sition of the drug being administered; (ii) the physical form of cycloalkyl group respectively. Similarly, the term “aryloxy the drug being administered or a pharmaceutical composition carbonyl refers to an ester Substituent including an aryl including the drug being administered; (iii) the makeup of a group wherein the carbonyl carbon is the point of attachment pharmaceutical composition including the drug being admin to the molecule. Similarly, the term “aryloxyalkylcarbonyl istered; (iv) the specific use of the drug being administered; refers to an ester Substituent including an alkyl group wherein (v) the target cell, organ, or receptor targeted by the drug the alkyl group is itself substituted by an aryloxy group. being administered; or (vi) additional agents administered 0192 Other combinations of substituents are known in the with the drug being administered; and art and, are described, for example, in U.S. Pat. No. 8,344,162 0199 (b) modifying the factor or parameter to improve the to Jung et al., incorporated herein by this reference. For efficacy and/or reduce the side effects of the drug therapy: example, the term “thiocarbonyl and combinations of sub wherein the drug therapy comprises administration of bisant stituents including “thiocarbonyl include a carbonyl group rene or a derivative or analog thereof. in which a double-bonded sulfur replaces the normal double 0200. As described in further detail below, yet another bonded oxygen in the group. The term “alkylidene' and simi aspect of the present invention is a method to improve the lar terminology refer to an alkyl group, alkenyl group, alkynyl efficacy and/or reduce the side effects of suboptimally admin group, or cycloalkyl group, as specified, that has two hydro istered drug therapy comprising the steps of gen atoms removed from a single carbon atom so that the 0201 (a) identifying at least one factor or parameter asso group is double-bonded to the remainder of the structure. ciated with the efficacy and/or occurrence of side effects of 0193 Accordingly, methods and compositions according the drug therapy; and to the present invention encompass bisantrene derivatives and 0202 (b) modifying the factor or parameter to improve the analogs including one or more optional Substituents as efficacy and/or reduce the side effects of the drug therapy: defined above, provided that the optionally substituted bisant wherein the drug therapy comprises administration of bisant rene derivative or analog possesses Substantially equivalent rene or a derivative or analog thereof; pharmacological activity to amonafide as defined in terms of and wherein the factor or parameter is use of bisantrene or a either or both topoisomerase II inhibition and DNA interca derivative or analog thereof in a combinatorial regime. lation. Methods for determination of topoisomerase II inhi 0203 (I) Suboptimal Therapeutics bition are known in the art and are described, for example, in 0204. In general, examples of compounds with subopti A. Constantinou et al., “Novobiocin- and Phorbol-12 mal therapeutic activity may include antimetabolites, DNA/ Myristate-13-Acetate-Induced Differentiation of Human nucleic acid binding/reactive agents, topoisomerase inibitors, Leukemia Cells Associates with a Reduction in Topoi anti-tubulin agents, signal transduction inhibitors, protein somerase II Activity.” Cancer Res. 49: 1110-1117 (1989), synthesis inhibitors, inhibitors of DNA transcribing enzymes, incorporated herein by this reference. Methods for determi DNA/RNA intercalating agents, DNA minor groove binders, nation of DNA intercalation are known in the art and are drugs that block steroid hormone action, photochemically described, for example, in H. Zipper et al., “Investigations on active agents, immune modifying agents, hypoxia selective DNA Intercalation and Surface Binding by SYBR Green I. Its cytotoxins, chemical radiation sensitizers and protectors, US 2016/0166546 A1 Jun. 16, 2016 antisense nucleic acids, oligonucleotide and polynucleotide ylene bisacetamide, amonafide, hydrazine Sulfate, 4-hy therapeutic agents, immune modifying agents, antitumor droxyandrostenedione, hydroxyurea, idarubicin HCl, ifosfa antibiotics, and other classes of therapeutic agents having mide, 4-ipomeanol, iproplatin, isotretinoin, leuproloide antineoplastic, antiproliferative, or immune-system-modu acetate, levamisole, liposomal daunorubicin, liposomal lating activity. Specific examples include: fluoropyrimidines, doxorubicin, lomustine, lonidamine, maytansine, mechloet thiopurines, inhibitors of nucleoside diphosphate reductase, hamine hydrochloride, melphalan, menogaril, 6-mercaptopu 2'-deoxyribonucleoside analogs, nucleosides, folic acid ana rine, mesna, methotrexate, N-methylformamide, mifepris logs, methotrexate, 6-diazo-5-oxo-norleucine, L-asparagi tone, mitoguaZone, mitomycin C, mitotane, mitoxantrone nase, N-(phosphoacetyl)-L-aspartic acid, nitrogen mustard, hydrochloride, nabilone, nafoxidine, neocarzinostatin, oct mechlorethamine, chlorambucil, melphalan, cyclophospha reotide acetate, ormaplatin, oxaliplatin, paclitaxel, pala, pen mide, estramustine, platinum complexes, nitrosoureas, to statin, piperazinedione, pipobroman, pirarubicin, piritr BCNU, CCNU, streptozotocin, alkyl sulfonates, busulfan, exim, piroXantrone hydrochloride, plicamycin, porfimer clomesone, triaZenylimidazoles and related triaZenes, mito Sodium, predimustine, procarbazine, progestins, pyrazofurin, Zolomide, temozolomide, aziridines, tris(1-aziridinyl)phos razoxane, Sargramostim, semustine, Spirogermanium, Strep phine sulfide, aziridinylphosphines, 3.6,-diaziridinyl-2,5-bis tonigrin, streptozocin, Sulofenur, Suramin Sodium, tamox (carboethoxyamino)-1,4-benzoquinone (diaziquone) (AZQ). ifen, taxotere, tegafur, teniposide, terephthalamidine, teroX AZQ analogs, procarbazine, hexamethylamine, topoi irone, thioguanine, thiotepa, thymidine, tiazofurin, Somerase I inhibitors, camptothecin, camptothecin analogs, topotecan, tormifene, treinoin, trifluoroperazine hydrochlo topoisomerase II inhibitors, anthracyclines, doxorubicin, epi ride, trifluridine, trimetrexate, uracil mustard, vinblastine sul rubicin, etoposide, DNA intercalating agents, amsacrine, fate, Vincristine sulfate, vindesine, vinorelbine, Vinzolidine, CI-921, 1'-carbamate analogs of amsacrine, 9-aminoacri Yoshi 864, Zorubicin, 2-Cl-2'-deoxyadenosine, 3-deazauri dine-4-carboxamides, acridine carboxamide, tricyclic car dine, 4-nitroestrone, 6-methylmercaptopurine riboside, boxamides, 1-nitroacridine, acridine derivatives, diacridines, triacridines, podophyllotoxins, ellipticine, merbarone, ben 9-aminocamptothecin, nitrocamptothecin, irinotecan, CPT Zisoquinolinediones, etoposide, teniposide, aminoan 11, acivicin, acodazole HCl, ADR-529, ICRF-187, amasa thraquinones, inhibitors of DNA-transcribing enzymes, tran crine, aminothiadiazole, ADTA, antibiotic FR901228, scription inhibitors, replication inhibitors, RNA replication aphidicolin glycinate, azacytidine, AZT, bizelesin, brefel inhibitors, polymerase inhibitors, rifamycins, actinomycins, dins, wortmannins, canthardins, bromodeoxyuridines, bry DNA minor groove binding compounds, Hoechst 33258, ostatin, BSO, CAI, caracemide, carboplatin, chlorosulfaqui mitomycins, CC-1065, mithramycins, chloromycins, olivo noxaline, Sulfonamide, cisplatin, clomesone, cyclocytidine mycins, phthalanilides, anthramycins, antimitotic agents, HCl, cyclodisone, cyclopentenylcytosine, deoxyspergualin, Vinca alkaloids, vinblastine and analogs, Vincristine and ana DHAC, didemnin B, dideoxy-B-fluorouracil, dideoxyad logs, navelbine, colchicine and analogs, bleomycin and ana enosine, dideoxyinosine, dihydrotriazine benzene Sulfonyl logs, estramustine, aromatase inhibitors, tamoxifen, LHRH fluoride, dolastatin 10, ecteinascidin 743, etanidazole, ethio antagonists and analogs, porfimer, hematoporphyrins, elec fos (WR-2721), fazarabine, flavopiridol, fludarabine phos tron-affinic oxygen mimetics, nitoaromatics, nitroheterocy phate, fostriecin, gallium nitrate, genistein, hepsulfam, clics, nitroimidizaoles, tirapazamine, mitomycins, menadi HMBA, hydrazine sulfate, iododeoxyuridine, ipomeanol, one and analogs, napthoguinones, aziridoquinones, amine KNI-272, leucovorin calcium, levamisole, melphalan, oxides, N-oxides, bioreductive agents, bioreductive alkylat menogaril, merbarone, methotrexate, misonidazole, ing agents, metal complexes, radiation sensitizers, radiation mitoguaZone, mitoxantrone HCl, mitoZolomide, N-methyl protectors, antisense agents, antigene agents, transcription formamide, O6-benzylguanine, PALA, pancratistatin, pen factor inhibitors, ODN complexes, ribozymes, double clomedine, pentamethylmelamine HCl, pentamidine Stranded RNA, antitumor antibiotics, acivicin, aclararubicin, isethionate, pentostatin, perillyl alcohol, phyllanthoside, acodazole, acronycine, adoZelesin, alanosine, allopurinol, pibenZimole HCl, piroXantrone, pyrazine diaZohydroxide, altretamine, aminoglutethimide, amonafide, amsacrine, pyrazoloacridine, quinocarmycins, rebeccamycins, rhizoxin, androgens, anguidine, aphidicolin glycinate, asaley, 5-azac semustine (methyl CCNU), Taxol, terephthalamidine, terox itidine, azathioprine, Baker's Antifol, B-2'-deoxythiogua irone, thioguanine, thymidine, tiazofurin, TMCA, 5-fluorou nosine, bisantrene HCl, bleomycin sulfate, busulfan, buthion racil, methotrexate, cyclophosphamide, ras inhibitors, farne ine sulfoximine (BSO), BWA 773U82, BW 502U83 HCl, Sylation inhibitors, bromodeoxyuridine, tetracycline BW 7U85 mesylate, caracemide, carbetimer, carboplatin, compounds, arsenic trioxide, combretastatins, 2-methox carmustine, chlorambucil, chloroquinoxaline Sulfonamide, yestradiol, thalidomide and analogs, cephalotaxine deriva chlorozotocin, chromomycin A3, cisplatin, cladribine, carbo tives, gleevec, stributyrin, triciribine phosphate, trimetrexate, platin, oxaliplatin, rhodamine compounds, corticosteroids, UCN-01, 7-hydroxystaurosporine, uridine, lycurium, ritro CPT-11, cristanol cyclocytidine, cyclophosphamide, cytara Sulfan, artemisinin, artesunate, lonidamine, mesna, bromo bine, cytemberna, dabis maleate, dacarbazine, dactinomycin, mannitol, hydrazine Sulfate, pipobroman, phenesterin, pyra daunorubicin HCl, deazauridine, dexraZOxane, dianhydroga Zine diaZohydroxide, cytemberna, Spirogermanium, lactitol (DAG), dibromodulcitol, didemnin B, diethyldithio terephthalamidine, bufalin, dibromodulcitol, gemcitabine, carbamate, diglycoaldehyde, dihydro-5-azacytidine, doxoru FMDC, colchicine, thiocolchicine, colchicine analogs, bicin, echinomycin, edatrexate, edelfosine, eflornithine, LHRH analogs, paclitaxel, MGBG, meisoindigo, indarubin elsamitrucin, epirubicin, esorubicin, estramustine phosphate, analogs, metformin, phlorizin, and other compounds, includ estrogens, etanidazole, ethiofos, etoposide, fadrazole, faZara ing homoharringtonine (HHT). bine, fenretinide, finasteride, flavone acetic acid, floxuridine, fludarabine phosphate, 5-fluorouracil, flutamide, gallium 0205. In particular, this invention is directed to bisantrene nitrate, gemcitabine, goserelinacetate, hepsulfam, hexameth and derivatives and analogs thereofas described above. US 2016/0166546 A1 Jun. 16, 2016 20

0206 (II) Dose Modification of disease for which the compound is administered. General 0207 Improvements for suboptimal chemotherapeutics examples include: the use of solid tumor agents for leukemias including bisantrene and analogs and derivatives thereof are and Vice versa, the use of antitumor agents for the treatment of made by alterations to the time that the compound is admin benign hyperproliferative disease such as psoriasis or benign istered, the use of dose-modifying agents that control the rate prostate hypertrophy, metabolic diseases, immunological dis of metabolism of the compound, normal tissue protective eases or infection. Specific inventive examples forbisantrene agents, and other alterations. General examples include: and analogs and derivatives thereof include: use for the treat Variations of infusion schedules (e.g., bolus i.v. versus con ment of refractory breast cancer; use for the treatment of tinuous infusion), the use of lymphokines (e.g., G-CSF, triple-negative breast cancer, use for the treatment of acute M-CSF, GM-CSF, EPO) to increase leukocyte count for leukemias, including, but not limited to, acute myelocytic improved immune response or for preventing anemia caused leukemia (AML); use for treatment of acute leukemias of by myelosuppressive agents, or the use of rescue agents such childhood, including acute myelocytic leukemia (AML) and as leucovorin for 5-FU or thiosulfate for cisplatin treatment. acute lymphocytic leukemia (ALL); use for treatment of Specific inventive examples for bisantrene and analogs and myelodysplastic syndrome; use for treatment of chronic derivatives thereof include: continuous i.v. infusion for hours myelocytic leukemia (CML), either subsequent to or in com to days; biweekly administration; doses greater than 5 bination with the administration of tyrosine kinase inhibitors mg/m/day: progressive escalation of dosing from 1 mg/m/ or homoharringtonine; use for treatment of chronic lympho day based on patient tolerance; doses less than 1 mg/m for cytic leukemia; use for treatment of ovarian cancer; use for greater than 14 days; use of caffeine to modulate metabolism: treatment of lymphoma including Hodgkin’s lymphoma and use of isoniazid to modulate metabolism; selected and inter non-Hodgkin’s lymphoma; use for treatment of mycosis fun mittent boost dose administrations: bolus single and multiple goides; use for treatment of prostate cancer, especially andro doses of 1-5 mg/m, oral dosing including multiple daily gen-resistant prostate cancer; use for treatment of lung small dosing: micro dosing, immediate release dosing: slow release cell carcinoma, either subsequent to or in combination with dosing; or controlled release dosing. the administration of EGFR inhibitors such as erlotinib 0208 (III) Route of Administration (Tarceva) or gefitinib (Iressa), wherein the lung small cell 0209) Improvements for suboptimal chemotherapeutics carcinoma is characterized by either wild-type or mutated including bisantrene and analogs and derivatives thereof are EGFR, use for treatment of lung non-small cell carcinoma, made by alterations in the route by which the compound is Subsequent to or in combination with EGFR inhibitors such administered. General examples include: changing route as erlotinib or gefitinib, wherein the lung non-small cell car from oral to intravenous administration and vice versa; or the cinoma is characterized by either wild-type or mutated use of specialized routes such as subcutaneous, intramuscu EGFR; use for treatment of breast cancer characterized by lar, intra-arterial, intraperitoneal, intralesional, intralym overexpressed Her-2-neu; use for treatment of glioblastoma 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 t1On. leukemias of childhood, including ALL and AML. 0210 (IV) Schedule of Administration 0214) (VI) Disease Stages 0211 Improvements for suboptimal chemotherapeutics 0215 Improvements for suboptimal chemotherapeutics including bisantrene and analogs and derivatives thereof are including bisantrene and analogs and derivatives thereofare 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 avoidanaphy 0216 (VII) Other Indications laxis. 0217. Improvements for suboptimal chemotherapeutics 0212 (V) Indications for Use including bisantrene and analogs and derivatives thereofare 0213 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 US 2016/0166546 A1 Jun. 16, 2016

infections, treatment of parasitic infections, usage to relieve response in an in vitro human tumor clonal assay and the pain, use for control of pleural effusions. Specific inventive quantity or activity of topoisomerase 23 present in cardiac examples for bisantrene and analogs and derivatives thereof cells. include: use as an anti-infective agent; use as an antiviral 0222 (X) Patient/Disease Genotype agent; use as an antibacterial agent; use for control of pleural 0223 Improvements for suboptimal chemotherapeutics effusions; use as an antifungal agent; use as an antiparasitic including bisantrene and analogs and derivatives thereof are agent; use for treatment of eczema, use for treatment of made by testing and analyzingapatient’s genotype for unique shingles; use for treatment of condylomata; use for treatment features that may be of value to predict efficacy, toxicity, of human papilloma virus (HPV); or use for treatment of metabolism, or other parameters relevant to therapeutic use of herpes simplex virus (HSV). the Suboptimal therapeutic. General examples include: 0218 (VIII) Patient Selection biopsy samples of tumors or normal tissues (e.g., white blood cells) may be taken and analyzed to specifically tailor or 0219. Improvements for suboptimal chemotherapeutics monitor the use of a particular drug against a gene target; including bisantrene and analogs and derivatives thereof are analysis of unique tumor gene expression pattern, SNPs made by alterations to the type of patient that would best (single nucleotide polymorphisms), to enhance efficacy or to tolerate or benefit from the use of the compound. General avoid particular drug-sensitive normal tissue toxicities. Spe examples include: use of pediatric doses for elderly patients, cific inventive examples for bisantrene and analogs and altered doses for obese patients; exploitation of co-morbid derivatives thereof include: genetic tests to determine the disease conditions such as diabetes, cirrhosis, or other con absence or nonfunctionality of ABCG2; genetic tests to deter ditions that may uniquely exploit a feature of the compound. mine the presence or functionality of FABP7; diagnostic Specific inventive examples for bisantrene and analogs and tools, techniques, kits and assays to confirm a patient’s par derivatives thereof include: patients with disease conditions ticular genotype; gene/protein expression chips and analysis; with high levels of metabolic enzymes such as histone Single Nucleotide Polymorphisms (SNPs) assessment; deacetylase, protein kinases, ornithine decarboxylase; SNPs for histone deacetylase, ornithine decarboxylase, patients with disease conditions with low levels of metabolic GPCRs, protein kinases, telomerase, jun; identification and enzymes such as histone deacetylase, protein kinases, or orni measurement of metabolism enzymes and metabolites; deter thine decarboxylase; patients with low or high susceptibility mination of the presence of one or more specific genetic to thrombocytopenia or neutropenia; patients intolerant of GI variants of the MDR1 gene associated with increased efficacy toxicities; patients characterized by over- or under-expres of an antineoplastic drug transported by MDR1 protein; iden sion of jun, GPCRs, signal transduction proteins, VEGF, tification of one or more biomarkers associated with sensitiv prostate specific genes, protein kinases, or telomerase; ity or resistance to bisantrene, derivatives or analogs thereof, patients selected by immune Screening; patients selected by or other intercalating agents or topoisomerase II inhibitors; DNA methylation screening. presence of single nucleotide polymorphisms rs229109 and 0220 (IX) Patient/Disease Phenotype rs72552784 associated with sensitivity to bisantrene; or 0221) 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 CEBPa, NPM1, DNMT3A, and IDH1. cating sensitivity to apoptosis-inducing agents; use of an in 0224 (XI) Pre-/Post-Treatment Preparation vitro human tumor clonal assay to determine patients with 0225 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, US 2016/0166546 A1 Jun. 16, 2016 22 specific protection of sensitive normal tissues or organ sys alkylating agents with anti-metabolites, topoisomerase tems. Specific inventive examples forbisantrene and analogs inhibitors with antitubulin agents. Specific inventive and derivatives thereof include: the use of colchicine or an examples for bisantrene and analogs and derivatives thereof analog thereof; the use of a uricoSuric; the use of uricase; the include: use with fraudulent nucleosides; use with fraudulent non-oral use of nicotinamide; the use of a Sustained-release nucleotides; use with thymidylate synthetase inhibitors; use form of nicotinamide; the use of an inhibitor of poly-ADP with signal transduction inhibitors; use with cisplatin or plati ribose polymerase; the use of caffeine; the use of leucovorin num analogs; use with alkylating agents; use with anti-tubulin rescue; infection control; or the use of an anti-hypertensive agents; use with antimetabolites; use with berberine; use with agent. apigenin; use with colchicine and analogs; use with genistein; 0226 (XII) Toxicity Management use with etoposide; use with cytarabine; use with camptoth 0227 Improvements for suboptimal chemotherapeutics ecins; use with Vinca alkaloids, including vinblastine; use including bisantrene and analogs and derivatives thereof are with topoisomerase inhibitors; use with 5-fluorouracil; use made by use of additional drugs or procedures to prevent or with curcumin; use with roSmarinic acid; use with mitogua reduce potential side-effects or toxicities. General examples Zone; use with meisoindigo; use withimatinib; use with dasa include: the use of anti-emetics, anti-nausea agents, hemato tinib, use with nilotinib, use with epigenetic modulators; use logical Support agents to limit or prevent neutropenia, ane with transcription factor inhibitors; use with taxol; use with mia, thrombocytopenia, Vitamins, antidepressants, treat homoharringtonine; use with pyridoxal; use with spirogerma ments for sexual dysfunction, or use of other agents or nium; use with caffeine; use with nicotinamide; use with methods to reduce potential side effects or toxicities. Specific methylglyoxalbisguanylhydraZone; use with epidermal inventive examples forbisantrene and analogs and derivatives growth factor receptor (EGFR) inhibitors; use with poly thereof include: the use of colchicine or analogs; the use of ADP ribose polymerase (PARP) inhibitors; use with Bruton's uricosurics such as probenecid; the use of diuretics; the use of tyrosine kinase (BTK) inhibitors; use with bis-thio-hy uricase; non-oral use of nicotinamide; use of Sustained drazide amides; use with Succinimide or maleimide deriva release forms of nicotinamide; use of inhibitors of poly-ADP tives as inhibitors oftopoisomerase II; use with HDAC inhibi ribose polymerase; the use of caffeine; leucovorin rescue; the tors; use with immunostimulants; use with inhibitors of use of Sustained release allopurinol; non-oral use of allopu telomerase; use with agents that inhibit the expression or rinol; administration of bone marrow transplant stimulants, activity of Her2: use with agents that inhibit the expression or blood, platelet infusions, Neupogen, G-CSF; or GM-CSF: activity of estrogen receptors; use with agents that inhibit the pain management; infection control; administration of anti expression or activity of antigens associated with specific inflammatories; administration of fluids; administration of tumor targets, such as CT antigens; use with G-quadruplex corticosteroids; administration of insulin control medica ligands; use with polycyclic lysophosphatidic receptor tions; administration of antipyretics; administration of anti antagonists; use with anti-CTGF agents; use with myeloid nausea treatments; administration of anti-diarrhea treat differentiation inducing agents; use with covalent diabodies 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 0228 (XIII) Pharmacokinetic/Pharmacodvnamic Moni cific antibodies binding to a portion of the CD44 protein or a toring binding protein derived from the light-chain or heavy-chain 0229 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 0230 (XIV) Drug Combinations inhibitors; or use with activatable antibodies targeting tumor 0231. Improvements for suboptimal chemotherapeutics specific markers. including bisantrene and analogs and derivatives thereof are 0232 (XV) Chemosensitization made by exploiting unique drug combinations that may pro 0233. 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 US 2016/0166546 A1 Jun. 16, 2016

sureable activity is observed when used alone but in combi maximum benefit to patients treated with a compound. Gen nation with other therapeutics a more than additive or syner eral examples include: pain management, nutritional Support, gistic improvement in efficacy is observed. General examples anti-emetics, anti-nausea therapies, anti-anemia therapy, include: misonidazole with alkylating agents, tirapazamine anti-inflammatories, growth factors. Specific inventive with cisplatin. Specific inventive examples forbisantrene and examples for bisantrene and analogs and derivatives thereof analogs and derivatives thereof include: as a chemosensitizer include: use with therapies associated with pain management; in combination with topoisomerase inhibitors; as a nutritional Support; anti-emetics; anti-nausea therapies; anti chemosensitizer in combination with fraudulent nucleosides; anemia therapy; anti-inflammatories: antipyretics; immune as a chemosensitizer in combination with fraudulent nucle stimulants; or growth factors. otides; as a chemosensitizer in combination with thymidylate 0238 (XVIII) Alternative Medicine/Therapeutic Support synthetase inhibitors; as a chemosensitizer in combination 0239 Improvements for suboptimal chemotherapeutics with signal transduction inhibitors; as a chemosensitizer in including bisantrene and analogs and derivatives thereof are combination with cisplatin or platinum analogs; as a made by the use of unapproved/non-conventional therapeu chemosensitizer in combination with alkylating agents; as a tics or methods to enhance effectiveness or reduce side chemosensitizer in combination with anti-tubulin agents; as a effects. General examples include: hypnosis, acupuncture, chemosensitizer in combination with antimetabolites; as a meditation, herbal medications and extracts, applied kinesi chemosensitizer in combination with berberine; as a ology. Specific inventive examples forbisantrene and analogs chemosensitizer in combination with apigenin; as a and derivatives thereof include: hypnosis; acupuncture; chemosensitizer in combination with colchicine or analogs of meditation; herbal medications created either synthetically or colchicine; as a chemosensitizer in combination with through extraction including natural anti-inflammatories (in genistein; as a chemosensitizer in combination with etopo cluding rhein or parthenolide); immunostimulants (such as side; as a chemosensitizer in combination with cytarabine; as those found in Echinacea); antimicrobials (such as ber a chemosensitizer in combination with camptothecins; as a berine); flavonoids, isoflavones, and flavones (such as api chemosensitizer in combination with Vinca alkaloids; as a genenin, genistein, genistin, 6"-O-malonylgenistin, 6"-O- chemosensitizer in combination with 5-fluorouracil; as a acetylgenistin, daidzein, daidzin, 6"-O-malonyldaidzin, chemosensitizer in combination with curcumin; as a 6"-O-acetylgenistin, glycitein, glycitin, 6"-O-malonylgly chemosensitizer in combination with roSmarinic acid; or as a citin, and 6-O-acetylglycitin); or applied kinesiology. chemosensitizer in combination with mitoguaZone. 0240 (XIX) Bulk Drug Product Improvements 0234 (XVI) Chemopotentiation 0241 Improvements for suboptimal chemotherapeutics 0235 Improvements for suboptimal chemotherapeutics including bisantrene and analogs and derivatives thereof are including bisantrene and analogs and derivatives thereof are made by alterations in the pharmaceutical bulk Substance. made by exploiting them as chemopotentiators where mini General examples include: Salt formation, homogeneous mal therapeutic activity is observed alone but in combination crystalline structure, pure isomers. Specific inventive 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 0242 (XX) Diluent Systems chemopotentiator in combination with fraudulent nucleo 0243 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 0244 (XXI) Solvent Systems logs of colchicine; as a chemopotentiator in combination with 0245 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. 0236 (XVII) Post-Treatment Patient Management 0246 (XXII) Excipients 0237 Improvements for suboptimal chemotherapeutics 0247 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 US 2016/0166546 A1 Jun. 16, 2016 24 agents, or preservatives required to stabilize and present a that include a compound that includes at least one ionizable chemical compound for proper administration. General group; the use of pH-dependent carriers that include a mono examples include: mannitol, albumin, EDTA, sodium carboxylic acid having at least 8 carbons and less than about bisulfite, benzyl alcohol. Specific inventive examples for 10% by weight of Zwitterionic phospholipids; the use of bisantrene and analogs and derivatives thereof include: the liposomes comprising the bisantrene or the derivative orana use of mannitol; the use of albumin; the use of EDTA; the use log thereof followed by administration of a lipid nanoparticle of sodium bisulfite; the use of benzyl alcohol; the use of comprising a triggering agent, or the use of nonpegylated carbonate buffers; the use of phosphate buffers; the use of liposomes. polyethylene glycol (PEG); the use of vitamin A; the use of vitamin D; the use of vitamin E: the use of esterase inhibitors; 0254 (XXVI) Drug Conjugate Forms the use of cytochrome P450 inhibitors; the use of multi-drug 0255 Improvements for suboptimal chemotherapeutics resistance (MDR) inhibitors; the use of organic resins; or the use of detergents. including bisantrene and analogs and derivatives thereof are made by alterations to the parent molecule with covalent, 0248 (Mall) Dosage Forms ionic, or hydrogen bonded moieties to alter the efficacy, tox 0249 Improvements for suboptimal chemotherapeutics icity, pharmacokinetics, metabolism, or route of administra are made by alterations in the potential dosage forms of the tion. General examples include: polymer systems such as compound dependent on the route of administration, duration polyethylene glycols, polylactides, polyglycolides, amino of effect, plasma levels required, exposure to normal tissues acids, peptides, multivalent linkers, albumin conjugates. Spe potentially resulting in side effects, and exposure to metabo cific inventive examples for bisantrene and analogs and lizing enzymes. General examples include: tablets, capsules, derivatives thereof include: the use of polymer systems such topical gels, creams, patches, suppositories. Specific inven as polyethylene glycols; the use of polylactides; the use of tive examples for bisantrene or derivatives or analogs thereof polyglycolides; the use of amino acids; the use of peptides; include: the use of tablets; the use of capsules; the use of the use of multivalent linkers; the use of conjugates to fatty topical gels; the use of topical creams; the use of patches; the acids; the use of conjugates to fatty alcohols; the use of use of Suppositories; the use of lyophilized dosage fills; the conjugates to elastin-like peptide; the use of conjugates with use of immediate-release formulations; the use of slow-re polyclonal or monoclonal antibodies, proteins, or peptides; lease formulations; the use of controlled-release formula the use of conjugates with cell-binding agents through a tions; the use of liquid in capsules; or the use of liposomal charged or pro-charged cross-linker, the use of conjugates to formulations. antibodies targeted to tumor markers; the use of biodegrad 0250 (XXIV) Dosage Kits and Packaging able polymer-bioactive moiety conjugates; the use of conju 0251 Improvements for suboptimal chemotherapeutics gates with 2-nitroimidazole compounds with a secondary including bisantrene and analogs and derivatives thereof are basic nitrogen atom and a linker, the use of conjugates with made by alterations in the dosage forms, container/closure ladder frame polyether compounds, including those derived systems, accuracy of mixing and dosage preparation and pre from brevenal, brevisin, tamulamide, brevetoxins, hemibre sentation. General examples include: amber vials to protect vetoxins, gambierols, and gambieric acids; the use of conju from light, or stoppers with specialized coatings. Specific gates to antibodies having one or more non-natural amino inventive examples forbisantrene and analogs and derivatives acid residues at specific positions in the heavy or light chains; thereof include: the use of amber vials to protect from light; the use of conjugates to a sialoadhesin binding moiety; the use and stoppers with specialized coatings to improve shelf-life of pheophorbide-C conjugates to bisantrene or a derivative or stability. Other forms of dosage kits and packaging are also analog thereof; the use of conjugates to multi-component known in the art and can include, for example, vials, ampules, nanochains; the use of conjugates to activatable antibodies jars, intravenous bags, or other containers. that include a masking moiety, a cleavable moiety, and an 0252 (XXV) Drug Delivery Systems antibody binding specifically to interleukin-6; the use of con 0253) Improvements for suboptimal chemotherapeutics jugates including hydrophilic linkers; the use of conjugates to including bisantrene and analogs and derivatives thereof are antibodies specific for p97; the use of conjugates including a made by the use of delivery systems to improve the potential modified amino acid incorporating an azido group; the use of attributes of a pharmaceutical product Such as convenience, albumin conjugates; or the use of conjugates to folate. duration of effect, or reduction of toxicities. General examples include: nanocrystals, bioerodible polymers, lipo 0256 (XXVII) Compound Analogs Somes, slow release injectable gels, microspheres. Specific 0257 Improvements for suboptimal chemotherapeutics inventive examples forbisantrene and analogs and derivatives including bisantrene and analogs and derivatives thereof are thereof include: the use of oral dosage forms; the use of made by alterations to the parent structure of a molecule with nanocrystals; the use of nanoparticles; the use of cosolvents; additional chemical functionalities that may alter efficacy, the use of slurries; the use of syrups; the use of bioerodible reduce toxicity, improve pharmacological performance, be polymers; the use of liposomes; the use of slow release inject compatible with a particular route of administration, or alter able gels; the use of microspheres; the use of amphiphilic the metabolism of the therapeutic agent. General examples block copolymer systems; the use of emulsion vehicles com include: alteration of side chains to increase or decrease lipo prising an emulsion of C-tocopherol stabilized by biocompat philicity; additional chemical functionalities to alter reactiv ible Surfactants; the use of biodegradable polymer composi ity, electron affinity, or binding capacity; Salt forms; conju tions containing phosphorus and desaminotyrosyl L-tyrosine gates to albumin. Specific inventive examples for bisantrene linkages in the polymer backbone; the use of Substantially and analogs and derivatives thereof include: alteration of side anhydrous injectable semi-solid compositions comprising a chains to increase or decrease lipophilicity; additional chemi water immiscible fatty acid matrix and a cytostatic agent; the cal functionalities to alter reactivity, electron affinity, or bind use of lipophilic vehicles; the use of pH-dependent carriers ing capacity; Salt forms; conjugates to albumin. 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0258 (XXWIII) Prodruqs sensitizers/potentiators with RNA interference; use in com 0259 Improvements for suboptimal chemotherapeutics bination with vaccines (cellular or non-cellular); or use in including bisantrene and analogs and derivatives thereof are combination with stem cells. made by alterations to the molecule Such that improved phar 0264 (XXXI) Biotherapeutic Resistance Modulation maceutical performance is gained with a variant of the active 0265 Improvements for suboptimal chemotherapeutics molecule in that after introduction into the body a portion of including bisantrene and analogs and derivatives thereof are the molecule is cleaved to reveal the preferred active mol made by exploiting their selective use to overcome develop ecule. General examples include: enzyme sensitive esters, ing or complete resistance to the efficient use of biotherapeu dimers, Schiffbases. Specific inventive examples for bisant tics. General examples include: tumors resistant to the effects rene and analogs and derivatives thereof include: the use of of biological response modifiers, cytokines, lymphokines, enzyme sensitive esters; the use of dimers; the use of Schiff therapeutic antibodies, antisense therapies, gene therapies. bases; the use of pyridoxal complexes; the use of caffeine Specific inventive examples for bisantrene and analogs and complexes; the use of plasmin-activated prodrugs; the use of derivatives thereof include: use against tumors resistant to the a drug targeting complex comprising a targeting carrier mol effects of biological response modifiers; use against tumors ecule that is selectively distributed to a specific cell type or resistant to the effects of cytokines; use against tumors resis tissue containing the specific cell type, a linker which is acted tant to the effects of lymphokines; use against tumors resis upon by a molecule that is present at an effective concentra tant to the effects of therapeutic antibodies; use against tion in the environs of the specific cell type, and a therapeu tumors resistant to the effects of antisense therapies; use tically active agent to be delivered to the specific cell type; or against tumors resistant to the effects of gene therapies; use the use of a prodrug molecule comprising a conjugate of against tumors resistant to the effects of ribozymes; or use bisantrene or a derivative or analog of bisantrene, a protease against tumors resistant to the effects of RNA interference. specific cleavable peptide, and optionally, a targeting peptide, 0266 (XXXII) Radiation Therapy Enhancement with the prodrug molecule being Substantially inactive prior 0267 Improvements for suboptimal chemotherapeutics to degradation of the protease-specific cleavable peptide by a including bisantrene and analogs and derivatives thereof are proteolytic enzyme within or in close proximity to the cancer made by exploiting their use in combination with ionizing cell. radiation, phototherapies, heat therapies, radio-frequency 0260 (XXIX) Multiple Drug Systems generated therapies. General examples include: hypoxic cell 0261) Improvements for suboptimal chemotherapeutics sensitizers, radiation sensitizers/protectors, photosensitizers, including bisantrene and analogs and derivatives thereof are radiation repair inhibitors. Specific inventive examples for made by the use of additional compounds, such as therapeutic bisantrene and analogs and derivatives thereof include: use or biological agents that when administered in the proper with hypoxic cell sensitizers; use with radiation sensitizers/ fashion, a unique and beneficial effect can be realized. Gen protectors; use with photosensitizers; use with radiation eral examples include: inhibitors of multi-drug resistance, repair inhibitors; use with thiol depletion; use with vaso specific drug resistance inhibitors, specific inhibitors of targeted agents; use with radioactive seeds; use with radio selective enzymes, signal transduction inhibitors, repair inhi nuclides; use with radiolabeled antibodies; use with brachy bition. Specific inventive examples for bisantrene and ana therapy, or use with bioreductive alkylating agents. logs and derivatives thereof include the use of bisantrene or 0268 (XXXIII) Novel Mechanisms of Action analogs and derivatives thereof with: the use of inhibitors of 0269. Improvements for suboptimal chemotherapeutics multi-drug resistance; the use of specific drug resistance including bisantrene and analogs and derivatives thereof are inhibitors; the use of specific inhibitors of selective enzymes: made by optimizing their utility by determining the various the use of signal transduction inhibitors; the use of meisoin mechanisms of actions or biological targets of a compound digo; the use of imatinib; the use of hydroxyurea; the use of for greater understanding and precision to better exploit the dasatinib; the use of capecitabine; the use of nilotinib; the use utility of the molecule. General examples include: imatinib of repair inhibition; the use of topoisomerase inhibitors with (Gleevec) for chronic myelocytic leukemia (CML), arsenic non-overlapping side effects; PARP inhibitors; EGFR inhibi trioxide for acute promyelocytic leukemia (APL), retinoic tors; or HDAC inhibitors. acid for APL. Specific inventive examples for bisantrene and 0262 (XXX) Biotherapeutic Enhancement analogs and derivatives thereof include: use with inhibitors of 0263 Improvements for suboptimal chemotherapeutics poly-ADP ribose polymerase; use with agents that affect including bisantrene and analogs and derivatives thereof are vasculature; use with agents that promote vasodilation; use made by its use in combination as sensitizers/potentiators with oncogenic targeted agents; use with signal transduction with biological response modifiers. General examples inhibitors; use with agents inducing EGFR inhibition; use include: use in combination as sensitizers/potentiators with with agents inducing Protein Kinase C inhibition; use with biological response modifiers, cytokines, lymphokines, agents inducing Phospholipase C downregulation; use with therapeutic antibodies, antisense therapies, gene therapies. agents includingjun down regulation; use with agents modu Specific inventive examples for bisantrene and analogs and lating expression of histone genes; use with agents modulat derivatives thereof include: use in combination as sensitizers/ ing expression of VEGF; use with agents modulating expres potentiators with biological response modifiers; use in com sion of ornithine decarboxylase; use with agents modulating bination as sensitizers/potentiators with cytokines; use in expression of jun D; use with agents modulating expression combination as sensitizers/potentiators with lymphokines; of V-jun, use with agents modulating expression of GPCRs: use in combination as sensitizers/potentiators with therapeu use with agents modulating expression of protein kinase A: tic antibodies; use in combination as sensitizers/potentiators use with agents modulating expression of protein kinases with antisense therapies; use in combination as sensitizers/ other than protein kinase A, use with agents modulating potentiators with gene therapies; use in combination as sen expression of telomerase; use with agents modulating expres sitizers/potentiators with ribozymes; use in combination as sion of prostate specific genes; use with agents modulating US 2016/0166546 A1 Jun. 16, 2016 26 expression of histone deacetylase; or use with agents modu tumor cells but generally inactive in most human Somatic lating expression of CHK2 checkpoint kinase. cells. Specific inventive examples for bisantrene and deriva (0270 (XXXIV) Selective Target Cell Population Thera tives and analogs thereof include: use to inhibit telomerase; or peutics use to induce telomere dysfunction. 0271 Improvements for suboptimal chemotherapeutics 0278. The use of derivatives of bisantrene to interfere with including bisantrene and analogs and derivatives thereof are telomeric function is disclosed in M. Folini et al., “Remark made by more precise identification and exposure of the able Interference with Telomeric Function by a G-Quadru compound to those select cell populations where the com plex Selective Bisantrene Regioisomer. Biochem. Pharma pounds effect can be maximally exploited. General examples col. 79: 1781-1790 (2010), incorporated herein by this include: tirapazamine and mitomycin c for hypoxic cells, reference. The enzyme telomerase is a ribonucleoprotein Vinca alkaloids for cells entering mitosis. Specific inventive reverse transcriptase responsible for telomere length mainte examples for bisantrene and analogs and derivatives thereof nance. Its expression is associated with cell immortalization include: use against radiation sensitive cells; use against and tumorigenesis, as it is expressed in most human tumor radiation resistant cells; use against energy depleted cells; use cells but is not active in most human Somatic cells. Typically, against endothelial cells. inhibition of telomerase results in cellular senescence or apo (0272 (XXXV) Use with Agents to Enhance Activity ptosis in a time-dependent manner correlating with initial 0273 Improvements for suboptimal chemotherapeutics telomere length. Alternatively, tumor cell crisis can be including bisantrene and analogs and derivatives thereof are induced rapidly by promoting telomere dysfunction; this made by use of agents to enhance activity of the amonafide or must be distinguished from the inhibition of telomerase activ the derivative or analog of amonafide. General examples ity. Many proteins are involved in preserving the complex include: use with nicotinamide, caffeine, tetandrine, or ber telomere architecture. When the complex telomere architec berine. Specific inventive examples for bisantrene and ana ture is disrupted or collapses, it activates a signaling cascade logs and derivatives thereof include: use with nicotinamide; comparable to that promoted by DNA damage and leads to use with caffeine; use with tetandrine; or use with berberine. cell cycle arrest (accelerated senescence) or apoptosis. (0274 (XXXVI) Use to Modulate DNA Methylation Telomerase substrates are telomeres in DNA. These are 0275 Improvements for suboptimal chemotherapeutics double-stranded DNA portions with a 3'-protruding overhang including bisantrene and derivatives and analogs thereof are 100-200 bases in length formed by a repeated noncoding made by use of bisantrene or derivatives or analogs thereof to sequence, typically TTAGGG (SEQID NO: 1) in humans. In modulate DNA methylation. It is known that aberrant DNA analogy to other guanine-rich structures, the single-stranded methylation is associated with malignancy. Specific inventive portion can fold into a structure called G-quadruplex, which examples for bisantrene and derivatives and analogs thereof includes four Hoogsten-paired guanine residues. Hoogsten include: use to promote gene silencing; or use with drugs that base-pairing is an alternative for base-pairing in DNA to the inhibit DNA methylation. The effect of demethylation is conventional Watson-Crick base pairs. Certain ligands stabi described in L. Suarez & S. D. Gore, “Demethylation Demys lize this unconventional DNA base-pairing arrangement and 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 (0276 (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", 0277 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 US 2016/0166546 A1 Jun. 16, 2016 27 telomere level. The results with bisantrene analogs and YM1155 Induce a DNA Damage Response.” Cancer derivatives suggest formation of additional specific interac Chemother: Pharmacol. 70: 207-212 (2012), incorporated tions between the 4,5-dihydro-1H-imidazol-2-yl hydrazone herein by this reference). Survivin is encoded by the BIRC5 groups and the G-quadruplex structure. These analogs and gene and is a member of the inhibitor of apoptosis (IAP) derivatives can act at both the telomerase level, by interfering family. The Survivin protein functions to inhibit caspase acti with Substrate recognition and thus Suppressing its catalytic Vation and thereby leads to negative regulation of apoptosis. activity, and at the telomere level, by Suppressing its organi The Survivin protein is frequently highly expressed in tumor Zation. These results suggest a drug-mediated activation of a cells. Survivin expression is highly regulated by the cell cycle senescence pathway. and is only expressed in the G2/M phase. Survivin localizes to 0279. These results suggest that bisantrene analogs and the mitotic spindle by interaction with tubulin during mitosis. derivatives can be used with other telomerase inhibitors, Regulation of survivin is linked to the p53 protein and is a including BPPA (2,6-bis(3-piperidinopropionamido)an direct target of the Wnt pathway; it is also upregulated by thraquinone), (-)-epigallocatechingallate, H-7 (2,6-bis(3-pi B-catenin. Accordingly, Survivin is a regulator of apoptosis peridinopropionamido)anthraquinone), 3-rubromycin, and and acts to counter apoptosis. As an anti-apoptotic protein, it BIBR1532 (2-(2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl 1 is a potential target for drug therapy for cancer as its activity ylaminobenzoic acid). may promote resistance to anti-neoplastic therapeutic agents. 0280 (XXXVIII) Use to Activate Macrophages or Innate Two major pathways of apoptosis have been identified in Immunity mammalian cells. A first pathway, designated the extrinsic 0281 Improvements for suboptional chemotherapeutics pathway, is triggered by the binding of ligands to cell-surface including bisantrene and derivatives or analogs thereof are trimeric membrane death receptors and leads to caspase-8 made by use of bisantrene or derivatives or analogs thereof to activation. A second pathway, designated the extrinsic path activate macrophages or induce innate immunity. Macroph way, involves mitochondria, which respond to pro-apoptotic ages bridge innate and adaptive immunity. The role of mac signals by releasing cytochrome c, which in turn binds and rophages is described in J. Rothman & Y. Patterson, “Live activates the apoptotic protease-activating factor-1, causing Attenuated Listeria-Based Immunotherapy. Exp. Rev. 12: assembly of a multiprotein caspase-activating complex (apo 493-504 (2013), incorporated herein by this reference, which ptosome) and leading to activation of caspase-9 and initiation shows the effectiveness of genetically engineered Listeria of a protease cascade. The extrinsic and intrinsic pathways for strains in promoting both innate and adaptive immune apoptosis converge on downstream effector caspases responses mediated by the activity of macrophages. Specific involved in apoptosis. Some of these, such as caspase-3 and inventive examples forbisantrene and derivatives and analogs caspase-7, are targets of Suppression by an endogenous fam thereof include: use to activate macrophages; use to induce ily of anti-apoptotic proteins called inhibitor of apoptosis innate immunity; or use to induce adaptive immunity. proteins (IAPs). Some members of this family also interfere 0282 B. S. Wang et al., “Immunotherapy of a Murine with caspase-9 processing, the upstream initiation of the Lymphoma by Adoptive Transfer of Syngeneic Macrophages mitochondrial pathway of apoptosis. The human genome 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 acids and is composed of a single baculovirus IAP repeat adaptive immunity via the activation of tumor killing T cells domain and an extended C-terminal C-helical coiled-coil directly, as allogeneic transplants of activated macrophages domain; the Survivin protein molecule does not contain the were shown to eliminate tumors in recipients, as well as RING-finger domain found in other IAPs. There is consider through innate immunity, as the Supernatants of bisantrene able evidence pointing to a functional role of survivin in both activated macrophages had a lesser, but still significant thera apoptosis control and cell division. Survivin is a chromo peutic effect on tumor bearing recipient mice. Additionally, Somal passenger protein that localizes to kinetochores at there exist immune agents that have the effect of inducing metaphase, transfers to the central spindle mid-Zone at apoptosis in cancer cells, and the use of Such agents is anaphase and accumulates in mid-bodies at telophase. Physi described further below. This approach is described in D. cal interactions with the inner centromere protein, Aurora B Tormo et al., “Targeted Activation of Innate Immunity for and Borealin/Dasra Bare required to target the complex to the Therapeutic Induction of Autophagy and Apoptosis in Mela kinetochore, to properly form the bipolar spindle and to com noma Cells. Cancer Cell 16: 103-114 (2009), incorporated plete cytokinesis. This function, involving preservation of herein by this reference. These agents include polyinosine genome fidelity and regulation of microtubule dynamics, polycytidylic acid, especially when complexed to polyethyl requires close control of cell-cycle-dependent transcription eneimine. of the Survivin gene during the mitotic phase, as well as (0283 (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 0284 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 US 2016/0166546 A1 Jun. 16, 2016 28 in G/M cell compartments in a number of cancer lines. Other 0285 Bisantrene orderivatives or analogs thereof can also non-cell-cycle-dependent mechanisms driving Survivin gene be used with survivin inhibitors or modulators. transcription independent of mitosis have been described, 0286 Survivin inhibitors include, but are not limited to, which involve tissue patterning circuits (Wnt/B-catenin), NSC80467 (2-methyl-1-(2-methylpropyl)-3-2-(4-nitrophe cytokine activation signal-transducer-and-activator-of-tran nyl)-2-oxoethylbenzof benzimidazol-3ium-4,9-dione bro Scription-3, costimulatory messages Such as those of OX-40, mide), YM1155 (1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3- and pleiotropic signaling mechanisms such as V-akt murine (pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphthoI2,3-d thymoma viral oncogene homolog 1 or protein kinase B imidazolium bromide), SPC3042 (a locked antisense nucleic (AkT) and nuclear factor-KB that are typically operative dur acid designed as an antisense 16-mer LNA gapmer (J. B. ing development and are upregulated in cancer cells. These Hansen et al., “SPC3042: A Proapoptotic Survivin Inhibitor.” non-cell-cycle-dependent pathways may be dominant in Mol. Cancer Ther. 7:2736-2745 (2008)), targeting the region comprising the stop codon of the open reading frame in exon tumor cells. The fraction of survivin produced through these 4 of the survivin transcript), NU6140 (4-(6-cyclohexyl non-cell-cycle-dependent mechanisms mediates apoptosis methoxy-9H-purin-2-ylamino)-N,N-diethylbenzamide), inhibition through intermolecular cooperation with cofactors toxoflavin, gambogic acid, LLP-3 (4-(3,5-bis(benzyloxy) including the hepatitis B virus X-interacting protein, a target phenyl)-6-(5-chloro-2-hydroxyphenyl)-2-oxo-1,2-dihydro of the oncogenic viral hepatitis B virus X protein and X-IAP, pyridine-3-carbonitrile) ISIS 23722, (6S.9S) N-benzyl-6- leading to the formation of complexes that inhibit caspase-9 (4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8- processing. Moreover, Subcellular compartmentalization of ylmethyl)octahydro-1H-pyrazino.2.1-c.1.2.4 triazine-1- Survivin in mitochondria seems to play a role in the anti carboxamide, 4-(((6S.9S)-1-(benzylcarbamoyl)-2.9- apoptotic function of the protein. Specifically, the existence dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1H ofa mitochondrial pool of Survivin was recently reported, and pyrazino.2.1-c.1.2.4 triazin-6-yl)methyl)phenyl it was found that in response to cell death stimulation, mito dihydrogen phosphate, tetra-O-methyl-nordihydroguaiaretic chondrial Survivin is rapidly discharged and released into the acid, butane-bridge-modified tetra-O-methyl-nordihy cytosol, where it prevents caspase activation and inhibits droguaiaretic acids, including 1,4-bis(3,4-bis3-(piperdin-1- apoptosis. Mitochondrial Survivin may be exclusively asso yl)propoxyphenyl-butane, tetra-Substituted nordihy ciated with tumor transformation. It also has been found that droguaiaretic acid derivatives via ether bonds or carbamate Survivin has a nuclear export signal and that in cancer cells the bonds, tetraglycinyl nordihydroguaiaretic acid, LY2181308, anti-apoptotic and mitotic roles of Survivin can be separated dichloroacetic acid, and ICG-001 ((6S.9aS)-6-(4-hydroxy through mutation of its nuclear export signal, which abro benzyl)-N-benzyl-8-(naphthalen-1-ylmethyl)-4,7-dioxo gates the cytoprotective activity of the protein but still allows hexahydro-2H-pyrazino 1,2-alpyrimidine-1 (6H)-carboxam mitosis to proceed. The stability and function of survivin ide). Other survivin inhibitors and methods for inhibiting the require a physical interaction with the molecular chaperone expression of survivin are disclosed in U.S. Pat. No. 8,455, heat shock protein 90 (Hsp90), which involves the Hsp90 488 to Odagami et al., U.S. Pat. No. 8.318,815 to Huang et al., U.S. Pat. No. 8,232,277 to Chen et al., U.S. Pat. No. 8,178, ATPase domain and the survivin baculovirus IAP repeat 527 to Chen et al., U.S. Pat. No. 7,959,923 to You et al., 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 0287. 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 wherein: X is hydrogen, halogen, hydroxyl, alkoxy, or C-C, useful in treating malignancies, especially by preventing or linear or branched alkyl; and R is C-C linear or branched reducing the development of resistance to chemotherapeutic alkyl or cycloalkyl optionally substituted with halogen, nitro, agents or by promoting apoptosis. amine, or dioxole). Inhibitors or modulators or survivin are

US 2016/0166546 A1 Jun. 16, 2016 30 dine; ivermectin; and quinidine. Additional multidrug resis Vation with at least one mTOR antagonist; use in a combina tance reversal agents are disclosed in U.S. Pat. No. 8,673.914 torial regime as an agent inducing macrophage activation to Chen et al.; these multidrug resistance reversal agents are with at least one Akt inhibitor, use in a combinatorial regime phosphodiesterase inhibitors, such as PDE5 inhibitors, and as an agent inducing macrophage activation with at least one include sildenafil. Vardenafil, tadalafil, lodenafil, udenafil, notch inhibitor, use in a combinatorial regime as an agent benzamidenafil, mirodenafil, avanafil. zaprinast, SLX-2101, inducing macrophage activation with at least one HSP inhibi UK-371,800, UK-122764, icariin, DA-8159, and 3-4-(2-hy tor, use in a combinatorial regime as an agent inducing mac droxyethyl)piperazin-1-yl-7-(6-methoxypyridin-3-yl)-1-(2- rophage activation with at least one phosphatidylinositide propoxyethyl)pyrido3,4-b-pyrazin-2(1H)-one. 3-kinase inhibitor, use in a combinatorial regime as an agent 0290 (XLI) Use in Combinatorial Regimes inducing macrophage activation with at least one kinase inhibitor; use in a combinatorial regime as an agent inducing 0291 Improvements for suboptimal chemotherapeutics macrophage activation with cytarabine; use in a combinato including bisantrene and derivatives or analogs thereof are rial regime as an agent inducing macrophage activation with made by use of bisantrene or derivatives or analogs thereof in taxane; or use in a combinatorial regime as an agent inducing combinatorial regimes. A significant area of research is macrophage activation with taxol. directed at methods for combining newer immunotherapies 0292 (XLII) Use with Directed Antibody Conjugates with older cytotoxic modalities. Specific inventive examples 0293 Improvements for suboptional chemotherapeutics for bisantrene and derivatives or analogs thereof include: use including bisantrene and derivatives or analogs thereof are in a combinatorial regime as a chemotherapeutic agent with at made by use of bisantrene or derivatives or analogs thereof least one agent inducing immunoactivity; use in a combina with directed antibody conjugates. torial regime as a chemotherapeutic agent with at least one 0294 (XLIII) Use with Adjuvants agent inducing macrophage activation; use in a combinatorial 0295 Improvements for suboptional chemotherapeutics regime as a chemotherapeutic agent with at least one cytok including bisantrene and derivatives or analogs thereof are ine; use in a combinatorial regime as a chemotherapeutic made by use of bisantrene or derivatives or analogs thereof agent with at least one agent inhibiting telomerase; use in a with adjuvants. The adjuvant can be, but is not limited to, combinatorial regime as a chemotherapeutic agent with at GM-CSF, poly-ICLC (carboxymethylcellulose, polyi least one agent inhibiting Survivin; use in a combinatorial nosinic-polycytidylic acid, and poly L-lysine), nanoparticles, regime as a chemotherapeutic agent with at least one agent microparticles, aluminum salts, squalene, QS-21 (a plant inducing demethylation; use in a combinatorial regime as a extract from Quillaia saponaria containing water-soluble chemotherapeutic agent with at least one adjuvant; use in a triterpene glycosides), Virosomes, IL-2, IL-7, IL-21, and type combinatorial regime as a chemotherapeutic agent with at 1 interferons. Other adjuvants are known in the art. least one antibody; use in a combinatorial regime as a che 0296. Accordingly, one aspect of the present invention is a motherapeutic agent with at least one innate or adaptive method to improve the efficacy and/or reduce the side effects immune stimulator, use in a combinatorial regime as a che of Suboptimally administered drug therapy comprising the motherapeutic agent with at least one checkpoint inhibitor; steps of: use in a combinatorial regime as a chemotherapeutic agent 0297 (1) identifying at least one factor or parameter asso with at least one mTOR antagonist; use in a combinatorial ciated with the efficacy and/or occurrence of side effects of regime as a chemotherapeutic agent with at least one Akt the drug therapy; and inhibitor, use in a combinatorial regime as a chemotherapeu 0298 (2) modifying the factor or parameter to improve the tic agent with at least one notch inhibitor, use in a combina efficacy and/or reduce the side effects of the drug therapy. torial regime as a chemotherapeutic agent with at least one 0299 Typically, the factor or parameter is selected from HSP inhibitor; use in a combinatorial regime as a chemo the group consisting of therapeutic agent with at least one phosphatidylinositide 3-ki 0300 (1) dose modification; nase inhibitor, use in a combinatorial regime as a chemothera 0301 (2) route of administration; peutic agent with at least one kinase inhibitor; use in a 0302 (3) schedule of administration; combinatorial regime as a chemotherapeutic agent with cyt 0303 (4) indications for use: arabine; use in a combinatorial regime as a chemotherapeutic 0304 (5) selection of disease stage; agent with taxane; use in a combinatorial regime as a chemo (0305 (6) other indications: therapeutic agent with taxol; use in a combinatorial regime as (0306 (7) patient selection: an agent inducing macrophage activation with at least one 0307 (8) patient/disease phenotype: agent inducing telomerase inhibition; use in a combinatorial 0308 (9) patient/disease genotype: regime as an agent inducing macrophage activation with at 0309 (10) prefpost-treatment preparation least one cytokine; use in a combinatorial regime as an agent inducing macrophage activation with at least one agent inhib 0310 (11) toxicity management; iting Survivin; use in a combinatorial regime as an agent 0311 (12) pharmacokinetic/pharmacodynamic monitor inducing macrophage activation with at least one agent induc 1ng ing demethylation; use in a combinatorial regime as an agent 0312 (13) drug combinations; inducing macrophage activation with at least one adjuvant; 0313 (14) chemosensitization; use in a combinatorial regime as an agent inducing macroph 0314 (15) chemopotentiation: age activation with at least one antibody; use in a combina 0315 (16) post-treatment patient management; torial regime as an agent inducing macrophage activation 0316 (17) alternative medicine/therapeutic support; with at least one innate or adaptive immune stimulator, use in 0317 (18) bulk drug product improvements: a combinatorial regime as an agent inducing macrophage 0318 (19) diluent systems: activation with at least one checkpoint inhibitor, use in a 0319 (20) solvent systems; combinatorial regime as an agent inducing macrophage acti 0320 (21) excipients: US 2016/0166546 A1 Jun. 16, 2016 31

0321 (22) dosage forms: carcinoma; and (5) cancers of the Vulva, including Vulvar 0322 (23) dosage kits and packaging; intraepithelial neoplasia (Grade I), Vulvar intraepithelial neo 0323 (24) drug delivery systems: plasia (Grade II), Vulvar intraepithelial neoplasia (Grade III) 0324 (25) drug conjugate forms: (squamous cell carcinoma in situ); squamous cell carcinoma, 0325 (26) compound analogs; Verrucous carcinoma, Paget’s disease of the Vulva, adenocar 0326 (27) prodrugs: cinoma (NOS), basal cell carcinoma (NOS), and Bartholin's 0327 (28) multiple drug systems; gland carcinoma, (C) cancers of the male reproductive sys 0328 (29) biotherapeutic enhancement; tem, including: (1) cancers of the penis, including squamous 0329 (30) biotherapeutic resistance modulation; cell carcinoma; (2) cancers of the prostate, including adeno 0330 (31) radiation therapy enhancement; carcinoma, sarcoma, and transitional cell carcinoma of the 0331 (32) novel mechanisms of action; prostate; (3) cancers of the testis, including seminomatous 0332 (33) selective target cell population therapeutics; tumor, nonseminomatous tumor, teratoma, embryonal carci 0333 (34) use with an agent enhancing its activity; noma, yolk sac tumor, and choriocarcinoma; (D) cancers of 0334 (35) use to modulate DNA methylation: the cardiac system, including sarcoma (angiosarcoma, fibro 0335 (36) use to inhibit telomerase or induce telomere sarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhab dysfunction; domyoma, fibroma, lipoma and teratoma; (E) cancers of the 0336 (37) use to activate macrophages or innate immu respiratory system, including squamous cell carcinoma of the nity; larynx, primary pleural mesothelioma, and squamous cell 0337 (38) use to inhibit expression of survivin or with carcinoma of the pharynx, (F) cancers of the lung, including survivin inhibitors or modulators; squamous cell carcinoma (epidermoid carcinoma), variants 0338 (39) use with multidrug resistance reversal agents: of squamous cell carcinoma, spindle cell carcinoma, Small 0339 (40) use in combinatorial regimes: cell carcinoma, carcinoma of other cells, carcinoma of inter 0340 (41) use with directed antibody conjugates; and mediate cell type, combined oat cell carcinoma, adenocarci 0341 (42) use with adjuvants. noma, acinar adenocarcinoma, papillary adenocarcinoma, 0342. The suboptimally administered drug therapy can bronchiolo-alveolar carcinoma, Solid carcinoma with mucus comprise administration of bisantrene or of a derivative or formation, large cell carcinoma, giant cell carcinoma, clear analog of bisantrene, as described above. cell carcinoma, and sarcoma; (G) cancers of the gastrointes 0343 Typically, when the suboptimally administered drug tinal tract, including: (1) cancers of the ampulla of Vater, therapy is used to treat a hyperproliferative disease, the hyper including primary adenocarcinoma, carcinoid tumor, and proliferative disease is cancer. Methods according to the lymphoma; (2) cancers of the anal canal, including adenocar present invention and compositions according to the present cinoma, squamous cell carcinoma, and melanoma; (3) can invention suitable for use in those methods are applicable to cers of the extrahepatic bile ducts, including carcinoma in many forms of cancer, including, but not limited to: (A) breast situ, adenocarcinoma, papillary adenocarcinoma, adenocar 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 US 2016/0166546 A1 Jun. 16, 2016 32

Langerhans, and carcinoid; (10) cancers of the salivary variant of squamous cell carcinoma, basal cell carcinoma, glands, including acinic (acinar) cell carcinoma, adenoid cys adenocarcinoma developing from Sweat or sebaceous gland, tic carcinoma (cylindroma), adenocarcinoma, squamous cell and malignant melanoma; (7) cancers of the eye, including: carcinoma, carcinoma in pleomorphic adenoma (malignant (a) cancers of the conjunctiva, including carcinoma of the mixed tumor), mucoepidermoid carcinoma (well differenti conjunctiva; (b) cancers of the eyelid, including basal cell ated or low grade), and mucoepidermoid carcinoma (poorly carcinoma, squamous cell carcinoma, melanoma of the eye differentiated or high grade); (11) cancers of the stomach, lid, and sebaceous cell carcinoma; (c) cancers of the lacrimal gland, including adenocarcinoma, adenoid cystic carcinoma, including adenocarcinoma, papillary adenocarcinoma, tubu carcinoma in pleomorphic adenoma, mucoepidermoid carci lar adenocarcinoma, mucinous adenocarcinoma, signet ring noma, and squamous cell carcinoma; (d) cancers of the uvea, cell carcinoma, adenosquamous carcinoma, squamous cell including spindle cell melanoma, mixed cell melanoma, and carcinoma, Small cell carcinoma, undifferentiated carcinoma, epithelioid cell melanoma; (e) cancers of the orbit, including lymphoma, sarcoma, and carcinoid tumor, and (12) cancers sarcoma of the orbit, Soft tissue tumor, and sarcoma of bone; of the Small intestine, including adenocarcinoma, lymphoma, and (f) retinoblastoma. In particular, methods according to carcinoid tumors, Kaposi's sarcoma, leiomyoma, heman the present invention and compositions according to the gioma, lipoma, neurofibroma, and fibroma; (H) cancers of the present invention are particularly suitable for the treatment of urinary system, including: (1) cancers of the kidney, includ the following types of cancers: (1) melanoma; (2) colon can ing renal cell carcinoma, carcinoma of Bellini’s collecting cer; (3) chronic lymphocytic leukemia; (4) skin cancer; (5) ducts, adenocarcinoma, papillary carcinoma, tubular carci lung cancer, including Small-cell lung cancer and non-Small noma, granular cell carcinoma, clear cell carcinoma (hyper cell lung cancer; (6) throat cancer; (7) stomach cancer; (8) nephroma), Sarcoma of the kidney, and nephroblastoma; (2) salivary gland cancer, (9) breast cancer, including triple cancers of the renal pelvis and ureter, including transitional negative breast cancer and breast cancer characterized by cell carcinoma, papillary transitional cell carcinoma, squa overexpression of Her-2-neu; (10) prostate cancer, including mous cell carcinoma, and adenocarcinoma; (3) cancers of the androgen-resistant prostate cancer, (11) pancreatic cancer, urethra, including transitional cell carcinoma, squamous cell (12) ovarian cancer, (13) uterine cancer, (14) endometrial carcinoma, and adenocarcinoma; and (4) cancers of the uri cancer; (15) other leukemias; (16) renal cell carcinoma; (17) nary bladder, including carcinoma in situ, transitional urothe multiple myeloma; (18) liver cancer; (19) pituitary gland lial cell carcinoma, papillary transitional cell carcinoma, cancer; (20) acute myeloid leukemia; (21) oophoroma; (22) squamous cell carcinoma, adenocarcinoma, undifferentiated; glioma; (23) head and neck cancer; (23) colorectal cancer, (I) cancers of muscle, bone, and soft tissue, including: (1) (24) bladder cancer; (25) HPV-induced papilloma; (26) cancers of bone, including: (a) bone-forming: osteosarcoma; Hodgkin’s lymphoma; (27) non-Hodgkin’s lymphoma; (28) (b) cartilage-forming: chondrosarcoma and mesenchymal chronic myelocytic leukemia; (29) mycosis fungoides; and chondrosarcoma; (c) giant cell tumor, malignant; (d) Ewings (30) myelodysplastic syndrome. In addition, methods sarcoma; (e) vascular tumors: hemangioendothelioma, according to the present invention and compositions accord hemangiopericytoma, and angiosarcoma, (f) connective tis ing to the present invention are also particularly suitable for Sue tumors: fibrosarcoma, liposarcoma, malignant mesen treatment of several non-malignant proliferative conditions, chymoma, and undifferentiated sarcoma; and (g) other including psoriasis and HSV-induced shingles. tumors: chordoma and adamantinoma of long bones; (2) can cers of Soft tissues, including: alveolar soft-part sarcoma, 0344) 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. domyosarcoma, synovial sarcoma, and sarcoma (NOS); (3) 0345 When the improvement is made by dose modifica cancers of the nervous system, including cancers of the skull tion, the dose modification can be, but is not limited to, at least (osteoma, hemangioma, granuloma, Xanthoma, osteitis one dose modification selected from the group consisting of deformans), cancers of the meninges (meningioma, menin 0346 (a) continuous i.v. infusion for hours to days; giosarcoma, gliomatosis), cancers of the brain (astrocytoma, 0347 (b) biweekly administration: medulloblastoma, glioma, ependymoma, germinoma (0348 (c) doses greater than 5 mg/m/day; (pilealoma), glioblastoma multiforme, oligodendroglioma, 0349 (d) progressive escalation of dosing from 1 Schwannoma, retinoblastoma, congenital tumors), and can mg/m/day based on patient tolerance; cers of the spinal cord neurofibroma, meningioma, glioma, 0350 (e) doses less than 1 mg/m for greater than 14 sarcoma); (4) hematologic cancers, including myeloid leuke days; mia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, 0351 (f) use of caffeine to modulate metabolism; multiple myeloma; myelodysplastic syndrome), Hodgkin’s 0352 (g) use of isoniazid to modulate metabolism; disease, and non-Hodgkin’s lymphoma (malignant lym 0353 (h) selected and intermittent boost dose adminis phoma); (5) cancers of the endocrine system, including: (a) trations; cancers of the thyroid gland, including papillary carcinoma 0354 (i) bolus single and multiple doses of 1-5 mg/m: (including those with follicular foci), follicular carcinoma, 0355 () oral dosing including multiple daily dosing: medullary carcinoma, and undifferentiated (anaplastic) car 0356 (k) micro-dosing: cinoma; and (b) neuroblastomas, including sympathicoblas toma, sympathicogonioma, malignant ganglioneuroma, gan 0357 (1) immediate release dosing: gliosympathicoblastoma, and ganglioneuroma; (6) cancers of 0358 (m) slow release dosing; and the skin, including squamous cell carcinoma, spindle cell 0359 (n) controlled release dosing. US 2016/0166546 A1 Jun. 16, 2016

0360. When the improvement is made by route of admin 0394 (p) use for treatment of malignancies character istration, the route of administration can be, but is not limited ized by overexpressed topoisomerase II; and to, a route of administration selected from the group consist ing of 0395 (q) use for treatment of malignancies character 0361 (a) central venous administration; ized by overexpressed and/or mutated EGFR. 0362 (b) intraperitoneal administration; 0396 Triple-negative breast cancer is a form of breast 0363 (c) intravenous administration; cancer that is characterized by tumors that do not express 0364 (d) intravesicular administration for bladder can estrogen receptor (ER), progesterone receptor (PR), or cer, 0365 (e) intrathecal administration; HER-2 genes. This form of breast cancer represents an impor 0366 (f) intra-arterial administration; tant clinical challenge because these cancers do not respond 0367 (g) continuous infusion; and to endocrine therapy or a number of targeted agents. Current 0368 (h) intermittent infusion. treatment strategies for triple-negative breast cancer include 0369. When the improvement is made by schedule of many chemotherapy agents, such as the anthracyclines, tax administration, the schedule of administration can be, but is anes, ixabepilone, and platinum agents, as well as selected not limited to, a schedule of administration selected from the biologic agents and possibly anti-EGFR drugs. group consisting of 0370 (a) administration to avoid anaphylaxis; 0397 Tyrosine kinase inhibitors used for treatment of 0371 (b) daily administration; chronic myelocytic leukemia (CML) include, but are not 0372 (c) weekly administration for three weeks; limited to, imatinib, bosutinib, nilotinib, dasatinib, erlotinib, 0373 (d) weekly administration for two weeks; afatinib, and dacomitinib. Additional tyrosine kinase inhibi 0374 (e) biweekly administration: tors are known in the art. For example, the use of tyrosine 0375 (f) biweekly administration for three weeks with kinase inhibitors is described in United States Patent Appli a 1-2 week rest period; cation Publication No. 2011/0206661 by Zhanget al., which 0376 (g) intermittent boost dose administration; and is directed to trimethoxyphenyl inhibitors of tyrosine kinase, 0377 (h) administration daily for one week then once and in United States Patent Application Publication No. 2011/ per week for multiple weeks. 0.195066, which is directed to quinolone inhibitors of tyrosine 0378 When the improvement is made by an indication for kinase, both of which are incorporated herein by this refer use, the indication for use can be, but is not limited to, an ence. The use of tyrosine kinase inhibitors is also described in indication for use selected from the group consisting of: United States Patent Application Publication No. 2011/ 0379 (a) use for treatment of refractory breast cancer; 053968 by Zhanget al., incorporated herein by this reference, 0380 (b)use for treatment of triple-negative breast can which is directed to aminopyridine inhibitors of tyrosine cer, kinase. The use of tyrosine kinase inhibitors is also described 0381 (c) use for treatment of acute leukemias, includ in United States Patent Application Publication No. 2010/ ing acute myelocytic leukemia (AML); 0291025, incorporated herein by this reference, which is 0382 (d) use for treatment of acute leukemias of child directed to indazole inhibitors of tyrosine kinase. The use of hood, including acute myelocytic leukemia (AML) and tyrosine kinase inhibitors is also described in United States acute lymphocytic leukemia (ALL); Patent Application Publication No. 2010/0190749 by Ren et 0383 (e) use for treatment of myelodysplastic syn al., incorporated herein by this reference; these tyrosine drome; kinase inhibitors are benzoxazole compounds; compounds of 0384 (f) use for treatment of chronic myelocytic leuke this class can also inhibit mTOR and lipid kinases such as mia (CML), either subsequent to or in combination with phosphoinositide 3-kinases. The use of tyrosine kinase the administration of tyrosine kinase inhibitors or homo inhibitors is also described in U.S. Pat. No. 8.242.270 by harringtonine; Lajeunesse et al., incorporated herein by this reference; these 0385 (g) use for treatment of chronic lymphocytic leu tyrosine kinase inhibitors are 2-aminothiazole-5-aromatic kemia; carboxamides. Still other tyrosine kinase inhibitors are 0386 (h) use for treatment of Hodgkin’s lymphoma; known in the art or are under development, and are described 0387 (i) use for treatment of non-Hodgkin’s lym in B. J. Druker & N. B. Lydon, “Lessons Learned from the phoma; Development of an Abl Tyrosine Kinase Inhibitor for Chronic 0388 () use for treatment of mycosis fungoides; Myelogenous Leukemia. J. Clin. Invest. 105: 3-7 (2000), 0389 (k) use for treatment of prostate cancer, especially incorporated herein by this reference. androgen-resistant prostate cancer, 0398 Homoharringtonine (omacetaxine mepesuccinate) 0390 (1) use for treatment of lung small-cell carcinoma, has the structure shown below: either Subsequent to or in combination with the admin istration of EGFR inhibitors such as erlotinib (Tarceva) or gefitinib (Iressa), wherein the lung Small-cell carci noma is characterized by either wild-type or mutated EGFR, 0391 (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: 0392 (n) use for treatment of breast cancer character ized by overexpressed Her-2-neu: 0393 (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; US 2016/0166546 A1 Jun. 16, 2016 34 and is a protein translation inhibitor. Homoharringtonine 490), N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-(((3aR, inhibits protein translation by preventing the initial elonga 5r,6aS)-2-methyl-octahydrocyclopentacpyrrol-5-yl) tion step of protein synthesis. It interacts with the ribosomal methoxy)guinazolin-4-amine (XL647), N-(3-bromophenyl)- A-site and prevents the correct positioning of amino acid side chains of incoming aminoacyl-tRNAS. 6,7-dimethoxyquinazolin-4-amine hydrochloride 0399 Androgen-resistant prostate cancer, also known as (PD 153035), and (S)-morpholin-3-ylmethyl 4-(1-(3-fluo castration-resistant prostate cancer, is characterized by reac robenzyl)-1H-indazol-5-ylamino)-5-methylpyrrolo 1.2-f1. tivation of androgen-regulated processes and is detectable by 2.4 triazin-6-ylcarbamate (BMS-599626). Still other EGFR an increase in prostate-specific antigen (PSA) despite the inhibitors are known in the art, including monoclonal anti administration of androgen deprivation therapy; it has been bodies and derivatives thereof. Such monoclonal antibodies Suggested that Sufficient androgens remain available even and derivatives thereof include cetuximab, panitumumab, Subsequent to the administration of androgen deprivation matuZumab, nimotuZumab, trastuzumab, Zalutumumab, and therapy through reactions employing progesterone as a start Zatuximab. In addition, Such monoclonal antibodies and ing material for the synthesis of dihydrotestosterone (J. A. derivatives thereof can be conjugated to therapeutic agents Locke et al., “Androgen Levels Increase by Intratumoral De Such as toxins or radionuclides. The conjugation of mono Novo Steroidogenesis During Progression of Castration-Re clonal antibodies to radionuclides is described in K. K. Bhar sistant Prostate Cancer.” Cancer Res.68: 6407-6415 (2008), gava & S. A. Acharya, "Labeling of Monoclonal Antibodies incorporated herein by this reference). with Radionuclides.” Semin. Nucl. Med. 19: 187-201 (1989), 04.00 EGFR inhibitors include, but are not limited to, incorporated herein by this reference. The conjugation of erlotinib (Tarceva) andgefitinib (Iressa). These EGFR inhibi monoclonal antibodies to non-radionucleotide therapeutic tors specifically inhibit the EGFR tyrosine kinase. Mutations agents is described in P. Chames et al., “Therapeutic Antibod in the EGFR gene may affect the sensitivity of EGFR to ies: Successes, Limitations, and Hopes for the Future. Br. J. EGFR inhibitors such as erlotinib and gefitinib. At least some Pharmacol. 157: 220-233 (2009), incorporated herein by this of these mutations may increase sensitivity to EGFR inhibi reference. The non-radionuclide therapeutic agents can tors (J. G. Paez et al., “EGFR Mutations in Lung Cancer: include, a fragment of Pseudomonas exotoxin, diphtheria Correlation with Clinical Response to Gefitinib Therapy.” toxin, the A chain of ricin, Staphylococcus aureus entero Science 304: 1497-1500 (2004), incorporated herein by this toxin, mertansine, a calicheamicin cytotoxic agent, interleu reference; R. Sordella et al., “Gefitinib-Sensitizing EGFR kin-2, and other agents known in the art. Monoclonal anti 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 04.01. Other EGFR inhibitors are known in the art. EGFR methods known in the art. inhibitors include, but are not limited to, erlotinib, gefitinib, lapatinib, lapatinib ditosylate, afatinib, canertinib, neratinib, 0402. Additional EGFR inhibitors, including derivatives (E)-2-methoxy-N-(3-(4-(3-methyl-4-(6-methylpyridin-3- of erlotinib and salts thereof, are described in United States yloxy)phenylamino)cquinazolin-6-yl)allyl)acetamide (CP Patent Application Publication No. 2013/0012528 by Cheng, 724,714), 2-(3,4-dihydroxyphenyl)methylene-propane incorporated herein by this reference. dinitrile (AG 18), 2-bromo-4-(6,7-dimethoxy-4- 0403. Overexpression of Her-2-neu, particularly in breast quinazolinyl)amino-phenol (WHI-P154), N-(2-(4-(3- cancer, is associated in some cases with advanced disease and chloro-4-(3-(trifluoromethyl)phenoxy)phenylamino)-5H relative resistance to conventional chemotherapy. In Such pyrrolo3.2-dpyrimidin-5-yl)ethyl)-3-hydroxy-3- cases, the use of cisplatin plus a recombinant humanized methylbutanamide (TAK-285), N-4-3-chloro-4-(3- anti-p185HER2 monoclonal antibody has been suggested fluorophenyl)methoxyphenylamino-6-quinazolinyl-2- (M. D. Pegram et al., “Phase II Study of Receptor-Enhanced propenamide 4-methylbenzenesulfonate (AST-1306), (R)— Chemosensitivity. Using Recombinant Humanized Anti N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)-N6-(4- p185HER2/neu Monoclonal Antibody Plus Cisplatin in methyl-4,5-dihydrooxazol-2-yl)guinazoline-4,6-diamine Patients with HER2/neu Overexpressing Metastatic Breast (ARRY334543), icotinib, N-(3-chlorophenyl)-6,7- Cancer Refractory to Chemotherapy Treatment.” J. Clin. dimethoxyquinazolin-4-amine (AG-1478), 2-3,5-bis(1,1- Oncol. 16: 2659-2671 (1998), incorporated herein by this dimethylethyl)-4-hydroxyphenylmethylene-propanedini reference). The overexpression of Her-2-neu is also associ trile (SF 6847), dacomitinib, desmethyl erlotinib. 2-(4-(3- ated with changes in the regulation of a number of genes, ethynylphenylamino)-7-(2-methoxyethoxy)guinazolin-6- including proline 4-hydroxylase, galectin 1, galectin 3. yloxy)ethanol hydrochloride (OSI-420), N-(3-(5-chloro-2- fibronectin 1. p-cadherin, which are genes involved in cell (4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4- matrix interactions, and genes involved with cell proliferation ylthio)phenyl)acrylamide (WZ-8040), N-(3-(5-chloro-2-(2- and transformation. A number of genes associated with MYC methoxy-4-(4-methylpiperazin-1-yl)phenylamino) signaling were also differentially expressed (A. Mackay et pyrimidin-4-yloxy)phenyl)acrylamide (WZ4002), N-(3-(5- al., “cDNA Microarray Analysis of Genes Associated with chloro-2-(4-(4-methylpiperazin-1-yl)phenylamino) ERBB2 (HER2/neu) Overexpression in Human Mammary pyrimidin-4-yloxy)phenyl)acrylamide (WZ3146), (E)-N- Luminal Epithelial Cells.” Oncogene 22: 2680-2688 (2003), benzyl-2-cyano-3-(3,4-dihydroxyphenyl)acrylamide (AG incorporated herein by this reference). US 2016/0166546 A1 Jun. 16, 2016

04.04 EGFR variant III is a variant of EGFR that does not 0427 (c) selecting patients with a low or high suscep respond to gefitinib, cells possessing the variant do not show tibility to a condition selected from the group consisting reduction of phosphorylation Subsequent to treatment with of thrombocytopenia and neutropenia; gefitinib. Additionally, although Such cells may show a degree 0428 (d) selecting patients intolerant of GI toxicities: of reduction of phosphorylation of EGFR after more 0429 (e) selecting patients characterized by over- or extended treatment with gefitinib, these cells continue to be under-expression of a gene selected from the group con resistant to the antineoplastic effects of gefitinib, possibly sisting of jun, GPCRs, signal transduction proteins, because the phosphorylation of Akt is unaffected in cells with VEGF, prostate specific genes, protein kinases, and variant III while being inhibited in EGFR-expressing cells telomerase; after treatment with gefitinib (C. A. Learn, “Resistance to 0430 (f) selecting patients as the result of immune Tyrosine Kinase Inhibition by Mutant Epidermal Growth Screening: Factor Receptor Variant III Contributes to the Neoplastic Phenotype of Glioblastoma Multiforme. Clin. Cancer Res. 0431 (g) selecting patients as the result of DNA methy 10:3216-3224 (2004), incorporated herein by this reference). lation screening; Conventional treatments for glioblastoma include temozolo 0432 (h) selecting patients with recurrent disease char mide, frequently administered with radiotherapy, bevaci acterized by the duration of their initial response; Zumab (Avastin), and the protein therapeutic APG 101. 0433 (i) selecting patients without mutations in p53; 04.05 When the improvement is made by selection of dis and ease stage, the selection of disease stage can be, but is not 0434 () selecting for patients without extensive prior limited to, at least one selection of disease stage selected from treatment, especially with agents that induce multidrug the group consisting of resistance. 0406 (a) use for the treatment of localized polyp stage 0435 The cellular proto-oncogene c-Jun encodes a pro colon cancer, tein that, in combination with c-Fos, forms the AP-1 early 0407 (b) use for the treatment of leukoplakia in the oral response transcription factor. This proto-oncogene plays a cavity; key role in transcription and interacts with a large number of 0408 (c) use to induce angiogenesis inhibition to pre proteins affecting transcription and gene expression. It is also vent or limit metastatic spread; involved in proliferation and apoptosis of cells that form part 04.09 (d) use against HIV with AZT, DDI, or reverse of a number of tissues, including cells of the endometrium transcriptase inhibitors: and glandular epithelial cells. G-protein coupled receptors 0410 (e) use for recurrent leukemia, including AML: (GPCRs) are important signal transducing receptors. The and Superfamily of G protein coupled receptors includes a large 0411 (f) use for recurrent breast cancer, including Her/ number of receptors. These receptors are integral membrane neu', ER" or triple negative breast cancer. proteins characterized by amino acid sequences that contain 0412. When the improvement is made by other indica seven hydrophobic domains, predicted to represent the trans tions, the other indications can be, but are not limited to, at membrane spanning regions of the proteins. They are found in least one other indication selected from the group consisting a wide range of organisms and are involved in the transmis sion of signals to the interior of cells as a result of their of: interaction with heterotrimeric G proteins. They respond to a 0413 (a) use as an anti-infective agent; diverse range of agents including lipid analogues, amino acid 0414 (b) use as an antiviral agent; derivatives, Small molecules Such as epinephrine and dopam 0415 (c) use as an antibacterial agent; ine, and various sensory stimuli. The properties of many 0416) (d) use for control of pleural effusions; known GPCR are summarized in S. Watson & S. Arkinstall, 0417 (e) use as an antifungal agent; “The G-Protein Linked Receptor Facts Book” (Academic 0418 (f) use as an antiparasitic agent; Press, London, 1994), incorporated herein by this reference. 0419 (g) use for treatment of eczema: GPCR receptors include, but are not limited to, acetylcholine receptors, B-adrenergic receptors, B-adrenergic receptors, 0420 (h) use for treatment of shingles: serotonin (5-hydroxytryptamine) receptors, dopamine recep 0421 (i) use for treatment of condylomata; tors, adenosine receptors, angiotensin Type II receptors, 0422 () use for treatment of human papilloma virus bradykinin receptors, calcitonin receptors, calcitonin gene (HPV); and related receptors, cannabinoid receptors, cholecystokinin 0423 (k) use for treatment of herpes simplex virus receptors, chemokine receptors, cytokine receptors, gastrin (HSV). receptors, endothelin receptors, y-aminobutyric acid (GABA) 0424. When the improvement is made by patient selection, receptors, galanin receptors, glucagon receptors, glutamate the patient selection can be, but is not limited to, a patient receptors, luteinizing hormone receptors, choriogonadotro selection carried out by a criterion selected from the group phin receptors, follicle-stimulating hormone receptors, thy consisting of: roid-stimulating hormone receptors, gonadotrophin-releas 0425 (a) selecting patients with a disease condition ing hormone receptors, leukotriene receptors, Neuropeptide characterized by a high level of a metabolic enzyme Y receptors, opioid receptors, parathyroid hormone recep Selected from the group consisting of histone deacety tors, platelet activating factor receptors, prostanoid (prostag lase, protein kinases, and ornithine decarboxylase; landin) receptors, somatostatin receptors, thyrotropin-releas 0426 (b) selecting patients with a disease condition ing hormone receptors, vasopressin and oxytocin receptors. characterized by a low level of a metabolic enzyme 0436 When the improvement is made by analysis of Selected from the group consisting of histone deacety patient or disease phenotype, the analysis of patient or disease lase, protein kinases, and ornithine decarboxylase; phenotype can be, but is not limited to, a method of analysis US 2016/0166546 A1 Jun. 16, 2016 36 of patient or disease phenotype carried out by a method R", R', and R'' is independently hydrogen, C-C alkyl, selected from the group consisting of: carboxyalkyl, Substituted or non-substituted aminoalkyl, or 0437 (a) use of a diagnostic tool, a diagnostic tech alkylsulfonate; (vi) T and U are independently hydrogen, nique, a diagnostic kit, or a diagnostic assay to confirm C-C2 alkyl, C-C2 alkoxy, aryloxy, amino, halo, cyano, a patient’s particular phenotype; carboxy, carboxyalkyl, acetoxymethylcarbonyl, carbonyl, 0438 (b) use of a method for measurement of a marker Sulfonyl, phosphonyl, boronic acid, aryl, and heteroaryl; and Selected from the group consisting of histone deacety (vii) V and W are each independently selected from OR'', lase, ornithine decarboxylase, VEGF, a protein that is a SR', or NR'R'', such that at least one of V or W. in com gene product of a prostate specific gene, a protein that is bination with NR'R'', forms a metal chelator, where each R', a gene product of jun, and a protein kinase; R. R. R. R', and R' are independently hydrogen, 0439 (c) Surrogate compound dosing: C-C alkyl, carboxyalkyl, alkoxy, or aryloxy. The mem 0440 (d) low dose pre-testing for enzymatic status; brane transporter inhibitors can comprise general inhibitors, 0441 (e) determination of the multi-drug resistance specific inhibitors, or a combination of general and specific activity of cells; inhibitors. General inhibitors include, but are not limited to, 0442 (f) determining expression or activation of a sig cyclosporin A, biricodar, tariquidar, plant polyphenols, cur naling or metabolic protein, where an alteration in the cumin, tRA98006, and imatinib mesylate. Specific inhibitors level of expression or activation of the signaling or meta include, but are not limited to, Valspodar, Verapamil, Vana bolic protein indicates the therapeutic potential of a che date, PAK-104P, MK-571, FTC, Kol34, elacridar, novobio motherapeutic agent; cin, probenecid, BIB-E, disulfuram, indomethacin, furo 0443 (g) detection or assay of expression of biomarkers semide, Penicillin G, Sulfinpirazole, laniquidar, ZoSuquidar, indicating sensitivity to apoptosis-inducing agents; ontogen, isothiocyanates, phytoestrogens, TAG-139, fla 0444 (h) use of an in vitro human tumor clonal assay to vonoids, MS-209, NSAIDs, mitotane, PK1 1195, cyclospo determine patients with enhanced responses; rine D, anthranilamide, pipecolinate, quinoline, OC-144-093, 0445 (i) use of an immunohistochemical assay to deter diallyl sulfide, amooranin, agosterol A, siRNA, rifampicin, mine overexpression of HIF-1C.; amiodarone, quinidine, quinine, nifedipine, dexniguldipin, 0446 () assessment of p53 mutation; and LY455776, V-104, tricyclic izoxazoles, pluronic L61, and 0447 (k) determination of the quantity or activity of fumitremorgin C. Verapamil acts as a reversal agent and acts topoisomerase 213 in cardiac cells. to bind and inhibit the activity of P-glycoprotein. This blocks 0448 Processes and kits for determination of the multi the efflux of antineoplastic agents such as bisantrene and drug resistance of cells are described in U.S. Pat. No. 8,445, thereby kills resistant cells. Verapamil has specifically been 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 N agents are described in United States Patent Application Pub R1 NR 7 lication No. 2012/0328.603, incorporated herein by this ref erence. The biomarkers can include certain fucosyltrans wherein: (i) R'-R are each independently hydrogen, halo, ferases, including fucosyltransferase 3 and carboxyl, alkoxy, aryloxy, thiol, alkylthiol, arylthiol, azido, fucosyltransferase 6, as well as sialyl Lewis A and/or X anti nitro, nitroso, cyano, amino, hydroxyl, phosphonyl, Sulfonyl, gens. The use of an immunohistochemical assay to determine carbonyl, boronic acid, aryl, heteroaryl, or alkyl or alkoxy overexpression of HIF-1C. as a marker for sensitivity to optionally substituted with one or more of halo, amino, anthracycline and anthracycline derivatives and analogs, hydroxy, phosphonyl, Sulfonyl, carbonyl, boronic acid, aryl, including bisantrene and derivatives and analogs thereof, is or heteroaryl; (ii) heteroatom Y is independently selected disclosed in K. Lee et al., “Anthracycline Chemotherapy from the group consisting of O, S, Se, NR, and CR'R''; (iii) Inhibits HIF-1 Transcriptional Activity and Tumor-Induced X is independently selected from the group consisting of Mobilization of Circulating Angiogenic Cells.” Proc. Natl. OR'', NR'R''; (iv) Z is independently selected from the Acad. Sci. 106: 2353-2358 (2009), incorporated herein by this group consisting of O and R'R'': (v) each R. R', R'', R', reference. Topoisomerase 2B activity in cardiac cells, such as US 2016/0166546 A1 Jun. 16, 2016 37 cardiomyocytes, has been shown to be associated with devel Lee et al., “Copy Number Variation and Human Health' in opment of cardiotoxicity as a consequence of administration Essentials of Genomic and Personalized Medicine (G. S. of anthracyclines and other therapeutic agents. Although Ginsburg & H. F. Willard, eds., Academic Press, Amsterdam, bisantrene is considered less cardiotoxic than other anthracy 2010), ch.5, pp. 46-59, incorporated herein by this reference. cline analogs or derivatives, cardiotoxicity may still exist. DNA methylation analysis is described in S. Cottrell et al., Topoisomerase 2B has been shown to be required for anthra “DNA Methylation Analysis: Providing New Insight into cycline to induce DNA double-strand breaks and changes in Human Disease' in Essentials of Genomic and Personalized the transcriptome, leading to mitochondrial dysfunction and Medicine (G. S. Ginsburg & H. F. Willard, eds., Academic generation of reactive oxygen species. Therefore, the quantity Press, Amsterdam, 2010), ch. 6, pp. 60-72, incorporated or activity of topoisomerase 2B can be used as a biomarker to herein by this reference. predict risk of cardiotoxicity before administration of bisant 0463 Specific genetic variants of the MDR1 gene encod rene or an analog or derivative thereof (P. Veipongsa & E. T. ing the MDR protein associated with increased therapeutic Yeh, “Topoisomerase 2B: A Promising Molecular Target for efficacy of an anticancer drug are disclosed in U.S. Pat. No. Primary Prevention of Anthracycline-Induced Cardiotoxic 7,445,897 to Ho et al., incorporated herein by this reference, ity.” Clin. Pharmacol. Ther: 95: 45-52 (2014), incorporated which also discloses hybridization methods with probes herein by this reference). incorporating these variants to detect their presence. 0449 When the improvement is made by analysis of patient or disease genotype, the analysis of patient or disease 0464 Methods for identification of one or more biomark genotype can be, but is not limited to, a method of analysis of ers associated with sensitivity or resistance to chemothera patient or disease genotype carried out by a method selected peutic agents are described in U.S. Pat. No. 8,445,198 to from the group consisting of Knudsen, incorporated herein by this reference. These biom 0450 (a) genetic tests to determine the absence or non arkers can be genes or microRNA; a change in the level of functionality of ABCG2: expression of the gene or microRNA indicates that the cell is 0451 (b) genetic tests to determine the presence or sensitive or resistant to a specific chemotherapeutic agent. functionality of FABP7: The gene can be one or more of ACTB, ACTN4, ADA, 0452 (c) use of a diagnostic tool, a diagnostic tech ADAMS, ADAMTS1, ADD1, AF1CR, AIF1, AKAP1, nique, a diagnostic kit, or a diagnostic assay to confirm AKAP13, AKR1C1, AKT1, ALDH2, ALDOC, ALG5, a patient’s particular genotype; ALMS1, ALOX15B, AMIGO2, AMPD2, AMPD3, ANAPC5, ANP32A, ANP32B, ANXA1, AP1G2, 0453 (d) use of a gene chip; APOBEC3B, APRT, ARHE, ARHGAP15, ARHGAP25, 0454 (e) use of gene expression analysis; ARHGDIB, ARHGEF6, ARL7, ASAH1, ASPH, ATF3, 0455 (f) use of single nucleotide polymorphism (SNP) ATIC, ATP2A2, ATP2A3, ATP5D, ATP5G2, ATP6V1B2, analysis; BC008967, BCAT1, BCHE, BCL11B, BDNF, BHLHB2, 0456 (g) measurement of the level of a metabolite or a BIN2, BLMH, BMI1, BNIP3, BRDT, BRRN1, BTN3A3, metabolic enzyme; C11orf2, C14orf139, C15orf25, C18orf10, C1orf24, 0457 (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, 0458 (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, 0459 () 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, 0460. 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, 0461) 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, FLJ224.57, 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, 0462 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.

US 2016/0166546 A1 Jun. 16, 2016 39 prec, mir-140No2, mir-142-prec, mir-143-prec, mir-144-pre 0481 (d) the non-oral use of nicotinamide: cNo2, mir-145-prec, mir-146bNo.1, mir-146-prec, mir-147 0482 (e) the use of a sustained-release form of nicoti prec, mir-148aNo.1, mir-148-prec, mir-149-prec, mir-150 namide: prec, mir-153-1-prec1, mir-154-prec1 No.1, mir-155-prec, 0483 (f) the use of an inhibitor of poly-ADP ribose mir-15aNo.1, mir-16-1No.1, mir-16-2No.1, mir-181 a-pre polymerase; cNo.1, mir-181b-1No.1, mir-181b-2No.1, mir-181b-precNo1, 0484 (g) the use of caffeine: mir-181b-precNo2, mir-181c-precNo.1, mir-181dNo.1, mir 0485 (h) the use of leucovorin rescue: 188-prec, mir-18bNo2, mir-191-prec, mir-192No2, mir 0486 (i) the use of sustained-release allopurinol: 193bNo2, mir-194-2No.1, mir-195-prec, mir-196-2-precNo2, 0487 () the non-oral use of allopurinol: mir-197-prec, mir-198-prec, mir-199a-1-prec, mir-199a-2- 0488 (k) the administration of bone marrow transplant prec, mir-199b-precNo.1, mir-200a-prec, mir-200bNo.1, mir stimulants, blood, platelet infusions, Neupogen, G-CSF: 200bNo2, mir-202*, mir-202-prec, mir-204-precNo2, mir or GM-CSF: 205-prec, mir-208-prec, mir-20bNo.1, mir-212-precNo1, 0489 (1) pain management; mir-212-precNo2, mir-213-precNo1, mir-214-prec, mir-215 0490 (m) infection control; and precNo2, mir-216-precNo1, mir-219-2No.1, mir-219-prec, 0491 (n) administration of anti-inflammatories: mir-223-prec, mir-29b–1 No.1, mir-29b–2=102prec7.1=7.2, 0492 (o) administration of fluids; mir-321 No.1, mir-321 No2, mir-324No.1, mir-324No2, mir 0493 (p) administration of corticosteroids; 328No.1, mir-342No.1, mir-361 No.1, mir-367No.1, mir 0494 (q) administration of insulin control medications: 37ONo.1, mir-371 No.1, miR-373*No1, mir-375, mir 0495 (r) administration of antipyretics; 376aNo.1, mir-379No.1, mir-380-5p, mir-382, mir-384, mir 0496 (s) administration of anti-nausea treatments; 409-3p, mir-423No.1, mir-424No2, mir-429No.1, mir 0497 (t) administration of anti-diarrhea treatment; 429No2, mir-4323p, mir-4325p, mir-449No.1, mir-450-1, 0498 (u) administration of antihistamines as pre-treat mir-450-2No.1, mir-483No.1, mir-484, mir-487No.1, mir ment to prevent anaphylaxis; 495No.1, mir-499No2, mir-501 No2, mir-503No.1, mir 0499 (v) administration of agents for reduction of gas 509No.1, mir-5 14-1No2, mir-515-15p, mir-515-23p, mir tric toxicity; 516-33p, mir-516-43p, mir-518e/526c, mir-519a-1/52, mir 0500 (w) administration of steroids as pre-treatment to 519a-2No2, mir-519b, mir-519c/52, mir-520c/52, mir-526a prevent anaphylaxis; 2No.1, mir-526a-2No2, MPR103 right, MPR121 left, 0501 (x) administration of sympathetomimetics as pre MPR121 left, MPR130 left, MPR130 right, MPR133 right, treatment to prevent anaphylaxis; and MPR141 left, MPR151 left, MPR156 left, MPR162 left, 0502 (y) administration of an agent to control or pre MPR174 left, MPR174 right, MPR185 right, MPR197 right, vent chemotherapy-induced thrombocytopenia. MPR203 left, MPR207 right, MPR215 left, MPR216 left, 0503 Uricosurics include, but are not limited to, MPR224 left, MPR224 right, MPR228 left, MPR234 right, probenecid, benzbromarone, and Sulfinpyrazone. A particu MPR237 left, MPR243 left, MPR244 right, MPR249 left, larly preferred uricosuric is probenecid. Uricosurics, includ MPR254 right, MPR74 left, MPR88 right, and MPR95 left. ing probenecid, may also have diuretic activity. 0465 Analysis for the SNPs rs229109 and rs72552784, (0504 Poly-ADP ribose polymerase inhibitors are associated with sensitivity to bisantrene, is disclosed in described in G. J. Southan & C. SzabO, “Poly(ADP-Ribose) United States Patent Application Publication No. 2014/ Inhibitors.” Curr. Med. Chem. 10:321-240 (2003), incorpo 0038836 by Higgins et al., incorporated herein by this refer rated herein by this reference, and include nicotinamide, CCC. 3-aminobenzamide, Substituted 3,4-dihydroisoquinolin-1 0466 When the improvement is made by pre-/post-treat (2H)-ones and isoquinolin-1 (2H)-ones, benzimidazoles, ment preparation, the method of pre-/post-treatment prepara indoles, phthalazin-1 (2H)-ones, quinazolinones, isoindoli tion can be, but is not limited to, a method of pre-treatment or nones, phenanthridinones, and other compounds. post-treatment preparation selected from the group consisting 0505 Leucovorin rescue comprises administration of foli of: nic acid (leucovorin) to patients in which methotrexate has 0467 (a) the use of colchicine or an analog thereof; been administered. Leucovorin is a reduced form of folic acid 0468 (b) the use of a uricosuric; that bypasses dihydrofolate reductase and restores hemato 0469 (c) the use of uricase; poietic function. Leucovorin can be administered either intra 0470 (d) the non-oral use of nicotinamide: venously or orally. 0471 (e) the use of a sustained-release form of nicoti 0506. In one alternative, wherein the prefpost treatment is namide: the use of a uricoSuric, the uricoSuric is probenecid or an 0472 (f) the use of an inhibitor of poly-ADP ribose analog thereof. polymerase; 0507 Filgrastim is a granulocytic colony-stimulating fac 0473 (g) the use of caffeine; tor (G-CSF) analog produced by recombinant DNA technol 0474 (h) the use of leucovorin rescue; ogy that is used to stimulate the proliferation and differentia 0475 (i) infection control; and tion of granulocytes and is used to treat neutropenia; G-CSF 0476 () the use of an anti-hypertensive agent. can be used in a similar manner. GM-CSF is granulocyte 0477. When the improvement is made by toxicity manage macrophage colony-stimulating factor and stimulates stem ment, the method of toxicity management can be, but is not cells to produce granulocytes (eosinophils, neutrophils, and limited to, a method of toxicity management selected from basophils) and monocytes; its administration is useful to pre the group consisting of vent or treat infection. 0478 (a) the use of colchicine or an analog thereof; 0508 Anti-inflammatory agents are well known in the art 0479 (b) the use of a uricosuric; and include corticosteroids and non-steroidal anti-inflamma 0480 (c) the use of uricase; tory agents (NSAIDs). Corticosteroids with anti-inflamma US 2016/0166546 A1 Jun. 16, 2016 40 tory activity include, but are not limited to, hydrocortisone, 0513. The use of an agent to control or prevent chemo cortisone, beclomethasone dipropionate, betamethasone, therapy-induced thrombocytopenia is disclosed in U.S. Pat. dexamethasone, prednisone, methylprednisolone, triamcino No. 8,183.342 to Matsuyama. The agent can be a Bax-inhib lone, fluocinolone acetonide, and fludrocortisone. Non-Ste iting peptide of the following formula: XPXLXX (SEQ roidal anti-inflammatory agents include, but are not limited ID NO: 2), wherein X" is an amino acid with a non-polar side to, acetylsalicylic acid (aspirin), sodium salicylate, choline chain, X is an amino acid with a non-polar side chain; X is magnesium trisalicylate, Salsalate, diflunisal, Sulfasalazine, an amino acid with a charged polar side chain, X is an amino olsalazine, acetaminophen, indomethacin, Sulindac, tol acid with a charged polar side chain, and either X" or X may metin, diclofenac, ketorolac, ibuprofen, naproxen, flurbipro be absent. Preferred peptides include VPMLKE (SEQID NO: fen, ketoprofen, fenoprofin, oxaprozin, mefenamic acid, 3), VPMLK (SEQ ID NO: 4), PMLKE (SEQ ID NO: 5), meclofenamic acid, piroxicam, meloxicam, nabumetone, PMLK (SEQ ID NO: 6), VPTLK (SEQ ID NO: 7), and rofecoxib, celecoxib, etodolac, nimeSulide, aceclofenac, VPALR (SEQID NO:8). alclofenac, alminoprofen, amfenac, ampiroXicam, apaZone, 0514 When the improvement is made by pharmacoki araprofen, azapropaZone, bendazac, benoxaprofen, benzy netic/pharmacodynamic monitoring, the pharmacokinetic/ damine, bermoprofen, benzpiperylon, bromfenac, bucloxic pharmacodynamic monitoring can be, but is not limited to a acid, bumadizone, butibufen, carprofen, cimicoxib, cinmeta method selected from the group consisting of: cin, cinnoxicam, clidanac, clofeZone, clonixin, clopirac, dar 0515 (a) multiple determinations of blood plasma lev bufelone, deracoxib, droxicam, eltenac, enfenamic acid, epi els; rizole, esflurbiprofen, ethenzamide, etofenamate, etoricoxib, 0516 (b) multiple determinations of at least one felbinac, fenbufen, fenclofenac, fenclozic acid, fenclozine, metabolite in blood or urine; fendosal, fentiazac, feprazone, filenadol, flobufen, florife 0517 (c) monitoring of immune function; nine, flosulide, flubichin methanesulfonate, flufenamic acid, 0518 (d) use of ELISPOT to measure immune flufenisal, flunixin, flunoxaprofen, fluprofen, fluproduaZone, responses; furofenac, ibufenac, imrecoxib, indoprofen, isofeZolac, isox 0519 (e) determination of surface marker upregulation; epac, isoxicam, licofelone, lobuprofen, lomoxicam, lona and Zolac, loxaprofen, lumaricoxib, mabuprofen, miroprofen, 0520 (f) monitoring of checkpoint inhibition. mofebutaZone, mofeZolac, moraZone, nepafanac, niflumic 0521. Typically, determination of blood plasma levels or acid, nitrofenac, nitroflurbiprofen, nitronaproxen, orpanoxin, determination of at least one metabolite in blood or urine is oxaceprol, OXindanac, OXpinac, oxyphenbutaZone, pam carried out by immunoassays. Methods for performing 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, 0522 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. 0509. The clinical use of corticosteroids is described in B. 0523 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 0510 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, 0511 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 0512 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 0524. 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 US 2016/0166546 A1 Jun. 16, 2016

(ELISPOT) Assay for Enumeration of Specific Antibody monitored for evidence of checkpoint inhibition by conven Secreting Cells,” J. Immunol. Meth., 65: 109-121 (1983), tional immunoassay methods, such as immunoassay of cell incorporated herein by this reference. In this assay, either a surface markers. T cell activation is mediated by the presen monoclonal or a polyclonal capture antibody is coated onto a tation of antigen by dendritic cells; a differentiated myeloid PVDF (polyvinylidene fluoride) microplate. The antibody is cell considered by Some a type of macrophage. Classical chosen for its specificity for the antigen in question. The plate macrophages themselves can have antigen presentation capa is then blocked, typically with a serum protein that is nonre bilities. In the same way that tumor killing T cells are acti active with any of the antibodies in the assay. After this, cells vated by antigen presentation, so are tumor protecting regu of interest are plated out at varying densities, along with an latory T cells and there are various subclasses of Tregs now antigen or a mitogen, and then placed in an incubator with identified. Thus, changes in the manner in which antigens are appropriate conditions for the growth and proliferation of the presented by myeloid cells, and alterations in the T cell phe cells. Cytokine (or another cell product to be detected) notypes mediated by cytokines produced by macrophages, secreted by activated cells is captured locally by the antibody can determine whether or not the predominantactivated T cell coated on the microplate. A biotinylated polyclonal antibody phenotypes kill or protect tumor cells. Thus, a theoretical specific for the chosen analyte (i.e., the cytokine or other cell relationship exists between macrophage activation and killer product to be detected) is added; this antibody is specific for VS regulatory T cell activation. a distinct epitope of the target cytokine or other cell product to 0527. When the improvement is made by drug combina be detected. The detected cytokine or other cell product is tion, the drug combination can be, but is not limited to, a drug then visualized using streptavidin conjugated to an enzyme combination selected from the group consisting of that produces a precipitable product, Such as horseradish per 0528 (a) use with fraudulent nucleosides; oxidase oralkaline phosphatase, and a precipitating Substrate. 0529 (b) use with fraudulent nucleotides; The colored end product, detectable as a spot, typically rep 0530 (c) use with thymidylate synthetase inhibitors; resents an individual cell producing the cytokine or other cell 0531 (d) use with signal transduction inhibitors; product to be detected. The spots can be counted manually or 0532 (e) use with cisplatin or platinum analogs; using an automated reader. 0533 (f) use with alkylating agents; 0525 Methods for determination of surface marker 0534 (g) use with anti-tubulin agents; upregulation are known in the art and are described in T. W. 0535 (h) use with antimetabolites: Kuijpers et al., “Membrane Surface Antigen Expression on 0536 (i) use with berberine: Neutrophils: A Reappraisal of the Use of Surface Markers for 0537 () use with apigenin: Neutrophil Activation.” Blood 78: 1105-1111 (1991), incor 0538 (k) use with colchicine or an analog thereof; porated herein by this reference. For determination of surface 0539 (1) use with genistein: marker upregulation, particularly of tumor cell markers, a 0540 (m) use with etoposide; number of Surface markers can be monitored. The cancer 0541 (n) use with cytarabine; testes (CT) antigens have all been used, including the MUC 0542 (o) use with camptothecins; series (e.g. MUC1), the MAGE series (e.g. MAGE-A), 0543 (p) use with Vinca alkaloids; NYESO-1, and others. HER-2/neu is a favorite can be moni 0544 (q) use with topoisomerase inhibitors; tored in breast cancer, as are estrogen receptors. The antian (0545 (r) use with 5-fluorouracil; giogenic markers like VEGF-1 or endoglin (CD-105) are also 0546 (s) use with curcumin; useful for monitoring. CA-125 has been used for colon can 0547 (t) use with rosmarinic acid; cer. Other cancer markers that can be monitored include, but 0548 (u) use with mitoguaZone: are not limited to, CA-9 (a marker of tumor related hypoxia), 0549 (v) use with meiso indigo; SCCE, the DAM series (DAM-6, DAM-10, and others), 0550 (w) use with imatinib: ELF2, Ep-CAM, GP-100, h-TERT (human telomerase), the 0551 (x) use with dasatinib; SART series (SART-1, SART-2, and SART-3), the MART 0552 (y) use with nilotinib; series (MART-1, MART-2, and others), WT-1, mutated p53, 0553 (Z) use with epigenetic modulators: and many other markers. In particular, for hematopoietic 0554 (aa) use with transcription factor inhibitors; tumors, the following markers may be useful: NuSAP1, 0555 (ab) use with taxol; CD56, MAGE-A3, PRAME, ROPN1, SCP-1, SLLP1, and 0556 (ac) use with homoharringtonine: SPO11 for AML; as described in S. Anguille et al., “Leuke 0557 (ad) use with pyridoxal; mia-Associated Antigens and Their Relevance to the Immu 0558 (ae) use with spirogermanium; notherapy of Acute Myeloid Leukemia. Leukemia 26: 2186 0559 (af) use with caffeine: 2 196 (2012), incorporated herein by this reference. For 0560 (ag) use with nicotinamide: lymphoma, the following markers may be useful: TCL-1, 0561 (ah) use with methylglyoxalbisguanylhydrazone: CD-20. HOX-11, and other markers. 0562 (ai) use with poly-ADP ribose polymerase 0526 Methods for monitoring checkpoint inhibition are (PARP) inhibitors: known in the art and are described in V. Sudakin et al., 0563 (a) use with EGFR inhibitors; “Checkpoint Inhibition of the APC/C in HeLa Cells Is Medi 0564 (ak) use with Bruton's tyrosine kinase (BTK) ated by a Complex of BUBR1, BUB3, CDC20, and MAD2,' inhibitors; J. Cell Biol. 154: 925-936 (2001), incorporated herein by this 0565 (al) use with bis-thio-hydrazide amides; reference. Down regulation of CTLA-4, PD-1. OX-40 or 0566 (am) use with succinimide or maleimide deriva many other checkpoint kinases known in the art can be moni tives as inhibitors of topoisomerase II; tored. Similarly, reduction of regulatory T cells (Tregs), regu 0567 (an) use with histone deacetylase (HDAC) inhibi latory DC, and regulatory neutrophils are prima facie evi tors; dence of checkpoint blockade and these cells can be 0568 (ao) use with immunostimulants; US 2016/0166546 A1 Jun. 16, 2016 42

0569 (ap) use with telomerase inhibitors; 0599 Signal transduction inhibitors are described in A. V. 0570 (aq) use with agents that inhibit the expression or Lee et al., “New Mechanisms of Signal Transduction Inhibi activity of Her2: tor Action: Receptor Tyrosine Kinase Down-Regulation and 0571 (ar) use with agents that inhibit the expression or Blockade of Signal Transactivation.” Clin. Cancer Res. 9: activity of estrogen receptors; 516s (2003), incorporated herein in its entirety by this refer 0572 (as) use with agents that inhibit the expression or CCC. activity of antigens associated with specific tumor tar 0600 Alkylating agents include, but are not limited to, getS. Shionogi 254-S, aldo-phosphamide analogues, altretamine, 0573 (at) use with G-quadruplex ligands; anaxirone, Boehringer Mannheim BBR-2207, bendamus 0574 (au) use with polycyclic lysophosphatidic recep tine, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, tor antagonists; carmustine, Chinoin-139, Chinoin-153, chlorambucil, cispl (0575 (av) use with anti-CTGF agents: atin, cyclophosphamide, American Cyanamid CL-286558, 0576 (aw) use with myeloid differentiation inducing Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto agents: DACHP(Myr), dianhydrogalactitol, dibromodulcitol, other 0577 (ax) use with covalent diabodies binding to a Substituted hexitols, diphenylspiromustine, diplatinum cyto tumor-associated antigen; static, Erba distamycin derivatives, Chugai DWA-2114R, ITI 0578 (ay) use with bispecific antibodies that have a E09, elmustine, Erbamont FCE-24517, estramustine phos cell-penetrating determinant and an intracellular target phate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI binding determinant; 17230, hepsulfam, ifosfamide, iproplatin, lomustine, mafos 0579 (az) use with multidomain molecules that com famide, melphalan, mitolactol, Nippon Kayaku NK-121, NCI prise a cell binding ligand that binds to cells in the tumor NSC-264395, NCINSC-342215, oxaliplatin, Upjohn PCNU, stroma Such as endothelial cells, fibroblasts, or immune prednimustine, Proter PTT-119, ranimustine, semustine, cells and an oligonucleotide that inhibits the nonsense SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus mediated decay pathway; tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, 0580 (ba) use with tumor-specific antibodies binding to teroxirone, tetraplatin and trimelamol, uramustine, as a portion of the CD44 protein or a binding protein described in U.S. Pat. No. 7,446,122 by Chao et al., incorpo derived from the light-chain or heavy-chain comple rated herein by this reference. mentary-determining regions of Such antibodies; 0601 Anti-tubulin agents include, but are not limited to, 0581 (bb) use with inhibitors of CXCR4; Vinca alkaloids, taxanes, podophyllotoxin, halichondrin B, 0582 (bc) use with pyruvate dehydrogenase kinase and homohalichondrin B. (PDK1) inhibitors; 0602 Antimetabolites include, but are not limited to: 0583 (bd) use with epherin receptor targeting agents; methotrexate, pemetrexed, 5-fluorouracil, capecitabine, cyt 0584 (be) use with binding proteins for Axl; arabine, gemcitabine, 6-mercaptopurine, and pentostatin, 0585 (bf) use with Wnt pathway inhibitors together alanosine, AG2037 (Pfizer), 5-FU-fibrinogen, acanthifolic with MAPK pathway inhibitors; acid, aminothiadiazole, brequinar Sodium, carmofur, Ciba 0586 (bg) use with TEC family kinase inhibitors: Geigy CGP-30694, cyclopentyl cytosine, cytarabine phos 0587 (bh) use with substituted macrocyclic com phate stearate, cytarabine conjugates, Lilly DATHF, Merrill pounds with proteasome activity; Dow DDFC, deazaguanine, dideoxycytidine, 0588 (bi) use with peptide-based PACE4 inhibitors: dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, 0589 (b) use with azaindole derivatives as JAK3 Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxu inhibitors; ridine, fludarabine phosphate, N-(2-furanidyl)-5-fluorou 0590 (bk) use with inhibitors of Myc; racil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly 0591 (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, 0592 (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 0593 (bn) use with PGE inhibitors; and Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, 0594) (bo) use with activatable antibodies targeting Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tumor-specific markers. tyrosine protein kinase inhibitors, Taiho UFT and uricytin. 0595 Topoisomerase inhibitors include, but are not lim 0603 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 0604 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. 0596 Fraudulent nucleosides include, but are not limited 0605 Colchicine is a tricyclic alkaloid that exerts its activ to, cytosine arabinoside, gemcitabine, and fludarabine; other ity by binding to the protein tubulin. Analogs of colchicine fraudulent nucleosides are known in the art. include, but are not limited to, cholchiceinamide, N-de 0597 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 0598. 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. H. Zweig & C. F. Chignell, “Interaction US 2016/0166546 A1 Jun. 16, 2016

of Some Colchicine Analogs, Vinblastine and Podophyllo has effects on mitochondria, but with no change in Bcl-2. toxin with Rat Brain Microtubule Protein. Biochem. Phar Bax, and Bid protein expression. macol. 22: 2141-2150 (1973) and B. Yang et al., “Syntheses 0.617 Meiso indigo also stimulates the cleavage of pro and Biological Evaluation of Ring C-Modified Colchicine caspase 3, 8, 9 and PARP in HL-60 myeloid cells. Meisoin Analogs.” Bioorg. Med. Chem. Lett. 20:3831-3833 (2010)), digo also is directed to multiple cellular targets, which are both of which are incorporated herein by this reference. possibly synergistic and complementary. For example, it pro 0606 Genistein is an isoflavone with the systemic name motes differentiation of human myeloblastic leukemic cells, 5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one. accompanied by down regulation of c-myb gene expression. Genistein has a number of biological activities, including It also promotes inhibition of DNA and RNA synthesis in activation of PPARs, inhibition of several tyrosine kinases, W256 cells, microtubule assembly, glycogen synthase inhibition of topoisomerase, antioxidative activity, activation kinase-3 B (GSK-3|8) (at 5-50 nM), CDK1/cyclin B, and of Nrf2 antioxidative response, activation of estrogen recep CDK5/p25 (tau microtubule protein phosphorylation). Addi tor beta, and inhibition of the mammalian hexose transporter tionally, meisoindigo decreases B-catenin and c-myc (HL-60 GLUT2. cells, but not in K562), affects the Wnt pathway through 0607 Etoposide is an anticancer agent that acts primarily inhibiting GSK-3B and down regulating B-catenin and c-myc as a topoisomerase II inhibitor. Etoposide forms a ternary protein expression. Meisoindigo also promotes upregulation complex with DNA and the topoisomerase II enzyme, pre of CD11b, promoting myeloid differentiation, and upregula vents re-ligation of the DNA strands and thus induces DNA tion of Ahi-1 in Jurkat cells (inducing phosphorylation of Strand breakage and promotes apoptosis of the cancer cells. c-Myb). Furthermore, meisoindigo exhibits antiangiogenic 0608 Cytarabine is a nucleoside analog replacing the effects, including decreased VEGF protection, VCAM-1, ribose with arabinose. It can be incorporated into DNA and tubule formulation in HUVEC, and ECV304 apoptosis. also inhibits both DNA and RNA polymerases and nucleotide 0618. Imatinib is an inhibitor of the receptor tyrosine reductase. It is particularly useful in the treatment of acute kinase enzyme ABL and is used to treat chronic myelogenous myeloid leukemia and acute lymphocytic leukemia, leukemia, gastrointestinal Stromal tumors, and other hyper 0609 Camptothecins include camptothecin, homocamp proliferative disorders. tothecin, topotecan, irinotecan, DB 67, BNP 1350, exatecan, lurtotecan, ST 1481, and CKD 602. These compounds act as 0619. 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. 0610 Vinca alkaloids include vinblastine, Vincristine, 0620. Nilotinib is another tyrosine kinase inhibitor vindesine, and vinorelbine. approved for the treatment of chronic myelogenous leukemia; 0611 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 0621 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 0612 5-fluorouracil is a base analog that acts as a rated herein by this reference. thymidylate synthase inhibitor and thereby inhibits DNA 0622 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- 0613 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 0.614 Rosmarinic acid is a naturally-occurring phenolic Transcription Factors with Small Organic Molecules. Curr. antioxidant that also has anti-inflammatory activity. Opin. Chem. Biol. 12: 464–471 (2008), incorporated herein 0615 MitoguaZone is an inhibitor of polyamine biosyn by this reference. thesis through competitive inhibition of S-adenosylmethion 0623 Tetrandrine has the chemical structure 6,6'7.12-tet ine decarboxylase. ramethoxy-2,2'-dimethyl-1 B-berbaman and is a calcium 0616 Meiso indigo is active via several, possibly novel channel blocker that has anti-inflammatory, immunologic, mechanisms of action. It has cell cycle specific effects, and antiallergenic effects, as well as an anti-arrhythmic effect including arrest in G(O)/G1 for AML cell lines and G2/M similar to that of quinidine. It has been isolated from arrest for HT-29 colorectal cell lines. It also stimulates apo Stephania tetranda and other Asian herbs. ptosis through a number of mechanisms, including the 0624 VEGF inhibitors include bevacizumab (Avastin), upregulation of p21 and p27 and the downregulation of Bcl-2 which is a monoclonal antibody against VEGF, itraconazole, in primary AML cells, as well as upregulation of Bak and Bax and Suramin, as well as batimastat and marimastat, which are in AML cells (DKO insensitive to chemotherapy), and a novel matrix metalloproteinase inhibitors, and cannabinoids and caspase-dependent pathway in K562 cells. Meisoindigo also derivatives thereof. US 2016/0166546 A1 Jun. 16, 2016 44

0625 Cancer vaccines are being developed. Typically, benzode anthracen-3-one compounds, described in U.S. cancer vaccines are based on an immune response to a protein Pat. No. 8,058,075 to Xu et al.: (16) dihydropyridophthalazi or proteins occurring in cancer cells that does not occur in nones, described in U.S. Pat. No. 8.012,976 to Wang et al., normal cells. Cancer vaccines include Provenge for meta (17) substituted azaindoles, described in U.S. Pat. No. 8,008, static hormone-refractory prostate cancer, Oncophage for 491 to Jiang et al.; (18) fused tricyclic compounds, described kidney cancer, CimaVax-EGF for lung cancer, MOBILAN, in U.S. Pat. No. 7.956,064 to Chua et al.; (19) substituted NeuVenge for Her2/neu expressing cancers such as breast 6a,7,8,9-tetrahydropyrido3.2-elpyrrolo 1,2-alpyrazin-6 cancer, colon cancer, bladder cancer, and ovarian cancer, (5H)-ones, described in U.S. Pat. No. 7,928,105 to Gangloff StimuVax for breast cancer, and others. Cancer vaccines are et al.; and (20) thieno2.3-c isoquinolines, described in U.S. described in S. Pejawar-Gaddy & O. Finn, “CancerVaccines: Pat. No. 7,825,129. Other PARP inhibitors are known in the Accomplishments and Challenges.” Crit. Rev. Oncol. Hema art. tol. 67:93-102 (2008), incorporated herein by this reference. 0628 EGFR inhibitors, including both small molecules 0626. The use of methylglyoxalbisguanylhydrazone in and monoclonal antibodies, are described above. Other cancer therapy has been described in D. D. Von Hoff, EGFR inhibitors are known in the art. “MGBG: Teaching an Old Drug New Tricks.” Ann. Oncol. 5: 0629 Brutons tyrosine kinase (BTK) is a kinase enzyme 487-493 (1994), incorporated herein by this reference. that plays a key role in the maturation of B cells and in mast 0627 Poly-ADP ribose polymerase inhibitors are cell activation through the high-affinity IgE receptor. Defi described in G. J. Southan & C. SzabO, “Poly(ADP-Ribose) ciencies in BTK activity are associated with the primary Inhibitors.” Curr. Med. Chem. 10: 321-240 (2003), incorpo immunodeficiency disease X-linked agammaglobulinemia. rated herein by this reference, and include nicotinamide, The Btk gene is located on the X-chromosome. BTK contains 3-aminobenzamide, Substituted 3,4-dihydroisoquinolin-1 a PH domain that binds phosphatidylinositol (3,4,5)-triphos (2H)-ones and isoquinolin-1 (2H)-ones, benzimidazoles, phate (PIP3). PIP3 induces BTK to phosphorylate phospho indoles, phthalazin-1 (2H)-ones, quinazolinones, isoindoli lipase C, which in turn hydrolyzes phosphatidyl inositol nones, phenanthridinones, and other compounds. Poly-ADP diphosphate into two second messengers, inositol triphos ribose polymerase (PARP) inhibitors include, but are not phate and diacylglycerol, which in turn modulate the activity limited to: (1) derivatives of tetracycline as described in U.S. of downstream proteins in B cells. BTK inhibitors include, 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 No. 8.338.439 to Singh et al., incorporated herein by this Fujio et al.; (5) 6-alkenyl-substituted 2-quinolinones, 6-phe reference; 6-phenyl-imidazol-2-alpyridine and 6-phenyl nylalkyl-substituted quinolinones, 6-alkenyl-substituted imidazo[1,2-bipyridazine derivatives, as disclosed in U.S. 2-quinoxalinones, 6-phenylalkyl-substituted 2-quinoxalino Pat. No. 8.324.211 to Dewdney et al., incorporated herein by nes, Substituted 6-cyclohexylalkyl Substituted 2-quinolino this reference; 5-phenyl-1H-pyridin-2-one, 6-phenyl-2H-py nes, 6-cyclohexylalkyl Substituted 2-quinoxalinones, Substi ridazin-3-one, and 5-phenyl-1H-pyrazin-2-one derivatives, tuted pyridones, quinazolinone derivatives, phthalazine as disclosed in U.S. Pat. No. 8,318,719 to Dewdney et al. and derivatives, quinazolinedione derivatives, and Substituted U.S. Pat. No. 8.2997,077, incorporated herein by this refer 2-alkyl quinazolinone derivatives, as described in U.S. Pat. ence: 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo3. No. 8,299,256 to Vialard et al.; (6) 5-bromoisoquinoline, as 4-dipyrimidin-1-yl)piperidin-lyl)prop-2-en-1-one, (E)-1-(3- described in U.S. Pat. No. 8,299,088 to Mateucci et al.; (7) (4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo 3,4-d 5-bis-(2-chloroethyl)amino-1-methyl-2-benzimidazolebu pyrimidin-1-yl)piperidin-1-yl)but-2-en-1-one, 1-(3-(4- tyric acid, 4-iodo-3-nitrobenzamide, 8-fluoro-5-(4-(methy amino-3-(4-phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin lamino)methyl)phenyl)-3,4-dihydro-2H-azepino 5.4.3-cd 1-yl)piperidin-1-yl)sulfonylethene, 1-(3-(4-amino-3-(4- indol-1 (6H)-one phosphoric acid, and N-3-(3,4-dihydro-4- phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) oXo-1-phthalazinyl)phenyl-4-morpholinebutanamide piperidin-1-yl)prop-2-yn-1-one, 1-(4-(4-amino-3-(4- methanesulfonate, as described in U.S. Pat. No. 8,227,807 to phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) Gallagher et al.; (8) pyridazinone derivatives, as described in piperidin-1-yl)prop-2-en-1-one, N-(1S.4s)-4-(4-amino-3- U.S. Pat. No. 8,268,827 to Branca et al.; (9) 4-3-(4-cyclo (4-phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) propanecarbonyl-piperazine-1-carbonyl)-4-fluorobenzyl cyclohexyl)acrylamide, 1-((R)-3-(4-amino-3-(4- 2H-phthalazin-1-one, as described in U.S. Pat. No. 8,247.416 phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) to Menear et al., (10) tetraaza phenalen-3-one compounds, as pyrrolidin-1-yl)prop-2-en-1-one, 1-(S)-3-(4-amino-3-(4- described in U.S. Pat. No. 8.236,802 to Xu et al.; (11) 2-sub phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) stituted-1H-benzimidazole-4-carboxamides, as described in pyrrolidin-1-yl)prop-2-en-1-one, 1-((R)-3-(4-amino-3-(4- U.S. Pat. No. 8,217,070 to Zhu et al.; (12) substituted 2-alkyl phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) quinazolinones, as described in U.S. Pat. No. 8,188,103 to piperidin-1-yl)prop-2-en-1-one, 1-((S)-3-(4-amino-3-(4- Vander Aa et al., (13) 1H-benzimidazole-4-carboxamides, as phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) described in U.S. Pat. No. 8,183,250 to Penning et al.; (13) piperidin-1-yl)prop-2-en-1-one, and (E)-1-(3-(4-amino-3- indenoisoquinolinone analogs, as described in U.S. Pat. No. (4-phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) 8,119,654 to Jagtap et al., (14) benzoxazole carboxamides, piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one, aS described in U.S. Pat. No. 8,088,760 to Chu et al: (15) diaza disclosed in U.S. Pat. No. 8,236,812 to Honigberg et al.,

US 2016/0166546 A1 Jun. 16, 2016 48 phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl)piperi ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H din-1-yl)prop-2-en-1-one, and (E)-1-(3-(4-amino-3-(4- pyrrolo2,3-dipyrimidin-4-amine), and BMS-599626 (S)- phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl) morpholin-3-ylmethyl 4-(1-(3-fluorobenzyl)-1H-indazol-5- piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one, disclosed ylamino)-5-methylpyrrolo 1.2-f 1.2.4 triazin-6- in U.S. Pat. No. 7,514,444 to Honigberg et al., incorporated ylcarbamate). herein by this reference; imidazol-2-alpyrazin-8-ylamines, disclosed in U.S. Pat. No. 7,405,295 to Currie et al., incorpo 0635 Agents that inhibit the expression or activity of rated herein by this reference; C-cyano-B-hydroxy-8-methyl estrogen receptors include, but are not limited to, fulvestrant. N-(2,5-dibromophenyl)-propenamide, C-cyano-3-hydroxy 0636) Agents that inhibit the expression or activity of anti B-methyl-N-4-(methylsulfonyl)phenyl-propenamide, gens associated with specific tumor targets include, but are C-cyano-B-hydroxy-3-methyl-N-3-methylsulfonyl)phe not limited to: (i) agents that inhibit the binding of estrogen to nyl-propenamide, C-cyano-B-hydroxy-3-methyl-N-3- the estrogen receptor, including tamoxifen, toremifene, and bromo-4-(trifluoromethoxy)-phenylpropenamide, C.-cyano fulvestrant; (ii) aromatase inhibitors, including anastroZole, B-hydroxy-3-methyl-N-(2,4-dibromophenyl)-propenamide, exemestane, and letrozole; (iii) tyrosine kinase inhibitors, C-cyano-B-hydroxy-3-methyl-N-(2,4-dichlorophenyl)-pro including imatinib mesylate, dasatinib, nilotinib, and bosu penamide, C-cyano-B-hydroxy-f-methyl-N-(2,5-dichlo tinib; (iv) antibodies binding to HER-2 or blocking its activ rophenyl)-propenamide, C-cyano-B-hydroxy-3-methyl-N- ity, including trastuzumab and pertuZumab, (v) Small-mol (3,4-didichlorophenyl)-propenamide, or pharmaceutically ecule agents that inhibit the tyrosine kinase activity of HER acceptable salts thereof, as disclosed in U.S. Pat. No. 6,753, 2, including lapatinib, (vi) Small-molecule agents that inhibit 348 to Uckun et al., incorporated herein by this reference; and the tyrosine kinase activity of EGFR, including gefitinib and calanolides, as disclosed in U.S. Pat. No. 6,306,897 to Uckun erlotinib; (vii) monoclonal antibodies binding to EGFR, et al., incorporated herein by this reference. Other inhibitors including cetuximab and panitumumab; (viii) Small-mol of BTK are known in the art. ecule agents that inhibit the serine/threonine kinase mTOR, 0630. Bis-thio-hydrazide amides, such as N',N'-dim including temsirolimus; (ix) Small-molecule agents that bind ethyl-N',N'-di(phenylcarbonothioyl)malonohydrazide, are to immunophilin FK-binding protein 12, including everoli disclosed as a compound that can be used with other antine mus; (X) Small-molecule agents that block the activity of oplastic agents, especially in the treatment of MDR-resistant multiple tyrosine kinase enzymes, including Vandetanib; (xi) malignancies, in U.S. Pat. No. 7,763,658 to Koya et al., incor Small-molecule agents that block the activity of an activated porated herein by this reference. Other bis-thio-hydrazide mutant form of the serine/threonine kinase BRAF, BRAF amides are also disclosed. V600E, including vemafuranib; (xii) small-molecule agents 0631 Use with succinimide or maleimide derivatives as that inhibit the tyrosine kinase activity of the EML4-ALK Topoisomerase II inhibitors is disclosed in United States fusion protein, including crizotinib; (xiii) Small-molecule Patent Application Publication 2007/0196360 by Jensen et agents that are inhibitors of histone deacetylase (HDAC) al., incorporated herein by this reference. activity, including Vorinostat and romidepsin; (xiv) small 0632 HDAC inhibitors include, but are not limited to, molecule agents that modulate the activity of retinoic acid compounds disclosed in PCT Patent Application Publication receptors, retinoid X receptors, or both, including beXarotene, No. WO 02/22577 by Bair et al., including, but not limited to, alitretinoin, and tretinoin, (XV) Small-molecule agents that are N-hydroxy-3-4-(2-hydroxyethyl)2-(1H-indol-3-yl) proteasome inhibitors, including bortezomib and carfil ethyl-aminomethylphenyl-2E-2-propenamide, Suberoy Zomib; (Xvi) Small-molecule agents that are antifolates and lanilide hydroxamic acid, 4-(2-amino-phenylcarbamoyl)- selectively accumulate in cells expressing RFC-1, overex benzyl-carbamic acid pyridine-3-ylmethyl ester and pressed in malignant cells, including pralatrexate: (Xvii) derivatives thereof, butyric acid, pyroxamide, trichostatin A, monoclonal antibodies that bind to VEGF or block activity of oXamflatin, apicidin, depsipeptide, depudecin, trapoxin, HC proteins involved in VEGF signaling, including bevaci toxin, and sodium phenylbutyrate. Zumab; (xviii) recombinant fusion proteins that bind to 0633 Immunostimulants include, but are not limited to, VEGF, including Ziv-aflibercept; (xix) small-molecule agents deoxycholic acid, tetrachlorodecaoxide, imiquimod, and that bind to VEGF or block activity of proteins involved in residuimod. VEGF signaling, including Sorafenib, Sunitinib, paZopanib 0634. Agents that inhibit the expression or activity of Her2 (which has other activities as well), regorafenib (which has include, but are not limited to, lapatinib ditosylate, afatinib, other activities as well), and cabozanitib (which has other lapatinib, CP-724714 ((E)-2-methoxy-N-(3-(4-(3-methyl-4- activities as well); and (XX) monoclonal antibodies binding to (6-methylpyridin-3-yloxy)phenylamino)quinazolin-6-yl)al tumor markers that trigger an anti-neoplastic immune lyl)acetamide), mulbritinib, canertinib, CUDC-101 (7-(4-(3- response, including rituximab (binding to CD20), alemtu ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N- Zumab (binding to CD52), ofatumumab (binding to CD20), hydroxyheptanamide), Tyrphostin AG 879 (2-(2E)-3-3,5-bis ipilimumab (binding to CTLA-4), to situmomab (binding to (1,1-dimethylethyl)-4-hydroxyphenyl-2-cyano-2- CD20; this monoclonal antibody can be conjugated to the propenethioamide), TAK-285 (N-(2-(4-(3-chloro-4-(3- radioisotope ''I), and ibritumomab (binding to CD20; this (trifluoromethyl)phenoxy)phenylamino)-5H-pyrrolo 3,2-d monoclonal antibody can be conjugated to '''1 n or 'Y). pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide), 0637 Agents that are G-quadruplex ligands include, but Arry 380 (N-(4-(12,4triazolo 1.5-alpyridin-7-yloxy)-3- are not limited to, 3,11-difluoro-6,8,13-trimethyl-8H-quino methylphenyl)-6-(5-((2-(methylsulfonyl)ethylamino)me 4.3.2-kill acridinium methosulfate, BRACO-19 (9-4-(N.N- thyl)furan-2-yl)guinazolin-4-amine), AV412, AZD8931 (2- dimethylamino)phenylamino-3,6-bis(3-pyrrolidino-propi (4-(4-(3-chloro-2-fluorophenylamino)-7- onamido)acridine), and telomestatin. These agents are methoxyquinazolin-6-yloxy)piperidin-1-yl)-N- described in United States Patent Application Publication No. methylacetamide), neratinib, AEE788 ((R)-6-(4-((4- 2008/0279961 by Burger, incorporated herein by this refer

US 2016/0166546 A1 Jun. 16, 2016 50 acid; 1-4-4-(6-cyclopentylethynyl-pyridin-2-ylamino)-3- second polypeptide chains of said diabody additionally com methyl-isoxazol-5-yl)-biphenyl-4-yl)-cyclopropanecar prises an E-coil or a K-coil separator; and (D) wherein when boxylic acid; 1-(4-3-methyl-4-6-(pyrrolidine-1-carbonyl)- said separator of said first or second polypeptide is an E-coil, pyridin-2-ylaminol-isoxazol-5-yl)-biphenyl-4-yl)- said separator of said serum-protein binding polypeptide is a cyclopropanecarboxylic acid; 1-4'-4-(6- K-coil, and when said separator of said first or second cyclopropylcarbamoyl-pyridin-2-ylamino)-3-methyl polypeptide is an K-coil, said separator of said serum-protein isoxazol-5-yl)-biphenyl-4-yl)-cyclopropanecarboxylic acid; binding polypeptide is an E-coil. 1-4'-4-(6-cyclohexyloxy-pyridin-2-ylamino)-3-methyl 0642 Bispecific antibodies that have a cell-penetrating isoxazol-5-yl)-biphenyl-4-yl)-cyclopropanecarboxylic acid; determinant and an intracellular target-binding determinant 1-4'-[4-(6-cyclobutoxy-pyridin-2-ylamino)-3-methyl-isox are disclosed in United States Patent Application Publication azol-5-yl)-biphenyl-4-yl)-cyclopropanecarboxylic acid; No. 2013/0266570 by Weisbart et al. In one alternative, the 1-(4-4-6-(1-cyclohexyl-ethoxy)-pyridin-2-ylamino-3- bispecific antibodies have Fv fragments with a cell-penetrat methyl-isoxazol-5-yl)-biphenyl-4-yl)-cyclopropanecar ing determinant and a second FV fragment with an intracel boxylic acid; 1-4-3-methyl-4-(6-phenethyloxy-pyridin-2- lular target-binding determinant. In one embodiment, the ylamino)-isoxazol-5-yl)-biphenyl-4-yl)- intracellular target-binding determinant is an E3 ubiquitin cyclopropanecarboxylic acid; 4'-3-methyl-4-(5-phenyl-1,3, protein ligase, or tumor Suppressor-interacting protein, Such 4oxadiazol-2-ylamino)-isoxazol-5-yl)-biphenyl-4- as MDM2. In one embodiment, the intracellular target-bind carboxylic acid; 1-(4-3-methyl-4-6-(2-oxo-oxazolidin-3- ing determinant may target an oncoprotein such as a myc or yl)-pyridin-2-ylaminol-isoxazol-5-yl)-biphenyl-4-yl)- ras oncoprotein. In another embodiment, the intracellular cyclopropanecarboxylic acid; 1-(4-4-6-(3-carbamoyl target-binding determinant may target DNA repair proteins phenyl)-pyridin-2-ylaminol-3-methyl-isoxazol-5-yl)- Such as a RAD52 protein, ataxia telangiectasia mutated pro biphenyl-4-ylycyclopropanecarboxylic acid; 1-(4-3- tein (ATM), CHK2 or CHK1 proteins, or BCL2 protein. methyl-4-6-(2H-tetrazol-5-yl)-pyridin-2-ylamino Additional examples of proteins associated with DNA repair isoxazol-5-yl)-biphenyl-4-yl)-cyclopropanecarboxylic acid; include but are not limited to BRCA1, MDC1, 53BP1, p53, and 1-4-4-(6-cyclopropylmethoxy-pyridin-2-ylamino)-3- ATR, and p21. methyl-isoxazol-5-yl)-biphenyl-4-yl)-cyclopropanecar 0643. Multidomain molecules that comprise a cell binding boxylic acid. ligand that binds to cells in the tumor stroma Such as endot 0639 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 0640 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 0641 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 0644 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 0645. 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 US 2016/0166546 A1 Jun. 16, 2016

peptides, cyclic peptides, natural amino-acids, unnatural rafenib), RAF265, BAY 73-4506, BAY 43-9006 (sorafenib), amino acids, and peptidomimetic compounds); 4F-ben SB590885, XL281 (BMS-908662), or GSK 21 18436436. ZoylTN24003: KRH-1120; KRH-1636; KRH-2731; 0650 TEC family kinase inhibitors are disclosed in PCT polyphemusin analogue: ALX40-4C; T-140; T-140 analogs Patent Application Publication WO 2014/071231 by Buggy and derivatives; TN14003: TC14012: TE14011; and any et al. and in PCT Patent Application WO 2014/071231 by combinations thereof. Additionally, the CXCR4 inhibitor can Buggy et al. Typically, the TEC family kinase inhibitor is a be used with a VEGF inhibitor, such as a VEGF inhibitor covalent inhibitor, such as ibrutinib. selected from the group consisting of ABT-869: AEE-788: 0651) Substituted macrocyclic compounds with protea AG-13736: AG-028262; Angiostatin; bevacizumab; AVE some activity are disclosed in PCT Patent Application Publi 8062: AZD-2171; Sorafenib; BMS-387032; CEP-7055; cation No. WO 2013/188750 by Pirrung et al. The com CHIR-258; GFKI; CP-547632; CP-564959; E-7080: pounds can be structurally related to glidobactins. 786034; GW-654652: IMC-1C11; KRN-951; PKC-412: 0652 Peptide-based PACE4 inhibitors are disclosed in PTK-787: SU 11248: SU-5416: SU-6668; AVE-0005; thali PCTPatent Application Publication No. WO 2013/029180 by domide; XL-647; XL-999; ZD-6474; ZK-304709; Pazo Day et al. panib; CDP791; Enzastaurin; BIBF 1120; BAY 573952; BAY 0653 AZaindole derivatives as JAK3 inhibitors are dis 734506; XL 184: IMC-1121B, CEP 701; SU 014813; SU closed in PCT Patent Application Publication No. WO 2014/ 10944: SU 12662: OSI-930; BMS 582664; ZD-6126: Ima 081732 by Goldstein et al. The compounds can be N-(3-(7- tinib: Glivec: Gleevec, STI-571; CGP-57148: RAD-001; pivaloyl-5H-pyrrolo2,3-bipyrazin-2-yl)phenyl)acrylamide: BMS-354825; Volociximab: CCI-779; 17-AAG; DMXAA; 2-(3-acrylamidophenyl)-N-(tert-butyl)-5H-pyrrolo2,3-b CI-1040: CI-1033; (5-5-fluoro-2-oxo-1,2-dihydroindol pyrazine-7-carboxamide; or N-(tert-butyl)-2-(3-(4-(dim (3Z)-ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic ethylamino)but-2-enamido)phenyl)-5H-pyrrolo2,3-b- acid 2-diethylaminoethylamide); 4TBPPAPC: AMG 706: pyrazine-7-carboxamide. Nexavar(R); and PTK/ZK. In another alternative, the CXCR4 0654) Inhibitors of Myc are disclosed in PCT Patent inhibitor can be used with a p38 MAPK inhibitor. The p38 Application Publication No. WO 2014/059429 by Gudkov et MAPK inhibitor can be selected from the group consisting of al. The inhibitors can have the structure of Formula (A-2): antisense p38 MAPK nucleic acids and fragments thereof, antibodies that bind p38 MAPK and fragments thereof, EO-1428, SB239063, SB281832, VX-702, VX-745, (A-2) ZM336372, RPR 200765A, N-(3-tert-butyl-1-methyl-5- OH pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea, H SB203580, SB2021.90, PD169316, fr-167653, trans-1-(4-hy NS droxycyclohexyl)-4-(4-fluorophenyl)-5-(2 methoxypyridi i-S N21 N midin-4-yl)imidazole, 2-(4-chlorophenyl)-4-)4-fluorophe O 2H(R'), nyl)-5-pyridin-4-yl-1,2-dihydropyrazol-3-one, and any combinations thereof. 0646 Pyruvate dehydrogenase kinase (PDK1) inhibitors wherein: (i) R' is alkyl, hydroxyl, amino, alkoxy, aryl, alk are disclosed in PCT Patent Application Publication No. WO enyl, alkynyl, or alkylenearyl; (ii) Het is heteroaryl; and (iii) 2013/174997 by Villalba et al. and include dichloroacetate, m and n are each independently 0, 1, 2, 3, or 4. antisense RNA, small inhibitory RNA, short hairpin RNA, 0655 Inhibitors of furin and other pro-protein convertases and ribozymes. are disclosed in PCT Patent Application Publication No. WO 0647 Epherin receptor targeting agents are disclosed in 2013/138666 by Stronginet al. The inhibitors can have the PCT Patent Application Publication No. WO 2013/106824 by structure of Formula (A-3): Xiong et al. and include peptide targeting agents such as TNYLFSPNGPIA (SEQ ID NO: 9) or TNYLFSPNGPI ARAW (SEQIDNO: 10), YSAYPDSVPMMS (SEQID NO: (A-3) 11) or a cyclic peptide including a lactambridge. O R O 0648 Binding proteins for Axl are disclosed in PCT Patent 1'n Application Publication No. WO 2013/064684 by Beau-Lar is-N-N-N-N N Y Voretal. and include monoclonal antibodies. The protein Axl H H R4 binds to the ligand Gas6 and has been shown to regulate O 5 O i various cellular processes including cell proliferation, adhe Sion, migration and Survival in a large variety of cells in vitro. (0649. Wnt pathway inhibitors, used together with MAPK pathway inhibitors, are disclosed in PCT Patent Application wherein: (i) R is alkyl, cycloalkyl, heteroalicyclyl, aryl, or Publication No. WO 2013/086260 by Hoey et al. The Wnt heteroaryl; (ii) R is alkyl, cycloalkyl, or heteroalicyclyl; (iii) pathway inhibitor can be an antibody that binds a frizzled R is —Z-guanidine or —Z C(NH)—NH, wherein Z is (FZD) protein or a portion thereof. Alternatively, the Wnt aryl or heteroaryl; (iv) R is W C(NH)—NR', wherein pathway inhibitor can be a soluble receptor. The MAPK path W is aryl, thiophenyl, furanyl, oxazolyl pyrrolyl, or picoli way inhibitor can be a MEK inhibitor, such as BAY 86-9766 nyl, and wherein R' is hydrogen or hydroxyl (v) Rs is —U- (RDEA119), PD0325901, 01-1040, PD98059, PD318088, guanidine, wherein U is alkyl, cycloalkyl, heteroalicyclyl, GSK1 120212 (JTP-74057), AZD8330 (ARRY-424704), aryl, or heteroaryl; (vi) X is —CH2—, —CH2CH2—, AZD6244 (ARRY-142886), ARRY-162, ARRY-300, - CH-NHC(=O) , —CHCHC(=O)NH-, or -CHC AS703026, UO126, CH4987655, or TAK-733, or a Raf (=O)NH , and (vii) Y is —CH2. —S(=O) , or inhibitor such as GDC-0879, PLX-4720, PLX-4032 (vemu —C(=O)—. US 2016/0166546 A1 Jun. 16, 2016 52

0656 GPBP-1 inhibitors, which can optionally be used wherein: (A)-A"- is a single bond or lower alkylene; (B) the together with a p21 inhibitor, are disclosed in PCT Applica moiety of Subformula (A-4(b)) tion Publication No. WO 2014/006020 by Saus et al. The GPBP-1 inhibitors comprise three phenyl moieties linked by methylene linkages wherein the phenyl moieties are variously substituted. The p21 inhibitor can be, but is not limited to, p21-specific antibodies, p21-specific siRNA, p21-specific shRNA, p21-specific antisense nucleic acids, and p21 expres O sion inhibitors. The p21 expression inhibitor can be, but is not limited to, flavopiridol, temsirolimus, roXithromyin, ralox is cyclo(C5-Co.)alkene, cyclo(C-C)alkane, bicyclo(C-C) ifene hydrochloride, rifampicin, megestrol acetate, pri alkene, or bicyclo(C5-Co.)alkane; and (C) -A- is a single maquine diphosphate, losartan potassium, Valsartan, perhex bond or lower alkylene; and iline maleate, or nisoldipine. An inhibitor of ATP-binding 0663 (vi) X is O. NH, or S. Additional compounds include SC560; sulforaphane; curcumin; ketorolac; bromfenac; and cassette transporter 7 (ABCC7) can also be used; the inhibitor nepafenac. of ABCC7 can be, but is not limited to, ABCC7-specific 0664) Activatable antibodies targeting tumor specific antibodies, ABCC7-specific siRNA, ABCC7-specific markers are disclosed in United States Patent Application shRNA, ABCC7-specific antisense nucleic acids, and Publication No. 2014/0023664 by Lowman et al. The activat ABCC7 expression inhibitors. The ABCC7 expression able antibody can be selected from the group consisting of inhibitor can be, but is not limited to, 3-(3-trifluoromethyl) activatable antibodies (i) an activatable antibody comprising: phenyl-5-(4-carboxyphenyl)methylene-2-thioxo-4-thia a non-binding steric moiety (NB); a cleavable linker (CL): Zolidinone, 7,9-dimethyl-11-phenyl-6-(5-methylfuran-2-yl)- and an antibody or antibody fragment (AB) that binds spe 5,6-dihydro-pyrimido-4,5'-3,4pyrrolo 1,2-aquinoxaline cifically to a target, wherein: the NB comprises a polypeptide 8, 10-(7H.9H)-dione, lonidamine, chromanol 293B, that does not bind specifically to the AB; the CL is a polypep glibenclamide, and N-(2-naphthalenyl)-((3,5-dibromo-2,4- tide of up to 50 amino acids in length that comprises a Sub dihydroxyphenyl)methylene)glycine hydrazide. strate (S) for an enzyme; the CL is positioned in the activat able antibody such that in an uncleaved state, the NB 0657 PGE inhibitors are disclosed in U.S. Pat. No. 6,245, interferes with binding of the AB to the target and in a cleaved 790 to Hattorietal. and include oxazole compounds, includ state, the NB does not interfere with binding of the AB to the ing compounds of Formula (A-4) target; and the NB does not inhibit cleavage of the CL by the enzyme; (ii) an activatable antibody comprising: a non-bind ing steric moiety (NB); a cleavable linker (CL); and an anti body or antibody fragment (AB) that binds specifically to a (A-4) target, wherein: the NB comprises a polypeptide that does not R2 AF N R3 bind specifically to the AB; the CL is a polypeptide that comprises a Substrate (S) for an enzyme; the CL is positioned R’KX X--KCX n R4 in the activatable antibody such that in an uncleaved state, the NB interferes with binding of the AB to the target and in a cleaved state, the NB does not interfere with binding of the AB to the target; the NB does not inhibit cleavage of the CL wherein: by the enzyme; and the activatable antibody in the uncleaved 0658 (i)R’ is: lower alkyl substituted with hydroxyl, car state has the structural arrangement from N-terminus to C-ter boxyl, or protected carboxyl; carboxyl; protected carboxyl: minus as follows: NB-CL-AB or AB-CL-NB; and (iii) an carbamoyl; a heterocyclic group; cyano; hydroxyl; halo activatable antibody comprising: a binding partner (BP) for a lower alkylsulfonyloxy; lower alkoxy optionally substituted non-binding steric moiety (NB); a cleavable linker (CL); and with hydroxyl or carbamoyl: aryl substituted with carboxyl, an antibody or antibody fragment (AB) that binds specifically protected carboxyl, carbamoyl, or heterocyclyl; or amino to a target, wherein: the BP is a polypeptide that binds to the optionally substituted with protected carboxyl or lower alkyl NB when exposed thereto; the NB does not bind specifically sulfonyl: to the AB; the CL is a polypeptide that comprises a substrate (S) for an enzyme; the CL is positioned in the activatable 0659 (ii) R is hydrogen or lower alkyl: antibody Such that in an uncleaved state in the presence of the NB, the NB interferes with binding of the AB to the target and 0660 (iii) R is aryl optionally substituted with halogen; in a cleaved state, the NB does not interfere with binding of 0661 (iv) R' is aryl optionally substituted with halogen; the AB to the target and the BP does not interfere with binding of the AB to the target; and the NB and the BP do not inhibit 0662 (v) Q is a group of Subformula (A-4(a)) cleavage of the CL by the enzyme. 0665. When the improvement is made by use of bisantrene or a bisantrene derivative or analog for chemosensitization, (A-4(a)) the chemosensitization can include, but is not limited to: 0.666 (a) use as a chemosensitizer in combination with topoisomerase inhibitors; --O--A2 0667 (b) use as a chemosensitizer in combination with fraudulent nucleosides; 0668 (c) use as a chemosensitizer in combination with fraudulent nucleotides; US 2016/0166546 A1 Jun. 16, 2016

0669 (d) use as a chemosensitizer in combination with 0700 (m) use as a chemopotentiator in combination thymidylate synthetase inhibitors: with genistein; 0670 (e) use as a chemosensitizer in combination with 0701 (n) use as a chemopotentiator in combination signal transduction inhibitors; with etoposide; 0671 (f) use as a chemosensitizer in combination with 0702 (o) use as a chemopotentiator in combination cisplatin or platinum analogs; with cytarabine; 0672 (g) use as a chemosensitizer in combination with 0703 (p) use as a chemopotentiator in combination alkylating agents; with camptothecins; 0673 (h) use as a chemosensitizer in combination with 0704 (q) use as a chemopotentiator in combination anti-tubulin agents; with Vinca alkaloids; 0674) (i) use as a chemosensitizer in combination with 0705 (r) use as a chemopotentiator in combination with antimetabolites; 5-fluorouracil; 0675 () use as a chemosensitizer in combination with 0706 (s) use as a chemopotentiator in combination with berberine; curcumin; 0676 (k) use as a chemosensitizer in combination with 0707 (t) use as a chemopotentiator in combination with apigenin, roSmarinic acid; and 0677 (1) use as a chemosensitizer in combination with 0708 (u) use as a chemopotentiator in combination colchicine or analogs of colchicine; with mitoguaZone. 0678 (m) use as a chemosensitizer in combination with 0709 When the improvement is made by post-treatment genistein; management, the post-treatment management can be, but is 0679 (n) use as a chemosensitizer in combination with not limited to, a method selected from the group consisting of etoposide; 0710 (a) a therapy associated with pain management; 0711 (b) nutritional support; 0680 (o) use as a chemosensitizer in combination with 0712 (c) administration of an anti-emetic: cytarabine; 0713 (d) an anti-nausea therapy: 0681 (p) use as a chemosensitizer in combination with 0714 (e) administration of an anti-inflammatory agent; camptothecins; 0715 (f) administration of an antipyretic agent; 0682 (q) use as a chemosensitizer in combination with 0716 (g) administration of an immune stimulant; and Vinca alkaloids; 0717 (h) administration of a growth factor. 0683 (r) use as a chemosensitizer in combination with 0718 When the improvement is made by alternative medi 5-fluorouracil; cine/post-treatment Support, the alternative medicine/post 0684 (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: 0685 (t) use as a chemosensitizer in combination with 0719 (a) hypnosis: roSmarinic acid; and 0720 (b) acupuncture; 0686 (u) use as a chemosensitizer in combination with 0721 (c) meditation; mitoguaZone. 0722 (d) administration of a herbal medication created 0687 When the improvement is made by use of bisantrene either synthetically or through extraction; and or a bisantrene analog or derivative for chemopotentiation, 0723 (e) applied kinesiology. the chemopotentiation can include, but is not limited to: 0724. In one alternative, when the method is administra 0688 (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 0689 (b) use as a chemopotentiator in combination thetically or through extraction can be selected from the with fraudulent nucleosides; group consisting of: 0690 (c) use as a chemopotentiator in combination with 0725 (a) a natural anti-inflammatory; fraudulent nucleotides; 0726 (b) an immunostimulant; 0691 (d) use as a chemopotentiator in combination 0727 (c) an antimicrobial; and with thymidylate synthetase inhibitors; 0728 (d) a flavonoid, isoflavone, or flavone. 0692 (e) use as a chemopotentiator in combination with 0729. When the herbal medication created either syntheti signal transduction inhibitors; cally or through extraction is a natural anti-inflammatory, the 0693 (f) use as a chemopotentiator in combination with natural anti-inflammatory can be selected from the group cisplatin or platinum analogs; consisting of rhein and parthenolide. When the herbal medi 0694 (g) use as a chemopotentiator in combination cation created either synthetically or through extraction is an with alkylating agents; immunostimulant, the immunostimulant can be a product 0695 (h) use as a chemopotentiator in combination found in or isolated from Echinacea. When the herbal medi with anti-tubulin agents; cation created either synthetically or through extraction is an 0696 (i) use as a chemopotentiator in combination with anti-microbial, the anti-microbial can be berberine. When the antimetabolites; herbal medication created either synthetically or through 0697 () use as a chemopotentiator in combination with extraction is a flavonoid or flavone, the flavonoid, isoflavone, berberine; or flavone can be selected from the group consisting of api 0698 (k) use as a chemopotentiator in combination genin, genistein, apigenenin, genistein, genistin, 6"-O-malo with apigenin, nylgenistin, 6"-O-acetylgenistin, daidzein, daidzin, 6"-O- 0699 (1) use as a chemopotentiator in combination with malonyldaidzin, 6"-O-acetylgenistin, glycitein, glycitin, colchicine or analogs of colchicine; 6"-O-malonylglycitin, and 6-O-acetylglycitin. US 2016/0166546 A1 Jun. 16, 2016 54

0730. When the improvement is made by a bulk drug 0781 Suitable cytochrome P450 inhibitors include, but product improvement, the bulk drug product can be, but is not are not limited to, 1-aminobenzotriazole, N-hydroxy-N-(4- limited to, a bulk drug product improvement selected from the butyl-2-methylphenyl)formamidine, ketoconazole, methox group consisting of salen, metyrapone, roquefortine C, proadifen, 2.3.4.5'-tet 0731 (a) preparation as a free base form: ramethylstilbene, and troleandomycin. (0732 (b) salt formation: 0733 (c) preparation as a homogeneous crystalline 0782. Suitable MDR inhibitors include, but are not limited Structure: to, 5'-methoxyhydnocarpin, INF240, INF271, INF277, INF 0734 (d) amorphous structure; 392, INF 55, reserpine, and GG918. MDR inhibitors are 0735 (e) preparation as a pure isomer; described in M. Zloh & S. Gibbons, “Molecular Similarity of (0736 (f) increased purity; MDR9 Inhibitors.” Int. J. Mol. Sci. 5:37-47 (2004), incorpo 0737 (g) preparation with lower residual solvent con rated herein by this reference. Other MDR inhibitors, tent; and described therein as MDR reversal agents, suitable for use 0738 (h) preparation with lower residual heavy metal with bisantrene or a derivative or analog thereof, are disclosed COntent. in U.S. Pat. No. 5,550,149 to Powell et al., U.S. Pat. No. 5,561,141 to Powell et al., and U.S. Pat. No. 5,639,887 to 0739 When the improvement is made by use of a diluent, Powell et al., all of which are incorporated herein by this the diluent can be, but is not limited to, a diluent selected from reference; these compounds are bicyclic amines including, the group consisting of but not limited to, C.-(3,4-dimethoxyphenyl)-1,3-dihydro-5, 0740 (a) an emulsion; 6-dimethoxy-O-(4-methyl phenyl)thiol-2H-isoindole-2- 0741 (b) dimethylsulfoxide (DMSO); heptanenitrile, 2-7-(3,4-dimethoxyphenyl)-7-(4-meth 0742 (c) N-methylformamide (NMF) ylphenyl)thioheptyl-2,3-dihydro-5,6-dimethoxy-1H 0743 (d) dimethylformamide (DMF) isoindole, 5.6 dichloro-O-(3,4-dimethoxyphenyl)-1,3- 0744 (e) dimethylacetamide (DMA); dihydro-O-(4-methylphenyl)thio-2-H-isoindole-2- 0745 (f)ethanol: heptanenitrile, C.-(3,4-dimethoxyphenyl)-1,3-dihydro-5-2- 0746 (g) benzyl alcohol; (1H-imidazol-1-yl)ethoxy-6-methoxy-O-(4-methylphenyl) 0747 (h) dextrose-containing water for injection; thio-2H-isoindole-2-heptanenitrile dihydrochloride, C.-(3,4- 0748 (i) Cremophor; dimethoxyphenyl)-1,3-dihydro-5,6-dimethoxy-O-(4- 0749 () cyclodextrins; and methylphenyl)thio-2H-isoindole-2-heptanoic acid methyl (0750 (k) PEG. ester, C.-(cyclohexylthio)-O-(3,4-dimethoxyphenyl)-1,3-di 0751. 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)- 0752 (a) an emulsion; heptanenitrile, C.-(4-chlorobutyl)-3,4-dimethoxy-O-(4- (0753) (b) DMSO, methylphenyl)-thiobenzeneacetonitrile, C.-(3-chloro-2- (0754) (c) NMF; methylpropyl)-3,4-dimethoxy-O-(4-methyl-phenyl) thio (0755 (d) DMF; benzeneacetonitrile, C.-(11-bromoundecyl)-3,4-dimethoxy (0756 (e) DMA; C-(4-methylphenyl)-thiobenzeneacetonitrile, C-(5- (0757 (f)ethanol: chloropentyl)-3,4-dimethoxy-O-(4-methylphenyl)-thio (0758 (g) benzyl alcohol: benzeneacetonitrile, C.-(5-bromooctyl)-3,4-dimethoxy-C.- 0759 (h) dextrose-containing water for injection; (4-methylphenyl)-thiobenzeneacetonitrile, C-(5- 0760 (i) Cremophor; iodopentyl)-3,4-dimethoxy-O-(4-methyl phenyl)-thio 0761 (i) PEG; and benzeneacetonitrile, C-(5-aminopentyl)-3,4-dimethoxy-C.- 0762) (k) salt systems. (4-methyl phenyl)-thiobenzeneacetonitrile, C-(5- 0763. When the improvement is made by use of an excipi chlorohexyl)-3,4-dimethoxy-O-(4-methyl phenyl)-thio ent, the excipient can be, but is not limited to, an excipient benzeneacetonitrile, 4-4-chloro-1-(4-methylphenyl)thio selected from the group consisting of: butyl-1,2-dimethoxybenzene, 4-6-bromo-1-(4- 0764 (a) mannitol; methylphenyl)thiohexyl-1,2-dimethoxybenzene, C-3,4- 0765 (b) albumin; dimethoxyphenyl)-3-(hydroxymethyl)-O-(4-methylphenyl) 0766 (c) EDTA; thiobenzenepropanenitrile, 3-(chloromethyl)-C.- 0767 (d) sodium bisulfite: (dimethoxyphenyl)-O-(4-methylphenyl)thio 0768 (e) benzyl alcohol: benzenepropanenitrile, 4-6-bromo-1-(4-methylphenyl) 0769 (f) carbonate buffers: thioheptyl-1,2-dimethoxybenzene, 5-7-bromo-1-(4- (0770 (g) phosphate buffers; methylphenyl)thioheptyl-2-methoxy-phenoxy(1.2- (0771) (h) PEG: dimethylethyl)dimethylsilane, C.-(5-chloropentyl)-O- (0772 (i) vitamin A; (cyclohexylthio)-3,4-dimethoxybenzeneacetonitrile, C.-(5- (0773) () vitamin D; aminopentyl)-O-(cyclohexylthio)-3,4- (0774 (k) vitamin E: dimethoxybenzeneacetonitrile, 5-6-bromo-1-(4- (0775 (1) esterase inhibitors: methylphenyl)thiohexyl-1,3-benzodioxole, 1-6-bromo-1- (0776 (m) cytochrome P450 inhibitors; (methylphenyl)thiohexyl)-4-(trifluoromethoxy)benzene, (0777 (n) multi-drug resistance (MDR) inhibitors: 1-6-bromo-1-(4-fluorophenyl)hexylthiol-4-methylben 0778 (o) organic resins; and Zene, C.-(5-bromopentyl)-3,4-dimethoxy-O-(4-methylphe (0779 (p) detergents. nyl)-thiobenzeneacetonitrile, (7-bromo-1-phenylheptyl) 0780 Suitable esterase inhibitors include, but are not lim thiobenzene, C.-(5-bromopentyl)-O-(cyclohexylthio)-3,4- ited to, ebelactone A and ebelactone B. dimethoxybenzeneacetonitrile, 7-bromo-2-(3,4- US 2016/0166546 A1 Jun. 16, 2016

dimethoxyphenyl)-2-(2-pyridylthio)-heptanonitrile, and hours; the shelf temperature is again adjusted to -5°C. and C.-(5-hydroxypentyl)-3,4-dimethoxy-O-(methylphenyl)- drying is carried out for at least 5 hours. thiobenzeneacetic acid methyl ester. U.S. Pat. No. 6,372.775 0807 (7) Secondary drying is started after the condenser to Rabindran et al., incorporated by this reference, discloses (set at -60° C.) and vacuum are turned on. In secondary the use of fumitremorgin A, B, and Cand diketopiperazines as drying, the shelf temperature is controlled at +5°C. for 1 to 3 MDR inhibitors. hours, typically 1.5 hours, then at 25° C. for 1 to 3 hours, 0783 Suitable organic resins include, but are not limited typically 1.5 hours, and finally at 35-40°C. for at least 5 to, a partially neutralized polyacrylic acid, as described in hours, typically for 9 hours, or until the product is completely U.S. Pat. No. 8,158,616 to Rodgers et al., incorporated herein dried. by this reference. 0808 (8) Break the vacuum with filtered inert gas (e.g., 0784 Suitable detergents include, but are not limited to, nitrogen). Stopper the vials in the lyophilizer. nonionic detergents such as a polysorbate or apoloxamer, and (0809 (9) Vials are removed from the lyophilizer chamber are described in PCT Patent Application Publication No. and sealed with aluminum flip-offseals. All vials are visually WO/1997/039768 by Bjornet al., incorporated herein by this inspected and labeled with approved labels. reference. 0810 Immediate-release formulations are described in 0785. When the improvement is made by use of a dosage U.S. Pat. No. 8,148,393 to van Dalen et al., incorporated form, the dosage form can be, but is not limited to, a dosage herein by this reference. Immediate-release formulations can form selected from the group consisting of: include, for example, conventional film-coated tablets. 0786 (a) tablets; 0811 Slow-release formulations are described in U.S. Pat. 0787 (b) capsules: No. 8,178,125 to Wen et al., incorporated herein by this 0788 (c) topical gels: reference. Slow-release formulations can include, for 0789 (d) topical creams: example, microemulsions or liquid crystals. 0790 (e) patches: 0812 Controlled-release formulations are described in 0791 (f) suppositories: U.S. Pat. No. 8,231,898 to Oshlacket al., incorporated herein 0792 (g) lyophilized dosage fills; by this reference. Controlled-release formulations can 0793 (h) immediate-release formulations: include, for example, a matrix that includes a controlled 0794 (i) slow-release formulations: release material. Such a controlled-release material can 0795 () controlled-release formulations: include hydrophilic and/or hydrophobic materials, such as 0796 (k) liquid in capsules; and gums, cellulose ethers, acrylic resins, protein derived mate 0797 (1) liposomal formulations. rials, waxes, shellac, and oils such as hydrogenated castor oil 0798 Formulation of pharmaceutical compositions in tab or hydrogenated vegetable oil. However, any pharmaceuti lets, capsules, and topical gels, topical creams or Supposito cally acceptable hydrophobic or hydrophilic controlled-re ries is well known in the art and is described, for example, in lease material which is capable of imparting controlled-re United States Patent Application Publication No. 2004/ lease of the amonafide or derivative or analog thereof may be used in accordance with the present invention. Preferred con 0023290 by Griffin et al., incorporated herein by this refer trolled-release polymers include alkylcelluloses such as eth CCC. ylcellulose, acrylic and methacrylic acid polymers and 0799 Formulation of pharmaceutical compositions as copolymers, and cellulose ethers, especially hydroxyalkyl patches Such as transdermal patches is well known in the art celluloses (e.g., hydroxypropylmethylcellulose) and car and is described, for example, in U.S. Pat. No. 7,728,042 to boxyalkylcelluloses. Preferred acrylic and methacrylic acid Eros et al., incorporated herein by this reference. polymers and copolymers include methyl methacrylate, 0800 Lyophilized dosage fills are also well known in the methyl methacrylate copolymers, ethoxyethyl methacrylates, art. One general method for the preparation of Such lyo cyanoethyl methacrylate, aminoalkyl methacrylate copoly philized dosage fills, applicable to dibromodulcitol and mer, poly(acrylic acid), poly(methacrylic acid), methacrylic derivatives thereof, comprises the following steps: acid alkylamine copolymer, poly(methyl methacrylate), poly 0801 (1) Dissolve the drug in water for injection pre (methacrylic acid) (anhydride), polymethacrylate, polyacry cooled to below 10°C. Dilute to final volume with cold water lamide, poly(methacrylic acid anhydride), and glycidyl meth for injection to yield a 40 mg/mL Solution. acrylate copolymers. 0802 (2) Filter the bulk solution through an 0.2-lum filter 0813 Aliposomal formulation suitable for bisantrene or a into a receiving container under aseptic conditions. The for derivative or analog thereof comprises Small unilamellar or mulation and filtration should be completed in 1 hour. multilamellar liposomes of size range between 0.01 and 100 (0803 (3) Fill nominal 1.0 mL filtered solution into steril uM, and between about 50-95% liposome-entrapped bisant ized glass vials in a controlled target range under aseptic rene, composed of hydrogenated Soy phosphatidylcholine, conditions. distearoyl phosphatidylglycerol, and cholesterol of natural or 0804 (4) After the filling, all vials are placed with rubber synthetic origin lipids, in aqueous solution which can be stoppers inserted in the “lyophilization position' and loaded reconstituted from a lyophilized form to an injectable lipo in the pre-chilled lyophilizer. For the lyophilizer, shelf tem Some Suspension. The composition is prepared by reconsti perature is set at +5°C. and held for 1 hour; shelf temperature tuting a lyophilized bisantrenefliposome composition to a is then adjusted to -5° C. and held for one hour, and the liposome concentrate, then diluting the concentrate for condenser, set to -60° C., turned on. parenteral administration for the treatment of cancer. (0805 (5) The vials are then frozen to 30° C. or below and 0814. When the improvement is made by use of dosage held for no less than 3 hours, typically 4 hours. kits and packaging, the dosage kits and packaging can be, but 0806 (6) Vacuum is then turned on, the shelf temperature are not limited to, dosage kits and packaging selected from is adjusted to -5°C., and primary drying is performed for 8 the group consisting of the use of amber vials to protect from US 2016/0166546 A1 Jun. 16, 2016 56 light and the use of stoppers with specialized coatings to ethanolamine, polyvinyl alcohol (PVA), polyvinylpyrroli improve shelf-life stability. Other forms of dosage kits and done (PVP), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer packaging are also known in the art and can include, for with ethylene oxide and formaldehyde (also known as tylox example, vials, ampules, jars, intravenous bags, or other con apol, Superione, and triton), poloxamers (e.g., Pluronics tainers. F68(R) and F108(R), which are block copolymers of ethylene 0815. When the improvement is made by use of a drug oxide and propylene oxide); poloxamines (e.g., Tetronic delivery system, the drug delivery system can be, but is not 908(R), also known as Poloxamine 908R, which is a tetrafunc limited to, a drug delivery system selected from the group tional block copolymer derived from sequential addition of consisting of: propylene oxide and ethylene oxide to ethylenediamine 0816 (a) oral dosage forms: (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 0817 (b) nanocrystals; 1508(R) (T-1508) (BASF Wyandotte Corporation), dialkylest 0818 (c) nanoparticles; ers of sodium sulfosuccinic acid (e.g., Aerosol OTR), which is 0819 (d) cosolvents; a dioctyl ester of Sodium Sulfo Succinic acid (American 0820 (e) slurries: Cyanamid)), dioctyl sodium sulfosuccinate (DOSS), docu 0821 (f) syrups; sate sodium (Ashland Chem. Co., Columbus, Ohio); Duponol 0822 (g) bioerodible polymers: P(R), which is a sodium lauryl sulfate (DuPont); Triton 0823 (h) liposomes; X-200R, which is an alkyl aryl polyether sulfonate (Rohm 0824 (i) slow-release injectable gels: and Haas); Crodestas F-110R, which is a mixture of sucrose 0825 () microspheres; Stearate and Sucrose distearate (Croda Inc.), p-isononylphe 0826 (k) amphiphilic block copolymer systems; noxy-poly-(glycidol), also known as Olin-IOG(R) or Surfac 0827 (1) emulsion vehicles comprising an emulsion of tant 10-G(R) (Olin Chemicals, Stamford, Conn.); Crodestas C-tocopherol stabilized by biocompatible surfactants; SL-40R (Croda, Inc.); and SA9CHCO, which is CH-CH 0828 (m) biodegradable polymer compositions con (CON(CH)-0CH (CHOH)(CHOH), (Eastman Kodak taining phosphorus and desaminotyrosyl L-tyrosine Co.); decanoyl-N-methylglucamide; n-decyl B-D-glucopyra linkages in the polymer backbone; noside; n-decyl B-D-maltopyranoside; n-dodecyl B-D-glu 0829 (n) substantially anhydrous injectable semi-solid copyranoside; n-dodecyl B-D-maltoside; heptanoyl-N-me compositions comprising a water immiscible fatty acid thyl-glucamide; n-heptyl-B-D-glucopyranoside; n-heptyl matrix and a cytostatic agent; B-D-thioglucoside; n-hexyl B-D-glucopyranoside; nonanoyl 0830 (o) lipophilic vehicles; N-methylglucamide; n-nonanoyl B-D-glucopyranoside; 0831 (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. 0832 (q) pH-dependent carriers that include a mono 0837 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 0833 (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, 0834 (s) nonpegylated liposomes. N-methylformamide, N,N-dimethylformamide, N-methy 0835 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. 0838 Slurries for use in pharmaceutical formulations are 0836 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 0839 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 0840 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 US 2016/0166546 A1 Jun. 16, 2016 57

6 months as measured by SEC. Useful bioerodible polymers 0847 Yet another drug delivery system potentially useful include polyesters, such as poly(caprolactone), poly(glycolic with bisantrene and analogs and derivatives thereof are the acid), poly(lactic acid), and poly(hydroxybutryate); polyan pharmaceutically acceptable Substantially anhydrous inject hydrides, such as poly(adipic anhydride) and poly(maleic able semi-solid compositions described in U.S. Pat. No. anhydride); polydioxanone; polyamines; polyamides; poly 5,573,781 to Brown et al., incorporated herein by this refer urethanes; polyesteramides; polyorthoesters; polyacetals; ence. The compositions comprise a water immiscible fatty polyketals; polycarbonates; polyorthocarbonates; polyphos acid matrix and a cytostatic agent, Such as bisantrene or a phaZenes; poly(malic acid); poly(amino acids); polyvi derivative or analog thereof. Typically, the matrix material nylpyrrolidone; poly(methyl vinyl ether); poly(alkylene will be fatty acid ester compositions, having the desired flow oxalate); poly(alkylene Succinate); polyhydroxycellulose; able and Viscosity characteristics, either as a natural charac chitin; chitosan; and copolymers and mixtures thereof. teristic or as a result of additives. Suitable lipid compositions 0841 Liposomes are well known as drug delivery will comprise fatty acid esters, either a single fatty acid ester vehicles. Liposome preparation is described in European or a mixture of fatty acid esters, which are biodegradable in Patent Application Publication No. EP 1332755 by Wenget the host, by themselves or in combination with one or more al., incorporated herein by this reference. Nonpegylated lipo physiologically acceptable thickening agents, particularly somes for drug delivery, specifically delivery of doxorubicin, are described in J. Baselga et al., “Phase III Trial of Nonp fatty acid salts or synthetic and/or longer chain fatty acid egylated Liposomal Doxorubicin in Combination with Tras esters, e.g. waxy esters. Suitable fatty acid ester compositions tuzumab and Paclitaxel in HER2-Positive Metastatic Breast will comprise a single or mixture offatty acid esters, and may Cancer.” Ann. Oncol. 25: 592-598 (2014), incorporated comprise two or more different fatty acid esters, usually not herein by this reference. more than ten different fatty acid esters. Suitable fatty acid 0842 Slow release injectable gels are known in the art and esters include mono-, di- and tri-glycerides, as well as mono are described, for example, in B. Jeong et al., “Drug Release and dibasic acid esters, e.g. ethyl oleate, isopropyl myristate, from Biodegradable Injectable Thermosensitive Hydrogel of or other such esters, where the carboxylic acid group will PEG-PLGA-PEG Triblock Copolymers,” J. Controlled usually have at least 6, more usually at least 8 carbon atoms, Release 63: 155-163 (2000), incorporated herein by this ref preferably at least about 12 carbon atoms, and may be satu CCC. rated or unsaturated, usually having not more than 3 sites of 0843. The use of microspheres for drug delivery is known ethylenic unsaturation per acid moiety, and the fatty acid in the art and is described, for example, in H. Okada & H. esters will have at least 8 carbon atoms and not more than Taguchi. “Biodegradable Microspheres in Drug Delivery.” about 60 carbonatoms, usually not more than about 50 carbon Crit. Rev. Ther. Drug Carrier Sys. 12: 1-99 (1995), incorpo atoms. Of particular interest are glycerides having fatty acids rated herein by this reference. offrom about 12 to 24 carbonatoms, saturated or unsaturated, 0844. Another drug delivery system potentially usable naturally occurring or synthetic. The alcohols will usually with bisantrene and analogs and derivatives thereof is the have from about 1 to 6, usually 1 to 5, more usually 1 to 3 amphiphilic block copolymer system described in U.S. Pat. hydroxyl groups and not more than two ether groups and will No. 7,311.901 to Seo et al., incorporated herein by this ref usually be from 2 to 6, more usually 2 to 3 carbon atoms. The erence. In general, the amphiphilic block copolymer com fatty acid esters of the subject invention will not include esters prises a hydrophilic block and a hydrophobic block with a which are modified with additional functional groups which terminal hydroxyl group, wherein the terminal hydroxyl increase the water Solubility properties of the esters, e.g. Such group of the hydrophobic block is substituted with a toco as polyoxyethylated castor oil or other alkyleneoxy modified pherol or cholesterol group. U.S. Pat. No. 7,311.901 to Seo et fatty acid esters. The fatty acid esters may be added as par al. further describes polymeric compositions capable of tially pure fractions or complex mixtures Such as Saturated or forming stable micelles in an aqueous solution, comprising partially Saturated glycerides, e.g. oils and fats. Any carboxy the amphiphilic block copolymerand a polylactic acid deriva lic acid ester oil which is physiologically acceptable can be employed as the matrix component, where the oil may be a tive wherein one or both ends of the polylactic acid derivative single or combination of oils, which may or may not be are covalently bound to at least one carboxyl group. partially hydrogenated. Specific physiologically acceptable 0845 Yet another drug delivery system potentially useful oils of interest include vegetable oils, such as sesame, peanut, with bisantrene and analogs and derivatives thereof is the Soybean, cottonseed, corn, olive, persic, castor, and the like. emulsion vehicle described in U.S. Pat. No. 6,485,383 to Lambert et al., incorporated herein by this reference. In gen 0848. Lipophilic vehicles are described in U.S. Pat. No. eral, this emulsion vehicle comprises an emulsion of C-toco 7.148.211 to Mazess et al., incorporated herein by this refer pherol stabilized by biocompatible surfactants. Also included ence. These lipophilic vehicles include polysorbate 20 as a in the emulsion is pegylated vitamin E. Pegylated C-toco non-ionic Solubilizer, butylated hydroxytoluene as a lipo pherol includes polyethylene glycol Subunits attached by a philic antioxidant, optionally, ethanol, and an aqueous Succinic acid diester at the ring hydroxyl of vitamin E and vehicle. Other alcohols or polyols can be used in place of or serves as a primary Surfactant and a stabilizer as well as a together with ethanol. Other non-ionic solubilizers can be secondary solvent in emulsions of C-tocopherol. used. Other lipophilic antioxidants can be used. 0846. Yet another drug delivery system potentially useful 0849. The use of pH-dependent carriers that include a with bisantrene and analogs and derivatives thereof are the compound that includes at least one ionizable group is dis biodegradable polymer compositions described in U.S. Pat. closed in United States Patent Application Publication No. No. 6,238.687 to Mao et al., incorporated herein by this 2014/0094526 by Marathi et al. The at least one ionizable reference. These polymers contain phosphorus and desami group can be a carboxylic acid group, hydroxy group, amino notyrosyl L-tyrosine linkages in the polymer backbone. group, amide groups, or other similarly ionizable groups. The US 2016/0166546 A1 Jun. 16, 2016

carriers are immiscible in water or soluble in oils, and, for Publication No. WO 2003/070823 by Elmaleh et al., incor weak acids, the ionizable groups have a pKa value greater porated herein by this reference. than or equal to about pH 3.5. 0880 Multivalent linkers are known in the art and are 0850. The use of pH-dependent carriers that include a described, for example, in United States Patent Application monocarboxylic acid having at least 8 carbons and less than Publication No. 2007/0207952 by Silva et al., incorporated about 10% by weight of Zwitterionic phospholipids is dis herein by this reference. For example, multivalent linkers can closed in United States Patent Application Publication No. contain a thiophilic group for reaction with a reactive cys 2014/0094439 by Marathi et al. teine, and multiple nucleophilic groups (such as NH or OH) 0851. The use of liposomes comprising the bisantrene or or electrophilic groups (such as activated esters) that permit the derivative or analog thereof followed by administration of attachment of a plurality of biologically active moieties to the a lipid nanoparticle comprising a triggering agent is disclosed linker. in PCT Patent Application Publication No. WO 2013/066903 0881 Conjugates to fatty acids are described in U.S. Pat. by Yang et al. The triggering agent can be non-ionic, such as No. 7,235,538 to Webb et al., incorporated herein by this TPGS or polyoxyethylene stearate. reference. The fatty acid is preferably a C-C unbranched 0852. When the improvement is made by use of a drug fatty acid such as caprylic acid, capric acid, lauric acid, myris conjugate form, the drug conjugate form can be, but is not tic acid, palmitic acid, palmitoleic acid, Stearic acid, oleic limited to, a drug conjugate form selected from the group acid, vaccinic acid, linoleic acid, C-linolenic acid, eleostearic consisting of: acid, B-linolenic acid, gondoic acid, dihomo-y-linolenic acid, 0853 (a) a polymer system; arachidonic acid, eicopentaenoic acid, docosenoic acid, 0854 (b) polylactides: docosatetraenoic acid, docosapentaenoic acid, docosa 0855 (c) polyglycolides: hexaenoic acid, and nervonic acid. 0856 (d) amino acids; 0882 Conjugates to fatty alcohols are disclosed in U.S. 0857 (e) peptides; Pat. No. 7,816,398 to Swindell et al., incorporated herein by 0858 (f) multivalent linkers; this reference. The fatty alcohol conjugates have the general 0859 (g) conjugates to fatty acids; structure RO C(O)—OX, where X is an antineoplastic 0860 (h) conjugates to fatty alcohols; agent moiety of an antineoplastic agent XOH, R is a Cs-C 0861 (i) conjugates to elastin-like peptide; fatty acid group of a fatty alcohol ROH wherein R is one of the 0862 () conjugates with polyclonal or monoclonal following fatty acids: octanoic (caprylic); nonanoic (pelar antibodies, proteins, or peptides: gonic); decanoic (capric), undecanoic (hendecanoic), dode 0863 (k) conjugates with cell-binding agents through a canoic (lauric); tridecanoic, tetradecanoic (myristic); penta charged or pro-charged cross-linker, decanoic; hexadecanoic (palmitic); heptadecanoic 0864 (1) conjugates to antibodies targeted to tumor (margaric); octadecanoic (stearic); 12-hydroxy Stearic; nona markers; decanoic, eicosanoic (arachidic); heneicosanoic; docosanoic 0865 (m) biodegradable polymer-bioactive moiety (behenic); tricosanoic, tetracosanoic (lignoceric); 10-unde conjugates: cenoic (hendecenoic); 11-dodecenoic; 12-tridecenoic; 9-tet 0866 (n) conjugates with 2-nitroimidazole compounds radecenoic (myristoleic); 9-trans-tetradecenoic (myriste with a secondary basic nitrogen atom and a linker; laidic); 10-pentadecenoic, 10-trans-pentadecenoic; 0867 (o) conjugates with ladder frame polyether com 9-hexadecenoic (palmitoleic); 8-trans-hexadecenoic (palm pounds, including those derived from brevenal, brevisin, itelaidic); 10-heptadecenoic, 10-trans-heptadecenoic, 6-oc tamulamide, brevetoxins, hemibrevetoxins, gambierols, tadecenoic (petroselinic), 6-trans-octadecenoic (petrose and gambieric acids; laidic); 8-octadecenoic (oleic): 9-11-octadecenoic (vaccenic); 11-trans-octadecenoic (transvaccenic); 9-cis-12 0868 (p) conjugates to antibodies having one or more hydroxy-octadecenoic (ricinoleic); 9-trans-12-hydroxy-octa non-natural amino acid residues at specific positions in decenoic (ricinelaidic); 7-nonadecenoic; 7-trans-nonade the heavy or light chains; cenoic, 10-nonadecenoic, 10-trans-nonadecenoic, 10-13 0869 (q) conjugates to a sialoadhesin binding moiety; nonadecadienoic, 10-13-trans-nonadecadienoic, 8-12 0870 (r) pheophorbide-C conjugates; octadecadienoic (linoleic); 9-trans-12-trans octadecadienoic 0871 (s) conjugates to multi-component nanochains: (linoelaidic); octadecadienoic (conjugated): 9-12-15-octade 0872 (t) conjugates to activatable antibodies that catrienoic (linolenic), 6-9-12-octadecatrienoic (Y-linolenic); include a masking moiety, a cleavable moiety, and an 11-trans-eicosenoic, 8-eicosenoic, 11-eicosenoic; 5-eicose antibody binding specifically to interleukin-6: noic; 11-14-eicosadienoic, 8-11-14-eicosatrienoic (homo-y- 0873 (u) conjugates including hydrophilic linkers; linolenic); 11-14-17-eicosatrienoic; 5-8-11-14-eicosatet 0874) (v) conjugates to antibodies specific for p97; raenoic (arachidonic); 5-8-11-14-17-eicosapentaenoic; 7-10 0875 (w) conjugates including a modified amino acid 13-16-19-docosapentaenoic: 13-docosenoic (erucic); incorporating an azido group; 13-transdocosenoic (brassidic); 13-16-docosadienoic; 0876 (x) conjugates to albumin; and 13-16-19-docosatrienoic, 7-10-13-16-docosatetraenoic, 4-7- 0877 (y) conjugates to folate. 10-13-16-19-docosahexaenoic (docosahexaenoic; DHA); 0878 Polylactide conjugates are well known in the art and 12-heneicosenoic, 12-15-heneicosadienoic; 14-tricosenoic; are described, for example, in R. Tong & C. Cheng, “Con and 15-tetracosenoic (nervonic). trolled Synthesis of Camptothecin-Polylactide Conjugates 0883 Conjugates to elastin-like peptides are described in and Nanoconjugates. Bioconjugate Chem. 21: 111-121 U.S. Pat. No. 8,252.740 to Raucher et al., incorporated herein (2010), incorporated by this reference. by this reference. Delivery by these conjugates is thermally 0879 Polyglycolide conjugates are also well known in the activated. In one alternative, the conjugate comprises: (i) the art and are described, for example, in PCT Patent Application cell-penetrating peptide Tat; (ii) an elastin-like peptide for US 2016/0166546 A1 Jun. 16, 2016 59 thermal targeting; (iii) a GFLG (SEQID NO: 12) peptide as is 0 or 1; n is 1; and T is a carrier moiety as described below. a cleavable linker; (iv) a cysteine residue; and (v) bisantrene Carrier moieties may be derived from polyclonal antibodies or a derivative of bisantrene. raised against tumor associated antigens; or from monoclonal 0884 Conjugates with polyclonal or monoclonal antibod antibodies binding to antigens preferentially or selectively ies, proteins, or peptides are disclosed in U.S. Pat. No. 8,389, expressed on tumor cell populations; or from natural or 697 to Beria et al., incorporated herein by this reference. recombinant peptides or proteins or growth factors preferen These compounds incorporating bisantrene or a derivative or tially or selectively binding to tumor cells; or from natural or analog of bisantrene are characterized by the general formula: synthetic polymeric carriers such as polylysine, polyglutamic acid, polyaspartic acid and their analogues and derivatives, or Bis-L-Z-T, Such as dextran or other polymeric carbohydrate analogues wherein: (i) Bis is a residue of bisantrene or a derivative or and their derivatives; or from Synthetic copolymers such as analog thereof; (ii) L is a linker; (iii) Z is a spacer; (iv) m is an those derived from N-(2-hydroxypropyl)methacrylamide integer from 1 to 30; and (v) T is a carrier Such as a protein, (HPMA), or from poly(amino acid) copolymers such as poly peptide, monoclonal or polyclonal antibody or a chemically (GluNa, Ala, Tyr) which are useful as targetable drug-carriers modified moiety thereof suitable to be attached to the Bis for lung tissue. The carrier portion may be also derived from L-Z moiety or moieties, or a polymeric character. In these portions of the above mentioned peptides or proteins obtained conjugates, the linker L is typically is —CH2O— —N(R), through recombinant DNA techniques. (C-C2 alkylene)-X'. - N(R)-, - N(R), (C-C2 alky 0885 Conjugates with cell-binding agents through a lene)-, —N(R), (C-C alkenylene)-, N(R)(CH2CH2O), . charged or pro-charged cross-linker are disclosed in United or the structures States Patent Application Publication No. 2009/0274713 by Chari et al., incorporated herein by this reference. In general, the cross-linkers possess three elements: (i) a Substituent that is either charged or that will become charged when a conju gate employing the cross-linker is metabolized in Vivo: the charge can be either anionic, which can be, but is not limited to, carboxylate, Sulfonate, or phosphate, or cationic, which 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 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 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 is an optional spacer selected from —CHC(O)—, —CHC hormones, growth factors, vitamins, nutrient-transport mol (O)NR(C-C alkylene)-, and the structures ecules Such as transferrin, or any other cell-binding agent. 0886 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. 0887 Biodegradable polymer-bioactive moiety conju gates are disclosed in U.S. Pat. No. 8,535,655 to O'Shea et al. 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, US 2016/0166546 A1 Jun. 16, 2016 60 p-phenylene diisocyanate, 2,4-toluene diisocyanate, 2,6-tolu Such conjugates can include 6-maleimidocaproyl hydrazone ene diisocyanate, 1.6-hexamethylene diisocyanate, 1,4-hex derivatives of bisantrene orderivatives or analogs thereof; the amethylene diisocyanate, 1.3-cyclohexane diisocyanate, 1,4- 6-maleimidocaproyl hydrazone moiety binds selectively to cyclohexane diisocyanate, hexahydro-toluene diisocyanate the cysteine-34 amino acid residue of albumin via the male and its isomers, isophorone diisocyanate, dicyclo-hexyl imide moiety. The bisantrene orderivative or analog thereof is methane diisocyanates, 1.5-napthylene diisocyanate, 4,4'- then released from the albumin carrier after cleavage of the diphenylmethane diisocyanate, 2,4'-diphenylmethane diiso acid-sensitive hydraZone linker in the acidic environment of cyanate, 4,4'-biphenylene diisocyanate, 3,3'-dimethoxy-4,4'- tumors. The use of conjugates linked to folate is disclosed in biphenylene diisocyanate, 3,3'-dimethyl-diphenylpropane-4, J. Clarhaut et al., “A Galactosidase-Responsive Doxorubicin 4'-diisocyanate, 2,4,6-toluene triisocyanate, 4,4'-dimethyl Folate Conjugate for Selective Targeting of Acute Myelog diphenylmethane-2.2".5.5'-tetraisocyanate, and alkyl esters enous Leukemia Blasts, Leukemia Res. 37: 948-955 (2013), of lysine diisocyanate. incorporated herein by this reference. 0888 Conjugates with 2-nitroimidazole compounds with 0898 Suitable reagents for cross-linking many combina a secondary basic nitrogen atom and a linker are disclosed in tions of functional groups are known in the art. For example, U.S. Pat. No. 8,518,371 to Lee et al. electrophilic groups can react with many functional groups, 0889 Conjugates with ladder frame polyether compounds including those present in proteins or polypeptides. Various are disclosed in United States Patent Application Publication combinations of reactive amino acids and electrophiles are No. 2014/00736.04 by Bourdelais et al. The polyether com known in the art and can be used. For example, N-terminal pounds can be derived from brevenal, brevisin, tamulamide, cysteines, containing thiol groups, can be reacted with halo brevetoxins, hemibrevetoxins, gambierols, and gambieric gens or maleimides. Thiol groups are known to have reactiv acids. ity with a large number of coupling agents, such as alkyl 0890 Conjugates to antibodies having one or more non halides, haloacetyl derivatives, maleimides, aziridines, acry natural amino acid residues at specific positions in the heavy loyl derivatives, arylating agents such as aryl halides, and or light chains are disclosed in United States Patent Applica others. These are described in G. T. Hermanson, “Bioconju tion Publication No. 2014/0046030 by Thanos et al. gate Techniques' (Academic Press, San Diego, 1996), pp. 0891 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 0892 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 0893 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 0894 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 0895. 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 0896. 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 0897. 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 US 2016/0166546 A1 Jun. 16, 2016 hydroxylamine (the nucleophile), described above, but is drugs' in Drug Discovery Handbook (S. C. Gad, ed., Wiley more general than that reaction; other groups can be used as Interscience, Hoboken, N.J., 2005), ch. 17, pp. 733-796, electrophile and nucleophile. Suitable groups are well known incorporated herein by this reference. This publication in organic chemistry and need not be described further in describes the use of enzyme sensitive esters as prodrugs. The detail. use of dimers as prodrugs is described in U.S. Pat. No. 7.879, 0899. Additional combinations of reactive groups for 896 to Allegretti et al., incorporated herein by this reference. cross-linking are known in the art. For example, amino The use of peptides in prodrugs is described in S. Prasadet al., groups can be reacted with isothiocyanates, isocyanates, acyl “Delivering Multiple Anticancer Peptides as a Single Prodrug Using Lysyl-Lysine as a Facile Linker. J. Peptide Sci. 13: azides, N-hydroxysuccinimide (NHS) esters, sulfonyl chlo 458–467 (2007), incorporated herein by this reference. The rides, aldehydes, glyoxals, epoxides, oxiranes, carbonates, use of Schiff bases as prodrugs is described in U.S. Pat. No. alkylating agents, imidoesters, carbodiimides, and anhy 7,619,005 to Epstein et al., incorporated herein by this refer drides. Thiol groups can be reacted with haloacetyl or alkyl ence. The use of caffeine complexes as prodrugs is described halide derivatives, maleimides, aziridines, acryloyl deriva in U.S. Pat. No. 6,443,898 to Unger et al., incorporated herein tives, acylating agents, or other thiol groups by way of oxi by this reference. dation and the formation of mixed disulfides. Carboxy groups 0914. Another potential prodrug system for bisantrene or can be reacted with diazoalkanes, diazoacetyl compounds, analogs or derivatives of bisantrene is the use of a plasmin carbonyldiimidazole, carbodiimides. Hydroxyl groups can activated prodrug as described in U.S. Pat. No. 7,402.556 to be reacted with epoxides, oxiranes, carbonyldiimidazole, Trouet et al., incorporated herein by this reference. In general, N,N'-disuccinimidyl carbonate, N-hydroxysuccinimidyl these prodrugs comprise: (1) the therapeutically active agent chloroformate, periodate (for oxidation), alkyl halogens, or capable of entering a target cell, in this case, bisantrene or a isocyanates. Aldehyde and ketone groups can react with derivative or analog of bisantrene as described above; (2) an hydrazines, reagents forming Schiffbases, and other groups oligopeptide having the formula X-Y, wherein X is a plasmin in reductive amination reactions or Mannich condensation peptide Substrate of 2-4 amino acids and Y is a peptide frag reactions. Still other reactions suitable for cross-linking reac ment comprising 1-2 amino acids having large side chains; tions are known in the art. Such cross-linking reagents and (3) a stabilizing group; and (4) optionally, a linker group not cleavable by plasmin. In this prodrug arrangement, the oli reactions are described in G. T. Hermanson, “Bioconjugate gopeptide is directly linked to the stabilizing group at a first Techniques” (Academic Press, San Diego, 1996), incorpo attachment site of the oligopeptide and the oligopeptide is rated herein by this reference. directly linked to the therapeutically active agent (i.e., amona 0900 When the improvement is made by use of a com fide or a derivative or analog of amonafide) or indirectly pound analog, the compound analog can be, but is not limited linked through the linker group to the therapeutically active to, a compound analog selected from the group consisting of agent at a second attachment site of the oligopeptide. The 0901 (a) alteration of side chains to increase or stabilizing group hinders cleavage of the oligopeptide by decrease lipophilicity; enzymes present in whole blood. The prodrug incorporating 0902 (b) addition of an additional chemical function the therapeutically active agent is cleavable by plasmin. ality to alter a property selected from the group consist 0915 Yet another potential prodrug system for bisantrene ing of reactivity, electron affinity, and binding capacity; and derivatives or analogs of bisantrene is the use of the drug and complex of U.S. Pat. No. 6,368.598 to D'Amico et al., incor (0903 (c) alteration of salt form. porated herein by this reference. In general, such a drug 0904. When the improvement is made by use of a prodrug complex comprises a targeting carrier molecule that is selec system, the prodrug system can be, but is not limited to, a tively distributed to a specific cell type or tissue containing the prodrug system selected from the group consisting of: specific cell type; a linker which is acted upon by a molecule that is present at an effective concentration in the environs of 0905 (a) the use of enzyme sensitive esters; the specific cell type; and a therapeutically active agent to be (0906) (b) the use of dimers: delivered to the specific cell type, such as, in this application, (0907 (c) the use of Schiffbases: bisantrene or a derivative or analog of bisantrene. In one 0908 (d) the use of pyridoxal complexes: application, the cell type is cells of the prostate and the drug (0909 (e) the use of caffeine complexes: complex is cleaved by the activity of prostate specific antigen 0910 (f) the use of plasmin-activated prodrugs: (PSA). 0911 (g) the use of a drug targeting complex compris 0916. The use of a prodrug molecule comprising a conju ing a targeting carrier molecule that is selectively dis gate of bisantrene or a derivative or analog of bisantrene, a tributed to a specific cell type or tissue containing the protease-specific cleavable peptide, and optionally, a target specific cell type; a linker which is acted upon by a ing peptide, with the prodrug molecule being Substantially molecule that is present at an effective concentration in inactive prior to degradation of the protease-specific cleav the environs of the specific cell type; and a therapeuti able peptide by a proteolytic enzyme within or in close proX cally active agent to be delivered to the specific cell type: imity to the cancer cell is described in U.S. Pat. No. 8.314,060 and to Gengrinovitch, incorporated herein by this reference. 0912. (h) the use of a prodrug molecule comprising a 0917. When the improvement is made by use of a multiple conjugate of bisantrene or a derivative or analog of drug system, the multiple drug system can be, but is not bisantrene, a protease-specific cleavable peptide, and limited to, a multiple drug system selected from the group optionally, a targeting peptide, with the prodrug mol consisting of the use of bisantrene or a derivative or analog of ecule being Substantially inactive prior to degradation of amonafide with: the protease-specific cleavable peptide by a proteolytic 0918 (a) inhibitors of multi-drug resistance: enzyme within or in close proximity to the cancer cell. 0919 (b) specific drug resistance inhibitors; 0913. The use of prodrug systems is described in T. Jarv 0920 (c) specific inhibitors of selective enzymes; inen et al., “Design and Pharmaceutical Applications of Pro 0921 (d) signal transduction inhibitors; US 2016/0166546 A1 Jun. 16, 2016 62

0922 (e) meiso indigo; 0156015 by Rabindran et al., incorporated herein by this 0923 (f) imatinib: reference, discloses agents that are capable of reversing mul 0924 (g) hydroxyurea; tidrug resistance, including fumitremorgin A, fumitremorgin 0925 (h) dasatinib; B, fumitremorgin C, and diketopiperazines. United States 0926 (i) capecitabine; Patent Application Publication No. 2007/0009535 by Sikic et 0927) () nilotinib: al., incorporated herein by this reference, discloses P-glyco 0928 (k) repair inhibition agents: protein efflux pump inhibitors such as ZoSuquidar, tariquidar, 0929 (1) topoisomerase inhibitors with non-overlap and tesmilifene. Still additional multidrug resistance inhibi ping side effects; tors are disclosed in United States Patent Application 2008/ 0207738 by Kiss, incorporated herein by this reference, 0930 (m) PARP inhibitors: including 9H-xanthene-9-carboxylic acid-3-4-2-(4-trim 0931 (n) EGFR inhibitors; and ethylsilanyl-methoxy-benzoyloxy)-ethyl-piperazin-1- 0932 (o) HDAC inhibitors. yl)propyl ester dihydrochloride. 0933) Multi-drug resistance inhibitors are described in U.S. Pat. No. 6,011,069 to Inomata et al., incorporated herein 0934 Specific drug resistance inhibitors are described in by this reference. Verapamil and calcium influx blocking T. Hideshima et al., “The Proteasome Inhibitor PS-341 Inhib agents have this property and have been used for this purpose. its Growth, Induces Apoptosis, and Overcomes Drug Resis Additional multi-drug resistance inhibitors of particular util tance in Human Multiple Myeloma Cells. Cancer Res.61: ity for increasing the activity of antineoplastic drugs are 3071-3076 (2001), incorporated herein by this reference. described in U.S. Pat. No. 5,436.243 to Sachs et al., incorpo 0935 Signal transduction inhibitors are described in A. V. rated herein by this reference, including aminoanthraquino Lee et al., “New Mechanisms of Signal Transduction Inhibi nes, preferably 1.4bis(N-substituted anthraquinones). Addi tor Action: Receptor Tyrosine Kinase Down-Regulation and tional multi-drug resistance inhibitors of particular utility for Blockade of Signal Transactivation.” Clin. Cancer Res. 9: increasing the activity of antineoplastic drugs are also 516s (2003), incorporated herein in its entirety by this refer described in U.S. Pat. No. 5,639,887 to Powell et al., incor ence. Signal transduction inhibitors can include, but are not porated herein by this reference, including the following limited to, BCL/ABL kinase inhibitors, epidermal growth compounds: C-(4-chlorobutyl)-3,4-dimethoxy-O-(4-meth factor (EGF) receptor inhibitors, her-2/neu receptor inhibi ylphenyl)-thiobenzeneacetonitrile; C.-(3-chloro-2-methyl tors, and farnesyl transferase inhibitors, as described in U.S. propyl)-3,4-dimethoxy-O-(4-methyl-phenyl)thiobenzene Pat. No. 8,008,281 by Prendergast et al., incorporated herein acetonitrile; C-(11-bromoundecyl)-3,4-dimethoxy-O-(4- by this reference. methylphenyl)-thiobenzeneacetonitrile; C-(5- 0936 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 0937 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 0938 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 0939 (a) biological response modifiers; benzenepropanenitrile; 4-6-bromo-1-(4-methylphenyl) (0940 (b) cytokines: thioheptyl-1,2-dimethoxybenzene: 5-7-bromo-1-(4- 0941 (c) lymphokines: methylphenyl)thioheptyl-2-methoxy-phenoxy(1.2- 0942 (d) therapeutic antibodies: dimethyl ethyl)dimethylsilane; C-(5-chloropentyl)-C.- 0943 (e) antisense therapies; (cyclohexylthio)-3,4-dimethoxybenzeneacetonitrile; C-(5- 0944 (f) gene therapies; aminopentyl)-O-(cyclohexylthio)-3,4- (0945 (g) ribozymes: dimethoxybenzeneacetonitrile; 5-6-bromo-1-(4- methylphenyl)thiohexyl-1,3-benzodioxole: 1-6-bromo-1- (0946 (h) RNA interference: (4-methylphenyl)thiohexyl)-4-(trifluoromethoxy)benzene: 0947 (i) vaccines (cellular and non-cellular); 1-6-bromo-1-(4-fluorophenyl)hexylthiol-4-methylben 0948) () stem cells; and Zene; C-(5-bromopentyl)-3,4-dimethoxy-O-(4-methylphe 0949 (k) autologous cell transplants. nyl)-thiobenzeneacetonitrile; (7-bromo-1-phenylheptyl) 0950 Biological response modifiers are described in T. E. thiobenzene: C-(5-bromopentyl)-O-(cyclohexylthio)-3,4- G. K. Murthy et al., “Biological Response Modifiers. Int. J. dimethoxybenzeneacetonitrile; 7-bromo-2-(3,4- Pharmtech Res. 2:2152-2160 (2010), incorporated herein by dimethoxyphenyl)-2-(2-pyridylthio)-heptanonitrile; and this reference. C.-(5-hydroxypentyl)-3,4-dimethoxy-O-(methylphenyl)- 0951 Antisense therapies are described, for example, in thiobenzeneacetic acid methyl ester. U.S. Pat. No. 5,994,130 B. Weiss et al., “Antisense RNA Gene Therapy for Studying to Shyan, incorporated herein by this reference, discloses and Modulating Biological Processes. Cell. Mol. Life Sci. another multi-drug resistance protein, MRP-B and methods 55:334-358 (1999), incorporated herein by this reference. of inhibition thereof, including the use of antisense nucle 0952 Ribozymes are described, for example, in S. Pas otides. United States Patent Application Publication 2002/ colo, “RNA-Based Therapies” in Drug Discovery Handbook US 2016/0166546 A1 Jun. 16, 2016

(S. C. Gad, ed., Wiley-Interscience, Hoboken, N.J., 2005), antibody selected from the group consisting of bevacizumab ch.27, pp. 1273-1278, incorporated herein by this reference. (Avastin), rituximab (Rituxan), trastuzumab (Herceptin), and 0953 RNA interference is described, for example, in S. cetuximab (Erbitux). Pascolo, “RNA-Based Therapies' in Drug Discovery Hand 0967. When the improvement is made by radiation therapy book (S. C. Gad, ed., Wiley-Interscience, Hoboken, N.J., enhancement, the radiation therapy enhancement can be, but 2005), ch.27, pp. 1278-1283, incorporated herein by this is not limited to, a radiation therapy enhancement agent or reference. technique selected from the group consisting of 0954. When the biotherapeutic enhancement is use in 0968 (a) use with hypoxic cell sensitizers; combination as sensitizers/potentiators with a therapeutic 0969 (b) use with radiation sensitizers/protectors; antibody, the therapeutic antibody can be, but is not limited to, 0970 (c) use with photosensitizers; a therapeutic antibody selected from the group consisting of 0971 (d) use with radiation repair inhibitors; bevacizumab (Avastin), rituximab (Rituxan), trastuzumab 0972 (e) use with thiol depletion: (Herceptin), and cetuximab (Erbitux). 0973 (f) use with vaso-targeted agents; 0955 Cancer vaccines are being developed. Typically, 0974 (g) use with radioactive seeds: cancer vaccines are based on an immune response to a protein 0975 (h) use with radionuclides; or proteins occurring in cancer cells that does not occur in 0976 (i) use with radiolabeled antibodies; and normal cells such as, Oncophage for kidney cancer, 0977) () use with brachytherapy; and CimaVax-EGF for lung cancer, MOBILAN, Neuvenge for 0978 (k) use with bioreductive alkylating agents. Her2/neu expressing cancers such as breast cancer, colon 0979 Hypoxic cell sensitizers are described in C. C. Ling cancer, bladder cancer, and ovarian cancer, StimuVax for et al., “The Effect of Hypoxic Cell Sensitizers at Different breast cancer, and others. Cancer vaccines are described in S. Irradiation Dose Rates.” Radiation Res. 109:396–406 (1987), Pejawar-Gaddy & O. Finn, “Cancer Vaccines: Accomplish incorporated herein by this reference. Radiation sensitizers ments and Challenges. Crit. Rev. Oncol. Hematol. 67: are described in T. S. Lawrence, "Radiation Sensitizers and 93-102 (2008), incorporated herein by this reference, by acti Targeted Therapies. Oncology 17 (Suppl. 13) 23-28 (2003), Vating cells via autologous transplant such as Provenge, or via incorporated herein by this reference. Radiation protectors checkpoint blockade, Such as Ipilimumab. are described in S. B. Vuyyuri et al., “Evaluation of D-Me 0956. Therapeutic applications of the use of stem cells for thionine as a Novel Oral Radiation Protector for Prevention of the treatment of malignancies are also being developed. One Mucositis.” Clin. Cancer Res. 14: 2161-2170 (2008), incor avenue for the use of stem cells in the treatment of malignan porated herein by this reference. Photosensitizers are cies involves the administration of stem cells to initiate described in R. R. Allison & C. H. Sibata, “Oncologic Pho immune-reconstruction following high dose chemotherapy todynamic Therapy Photosensitizers: A Clinical Review.” or radiation. Typically, in this alternative, the stem cells used Photodiagnosis Photodynamic Ther. 7: 61-75 (2010), incor are hemopoietic stem cells (HSGs). This use of stem cells is porated herein by this reference. Radiation repair inhibitors described in J. Sagar et al., “Role of Stem Cells in Cancer and DNA repair inhibitors are described in M. Hingorani et Therapy and Cancer Stem Cells: A Review.” Cancer Cell al., “Evaluation of Repair of Radiation-Induced DNA Dam Internat. 7:9 (2007), incorporated herein by this reference. age Enhances Expression from Replication-Defective Aden This may be particularly useful formalignancies affecting the oviral Vectors.” Cancer Res.68:9771-9778 (2008), incorpo immune system, Such as lymphomas. Another use of stem rated herein by this reference. Thiol depleters are described in cells in cancer therapy is by targeting malignant cells directly K. D. Held et al., “Postirradiation Sensitization of Mamma with stem cells. Stem cells have tumoritropic migratory prop lian Cells by the Thiol-Depleting Agent Dimethyl Fumarate.” erties, and can be modified by the insertion of transgenes with Radiation Res. 127:75-80 (1991), incorporated herein by this antitumor effects. Transgene effects can include direct tumor reference. Vaso-targeted agents are described in A. L. Seyn cell killing, promotion of local immune responses, oncolytic haeve et al., “Tumor Necrosis Factor C. Mediates Homoge virus production, and prodrug activation schemes. This use of neous Distribution of Liposomes in Murine Melanoma that stem cells in cancer therapy is described in M. F. Corsten & K. Contributes to a Better Tumor Response.” Cancer Res. 67: Shah, “Therapeutic Stem-Cells for Cancer Treatment: Hopes 9455-9462 (2007), incorporated herein by this reference. and Hurdles in Tactical Warfare. Lancet Oncol. 9: 376-384 Bioreductive alkylating agents include tirapazamine, (2008), incorporated herein by this reference. described in W. A. Denny, “Prospects for Hypoxia-Activated 0957. When the improvement is made by use of biothera Anticancer Drugs.” Curr. Med. Chem. 4: 395-399 (2004), peutic resistance modulation, the biotherapeutic resistance incorporated herein by this reference. Bioreductive alkylating modulation can be, but is not limited to, use against tumors agents also include nitroimidazoles, such as metronidazole, resistant to a therapeutic agent or technique selected from the tinidazole, and nimorazole, and other Substituted nitrohetero group consisting of cycles, described in A. Mital, “Synthetic Nitroimidazoles: 0958) (a) biological response modifiers; Biological Activities and Mutagenicity Relationships. Sci. 0959 (b) cytokines: Pharm. 77: 497-520 (2009) and in M. R. Juchau, “Bioactiva 0960 (c) lymphokines: tion in Chemical Teratogenesis.” Annu. Rev. Pharmacol. 0961 (d) therapeutic antibodies; Toxicol. 29: 165-187 (1989). 0962 (e) antisense therapies; 0980 When the improvement is made by use of a novel 0963 (f) gene therapies; mechanism of action, the novel mechanism of action can be, 0964 (g) ribozymes; and but is not limited to, a novel mechanism of action that is a 0965 (h) RNA interference. therapeutic interaction with a target or mechanism selected 0966 When the biotherapeutic resistance modulation is from the group consisting of use against tumors resistant to therapeutic antibodies, the 0981 (a) inhibitors of poly-ADP ribose polymerase: therapeutic antibody can be, but is not limited to, atherapeutic 0982 (b) agents that affect vasculature; US 2016/0166546 A1 Jun. 16, 2016 64

0983 (c) agents that promote vasodilation; Pheochromocytomas Is Associated to Malignancy and Inhib 0984 (d) oncogenic targeted agents; ited by anti-VEGF Antibodies in Experimental Tumors. Sur 0985 (e) signal transduction inhibitors; gery 132: 1056-1063 (2002), incorporated herein by this ref 0986 (f) agents inducing EGFR inhibition; erence. The role of ornithine decarboxylase as a target for 0987 (g) agents inducing Protein Kinase C inhibition; therapeutic intervention is described in J. A. Nilsson et al., 0988 (h) agents inducing Phospholipase C down regu “Targeting Ornithine Decarboxylase in Myc-Induced Lym lation; phomagenesis Prevents Tumor Formation. Cancer Cell 7: 0989 (i) agents includingjun downregulation; 433-444 (2005), incorporated herein by this reference. The 0990 () agents modulating expression of histone role of ubiquitin C as a target for therapeutic intervention is genes. described in C. Aghajanian et al., “A Phase I Trial of the Novel 0991 (k) agents modulating expression of VEGF: Proteasome Inhibitor PS341 in Advanced Solid Tumor 0992 (1) agents modulating expression of ornithine Malignancies.” Clin. Cancer Res. 8: 2505-2511 (2002), decarboxylase; incorporated herein by this reference. The role of Jun D as a 0993 (m) agents modulating expression of jun D; target for therapeutic intervention is described in M. M. Caf 0994) (n) agents modulating expression of V-jun: farel et al., “Juni) Is Involved in the Antiproliferative Effect of 0995 (o) agents modulating expression of GPCRs: A-Tetrahydrocannibinol on Human Breast Cancer Cells.” 0996 (p) agents modulating expression of protein Oncogene 27: 5033-5044 (2008), incorporated herein by this kinase A: reference. The role of V-Jun as a target for therapeutic inter 0997 (d) 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: 0998 (r) agents modulating expression of telomerase: 4229-4235 (1996), incorporated herein by this reference. The 0999 (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 1000 (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 1001 (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 1002 (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. 1003 Inhibitors of poly ADP-ribose polymerase include The role of histone deacetylase as a target for therapeutic veliparib (ABT-888), AG014699, 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 1004 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 (SEQID 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. Downregulation 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 US 2016/0166546 A1 Jun. 16, 2016

ptotic genes through phosphorylation of the transcription fac induce telomere dysfunction, the use of bisantrene or a tor. It is also believed to act as a tumor suppressor. It may also derivative or analog of bisantrene can be, but is not limited to, have a DNA damage-independent function in mitotic spindle a use selected from the group consisting of: assembly by phosphorylating BRCA1. Its absence may be a 1021 (a) use to inhibit telomerase; and cause of the chromosomal instability observed in some can 1022 (b) use to induce telomere dysfunction. cer cells. A deletion mutation at position 1100 of CHEK2, 1023 Bisantrene and derivatives or analogs thereof can be which encodes the CHK2 checkpoint kinase, is associated used with telomerase inhibitors such as, but not limited to, with an increased risk of breast cancer, particularly in the BPPA (2,6-bis(3-piperidinopropionamido)anthraquinone), European population (H. Meijers-Heiboer et al., “Low-Pen (-)-epigallocatechin gallate, H-7 (2,6-bis(3-piperidinopropi etrance Susceptibility to Breast Cancer Due to CHEK2(*) onamido)anthraquinone), B-rubromycin, and BIBR1532 (2- 1100delC in Noncarriers of BRCA1 or BRCA2 Mutations.” (2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl1-yl)aminoben Nat. Genet. 31: 55-59 (2002), incorporated herein by this Zoic acid). reference). The activity of CHK2 checkpoint kinase is further 1024. When the improvement is made by use of bisantrene described in J. Liet al., “Structural and Functional Versatility or a derivative or analog thereof to activate macrophages or of the FHA Domain in DNA-DamageSignaling by the Tumor induce innate and/or adaptive immunity, the use of bisantrene Suppressor Chk2,' Mol. Cell 9: 1045-1054 (2002), incorpo or a derivative or analog of bisantrene can be, but is not rated herein by this reference. Inhibitors and modulators of the activity of CHK2 checkpoint kinases are known in the art, limited to, a use selected from the group consisting of and are described, for example, in U.S. Pat. No. 8,334.309 to 1025 (a) use to activate macrophages; Klein et al., U.S. Pat. No. 8,329,709 to Banka et al., U.S. Pat. 1026 (b) use to induce innate immunity; and No. 8,329,701 to Mitchell et al., U.S. Pat. No. 8,318,740 to 1027 (c) use to induce adaptive immunity. Wu, U.S. Pat. No. 8,318,735 to Shipps, Jr. et al., U.S. Pat. No. 1028. 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: 1005 When the improvement is made by use of selective 1029 (a) use to inhibit expression of survivin; and target cell population therapeutics, the use of selective target 1030 (b) use with an inhibitor of survivin. cell population therapeutics can be, but is not limited to, a use 1031. Inhibitors of survivin are described above. selected from the group consisting of: 1032. When the improvement is made by use of bisantrene 1006 (a) use against radiation sensitive cells; or a derivative or analog thereof with a multidrug resistance 1007 (b) use against radiation resistant cells; reversal agent, the use of bisantrene or a derivative or analog 1008 (c) use against energy depleted cells; and of bisantrene can be, but is not limited to, use with a multidrug 1009 (d) use against endothelial cells. resistance reversal agent to reduce multidrug resistance. Mul 1010 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 1033. 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 1011 (a) nicotinamide: can be employed in Such combinatorial regimes, typically by 1012 (b) caffeine; combining newer immunotherapies with older cytotoxic 1013 (c) tetandrine; and modalities. Combinatorial therapy is described in L. S. Lie 1014 (d) berberine. bovitch et al., “Developing Combinatorial Multi-Component 1015 When the improvement is made by use of bisantrene Therapies (CMCT) of Drugs That Are More Specific and or a derivative or analog thereof to modulate DNA methyla Have Fewer Side Effects Than Traditional One Drug Thera tion, the use of bisantrene or a derivative or analog thereof to pies.” Nonlinear Biomed. Phys. 1: 11 (2007), and in B. Al modulate DNA methylation can be, but is not limited to, a use Lazikani et al., “Combinatorial Drug Therapy for Cancer in selected from the group consisting of: the Post-Genomic Era,” Nat. Biotechnol. 10: 679-692 (2012), 1016 (a) use to promote gene silencing; and both incorporated herein by this reference. Combinations for 1017 (b) use with a drug that inhibits DNA methyla combinatorial therapeutics can be selected based on genom tion. ics or proteomics; for example, therapeutic agents can be 1018. The use of bisantrene or a derivative or analog chosen based on interactions with receptors or kinases in a thereof to promote gene silencing is described in L. Suarez & single pathway or in pathways that interact. The use of bisant S. D. Gore, “Demethylation Demystification.” Blood 121: rene or a derivative or analog thereof in a combinatorial 1488-1489 (2011), incorporated herein by this reference. regime can be, but is not limited to: 1019 Drugs that inhibit DNA methylation include, but are 1034 (a) use in a combinatorial regime as a chemo not limited to, 5'-azacytidine, 5-aza-2'-deoxycytidine, Zebu therapeutic agent with at least one agent inducing immu larine, L-methionine, apicidine, hydralazine, procainamide, noactivity; antisense oligonucleotides directed against mRNA for DNA 1035 (b) use in a combinatorial regime as a chemo methyltransferase, and histone deacetylase (HDAC) inhibi therapeutic agent with at least one agent inducing mac tOrS. rophage activation; 1020 When the improvement is made by use of bisantrene 1036 (c) use in a combinatorial regime as a chemo or a derivative or analog thereof to inhibit telomerase or therapeutic agent with at least one cytokine; US 2016/0166546 A1 Jun. 16, 2016 66

1037 (d) use in a combinatorial regime as a chemo 1062 (ac) use in a combinatorial regime as an agent therapeutic agent with at least one agent inhibiting inducing macrophage activation with at least one Akt telomerase; inhibitor; 1038 (e) use in a combinatorial regime as a chemo 1063 (ad) use in a combinatorial regime as an agent therapeutic agent with at least one agent inhibiting Sur inducing macrophage activation with at least one notch vivin; inhibitor; 1039 (f) use in a combinatorial regime as a chemo 1064 (ae) use in a combinatorial regime as an agent therapeutic agent with at least one agent inducing dem inducing macrophage activation with at least one HSP ethylation; inhibitor; 1040 (g) use in a combinatorial regime as a chemo 1065 (af) use in a combinatorial regime as an agent therapeutic agent with at least one adjuvant; inducing macrophage activation with at least one phos 1041 (h) use in a combinatorial regime as a chemo phatidylinositide 3-kinase inhibitor; therapeutic agent with at least one antibody; 1066 (ag) use in a combinatorial regime as an agent 1042 (i) use in a combinatorial regime as a chemothera inducing macrophage activation with at least one kinase peutic agent with at least one innate or adaptive immune inhibitor; stimulator; 1067 (ah) use in a combinatorial regime as an agent 1043 () use in a combinatorial regime as a chemothera inducing macrophage activation with cytarabine; peutic agent with at least one checkpoint inhibitor, 1068 (a) use in a combinatorial regime as an agent 1044 (k) use in a combinatorial regime as a chemo inducing macrophage activation with taxane; and (ak) therapeutic agent with at least one mTOR antagonist; use in a combinatorial regime as an agent inducing mac 1045 (1) use in a combinatorial regime as a chemothera rophage activation with taxol. peutic agent with at least one Akt inhibitor, 1069 Agents inducing demethylation include, but are not 1046 (m) use in a combinatorial regime as a chemo limited to, 5-azacytidine, 5-aza-2'-deoxycytidine, Zebularine, therapeutic agent with at least one notch inhibitor; L-methionine, apicidine, hydralazine, procainamide, and 1047 (n) use in a combinatorial regime as a chemo antisense oligonucleotides directed against mRNA for DNA therapeutic agent with at least one HSP inhibitor; methyltransferase. Additional drugs that inhibit DNA methy 1048 (o) use in a combinatorial regime as a chemo lation include inhibitors of histone deacetylase (HDAC). therapeutic agent with at least one phosphatidylinositide These compounds include, but are not limited to, compounds 3-kinase inhibitor; disclosed in PCT Patent Application Publication No. WO 1049 (p) use in a combinatorial regime as a chemo 02/22577 by Bair et al., incorporated herein by this reference, therapeutic agent with at least one kinase inhibitor, including, but not limited to, N-hydroxy-3-4-(2-hydroxy 1050 (q) use in a combinatorial regime as a chemo ethyl)2-(1H-indol-3-yl)ethyl-aminomethylphenyl-2E-2- therapeutic agent with cytarabine; propenamide, Suberoylanilide hydroxamic acid, 4-(2-amino 1051 (r) use in a combinatorial regime as a chemo phenylcarbamoyl)-benzyl-carbamic acid pyridine-3- therapeutic agent with taxane; ylmethyl ester and derivatives thereof, butyric acid, 1052 (s) use in a combinatorial regime as a chemo pyroxamide, trichostatin A, oxamflatin, apicidin, depsipep therapeutic agent with taxol; tide, depudecin, trapoxin, HC toxin, and Sodium phenylbu 1053 (t) use in a combinatorial regime as an agent tyrate. inducing macrophage activation with at least one agent 1070. Survivin is a regulator of apoptosis and acts to inducing telomerase inhibition; counter apoptosis as described above. Inhibitors or modula 1054 (u) use in a combinatorial regime as an agent tors of survivin activity or expression are described above. inducing macrophage activation with at least one cytok 1071 Macrophage activators include, but are not limited ine; to: Bacillus Calmette-Guerin; Corynebacterium parvum; 1055 (v) use in a combinatorial regime as an agent endotoxins; muramyl dipeptide; pl.:pC copolymer; pyran inducing macrophage activation with at least one agent copolymer, lymphokines; Adriamycin; cyclophosphamide; inhibiting Survivin; mitomycin C. mycoplasmal lipoproteins; bisacyloxypropyl 1056 (w) use in a combinatorial regime as an agent cysteine conjugates, as described in U.S. Pat. No. 8,119,689 inducing macrophage activation with at least one agent to Ebenstein et al. incorporated herein by this reference; inducing demethylation; glycolipopeptides as described in U.S. Pat. No. 7.820,797 to 1057 (x) use in a combinatorial regime as an agent Boons, incorporated herein by this reference; mineral oil; inducing macrophage activation with at least one adju starch; polycarbophil; and bisantrene, as well as various Vant, chemokines, lymphokines, and cancer vaccines described 1058 (y) use in a combinatorial regime as an agent previously herein. inducing macrophage activation with at least one anti 1072 Checkpoint kinases are involved in the regulation of body; a number of cellular processes, including the cell cycle. 1059 (Z) use in a combinatorial regime as an agent Eukaryotes have evolved elaborate sensory networks to inducing macrophage activation with at least one innate detect and repair DNA damage and prevent alterations in their or adaptive immune stimulator; genetic material. In response to DNA damage, eukaryotic 1060 (aa) use in a combinatorial regime as an agent cells arrest either in G1 or S phase, to prevent replication of inducing macrophage activation with at least one check damaged genes, or in G2 phase to avoid segregation of defec point inhibitor; tive chromosomes. Checkpoint kinases, CHK1 and CHK2, 1061 (ab) use in a combinatorial regime as an agent participate in various DNA-damage responses, including inducing macrophage activation with at least one mTOR cell-cycle checkpoints, genome maintenance, DNA repair, antagonist; and apoptosis. They phosphorylate several key proteins US 2016/0166546 A1 Jun. 16, 2016 67 involved in the cell cycle and block their activity. CHK1, an U.S. Pat. No. 7,470,709 to Barsanti et al.; U.S. Pat. No. evolutionarily conserved protein kinase, is expressed in the S 7.462,713 to Benedictet al.: U.S. Pat. No. 7,202,244 to Boyle and G2 phases of cell cycle of proliferating cells. It is acti et al.; U.S. Pat. No. 7,132,533 to Benedict et al.; U.S. Pat. No. vated by phosphorylation on Ser7 and Ser' in response to 7,094,798 to Booth et al.: U.S. Pat. No. 7,067,506 to Keegan DNA damage. Once activated, CHK1 phosphorylates Ser' et al.; U.S. Pat. No. 6,967,198 to Benedict et al.; U.S. Pat. No. of Cdc25A, which targets it for ubiquitin-mediated degrada 6,670,167 to Chen et al.; United States Patent Application tion. The phosphorylated Cdc25A cannot dephosphorylate Publication No. 2013/0045286 by Le Huerou et al.; United and activate Cdk1 and Cdk2, resulting in an arrest of cell cycle in the G1, S, and G2 phases. CHK1 also phosphorylates States Patent Application Publication No. 2012/0232082 by Ser' (14-3-3 binding site) on Cdc25C and prevents its acti Wu: United States Patent Application Publication No. 2012/ vation in the G2 phase. Phosphorylated Cdc25C cannot 0184505 by Popovici-Muller et al.; United States Patent dephosphorylate and activate Cdk1. Recent research indi Application Publication No. 2012/0114765 by Cao et al.: cates that CHK1 is an ideal chemosensitization target and its United States Patent Application Publication No. 2011/ inhibition can sensitize tumors, particularly those with p53 0201592 by Collins et al.; United States Patent Application deficiency, to various chemotherapeutic agents. CHK2 is Publication No. 2011/0183938 by Dyke et al.; United States structurally different from CHK1, but they share overlapping Patent Application Publication No. 2011/0183933 by Guzi et substrate specificities. CHK2 is activated following exposure al.; United States Patent Application Publication No. 2011/ to infrared light or topotecan, whereas CHK1 is activated by 0.124654 by Chen et al.; United States Patent Application agents that interfere with DNA replication. This observation Publication No. 2011/01 18230 by Chen et al.: United States has led to the belief that CHK1 blocks cell-cycle progression Patent Application Publication No. 2011/0021498 by Stokes when replication is inhibited, whereas CHK2 acts when there et al.; United States Patent Application Publication No. 2011/ are double-strand breaks induced in DNA. CHK2 is activated 00094.15 by Wu: United States Patent Application Publica by DNA-strand-breaking agents such as ionizing radiation tion No. 2010/0260868 by Humphries et al.: United States and topoisomerase inhibitors through the ATM-dependent Patent Application Publication No. 2010/0226917 by Brown pathway. The role of CHK2 in checkpoints is not clearly et al.; United States Patent Application Publication No. 2010/ understood. However, it is reported to phosphorylate Cdc25A 0143332 by Parry et al. (including pyrazolopyrimidines, imi 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, diaryl 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 1073 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)- 1074. 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-

US 2016/0166546 A1 Jun. 16, 2016 70 methoxypyridin-3-yl)-4-methylpyrido2,3-dipyrimidin-7 tively. A second, as of yet unknown, kinase is required for the (8H)-one); CH132799; RG7422 (S)-1-(4-((2-(2- phosphorylation of Ser473, Ser474 or Ser472 in the C-termi aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno3,2-d nal tails of Akt-1, -2 and -3 respectively, in order to yield a pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1- fully activated Aktenzyme. Once localized to the membrane, one); Palomid 529 (3-(4-methoxybenzyloxy)-8-(1- Akt mediates several functions within the cell including the hydroxyethyl)-2-methoxy-6H-benzocchromen-6-one); metabolic effects of insulin, induction of differentiation and/ PP242 (2-(4-amino-1-isopropyl-1-pyrazolo 3,4-dipyrimi or proliferation, protein synthesis, and stress responses. din-3-yl)-1H-indol-5-ol); XL765 (N-4-3-(3,5-dimethox 1079 Akt inhibitors include, but are not limited to: tricir yphenyl)amino-2-quinoxalinyl)aminosulfonylphenyl-3- ibine: RX-0201 (a 20-mer oligonucleotide); perifosine: methoxy-4-methyl-benzamide); GSK105.9615 ((Z)-5-((4- PX-316 ((R)-2-methoxy-3-(octadecyloxy)propyl ((1R,2R, (pyridin-4-yl)guinolin-6-yl)methylene)thiazolidine-2,4- 3S,4R,6R)-2,3,4,6-tetrahydroxycyclohexyl) hydrogen phos dione); PKI-587 (1-(4-(4-(dimethylamino)piperidine-1- phate); API-1 (4-amino-5,8-dihydro-5-oxo-8-3-D-ribofura carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2- nosyl-pyrido2,3-dipyrimidine-6-carboxamide); SR 13668 yl)phenyl)urea); WAY-6OO (6-(1H-indol-5-yl)-4- (diethyl 6-methoxy-5,7-dihydroindolo2,3-bcarbazole-2, morpholino-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1H 10-dicarboxylate); AZD5363 (4-amino-N-(1S)-1-(4-chlo pyrazolo 3,4-dpyrimidine); WYE-687 (nethyl 4-(4- rophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo2,3-dipyrimi morpholino-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1H din-4-yl)-4-piperidinecarboxamide); miltefosine; pyrazolo 3,4-dipyrimidin-6-yl)phenylcarbamate); miltefosine; GSK690693 (4-(2-(4-amino-1,2,5-oxadiazol-3- WYE-125132 (N-4-1-(1,4-dioxaspiro4.5 dec-8-yl)-4-(8- yl)-1-ethyl-7-((S)-piperidin-3-ylmethoxy)-1H-imidazo[4,5- oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo 3,4-dpyri cpyridin-4-yl)-2-methylbut-3-yn-2-ol); A-443654 ((2S)-1- midin-6-yl)phenyl)-N'-methyl-urea); and WYE-354. (1H-indol-3-yl)-3-5-(3-methyl-2H-indazol-5-yl)pyridin-3- 1077 Additional inhibitors of mTOR are described in the yloxypropan-2-amine); and SR 13668 (diethyl 6-methoxy-5, following United States patents and patent applications, all of 7-dihydroindolo2,3-bcarbazole-2,10-dicarboxylate). which are incorporated herein by this reference: U.S. Pat. No. 1080 Additional inhibitors of Akt are described in the 8,461,157 to Caietal.; U.S. Pat. No. 8,440,662 to Smith et al.: following United States patents and patent applications, all of U.S. Pat. No. 8,436,012 to Ohtsuka et al.; U.S. Pat. No. which are incorporated herein by this reference: U.S. Pat. No. 8,394,818 to Gray et al.: U.S. Pat. No. 8.362,241 to D'Angelo 8,450.305 to Winssinger et al.: U.S. Pat. No. 8,445,509 to et al.; U.S. Pat. No. 8,314,111 to Chen et al.; U.S. Pat. No. Miyamoto et al. (N-4-(2-(cyclopropylcarbonyl)amino 8,309,546 to Nakayama et al. (including 6-morpholinopurine imidazo[1,2-alpyridin-6-yloxy)-3-fluorophenyl)-N'-phe derivatives); U.S. Pat. No. 8,268.819 to Jinet al.; U.S. Pat. No. nylcyclopropane-1,1-dicarboxamide, N-4-(2-(cyclopro 8,211,669 to Reed et al.; U.S. Pat. No. 8,163,755 Jin et al.: pylcarbonyl)aminoimidazo[1,2-alpyridin-6-yloxy)-3- U.S. Pat. No. 8,129,371 Zasket al.; U.S. Pat. No. 8,097,622 to fluorophenyl-6-methyl-2-oxo-1-phenyl-1,2- Nakayama et al.; U.S. Pat. No. 8,093,050 to Cho et al.; U.S. dihydropyridine-3-carboxamide, N-4-(2- Pat. No. 8,008,318 to Beckmann et al.; U.S. Pat. No. 7,943, (cyclopropylcarbonyl)aminoimidazol-2-alpyridin-6- 767 to Chen et al.; U.S. Pat. No. 7,923,555 to Chen et al.; U.S. yloxy)-3-fluorophenyl-1-(4-fluorophenyl)-6-methyl-2- Pat. No. 7,897,608 to Wilkinson et al.; U.S. Pat. No. 7,700, oxo-1,2-dihydropyridine-3-carboxamide, and N-5-(2- 594 to Chen et al.; U.S. Pat. No. 7,659,274 to Crew etal. U.S. (cyclopropylcarbonyl)aminoimidazol-2-alpyridin-6- Pat. No. 7,655,673 to Zhang et al. (39-desmethoxyrapamy yloxy)pyridin-2-yl)-6-(4-fluorophenyl)-5-methylpyridine cin); U.S. Pat. No. 7,648,996 to Beckman et al.; U.S. Pat. No. 2-carboxamide 1-oxide); U.S. Pat. No. 8,436,002 to Beight et 7,504,397 to Hummersone et al.; U.S. Pat. No. 7,169,817 to al. ((R)-5-methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(3.3, Panet al.: U.S. Pat. No. 7,160,867 to Abeletal. (carbohydrate 3-trifluoropropyl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-di derivatives of rapamycin): U.S. Pat. No. 7,091,213 to Metcalf hydropyrido 2,3-dipyrimidin-7(8H)-one; (R)-4-(4-(4-ethyl III et al. (“rapalogs’); United States Patent Application Pub 1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1- lication No. 2013/0079303 by Andrews et al.; and United yl)-5-methyl-5,6-dihydropyrido 2,3-dipyrimidin-7(8H)- States Patent Application Publication No. 2013/0040973 by one; and (R)-4-(4-(1-(2-(aZetidin-1-yl)ethyl)-4-(2.2.2- Vannuchi et al. trifluoroethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5- 1078 Akt, also known as Protein Kinase B, is a serine/ (trifluoromethyl)-5,6-dihydropyrido2,3-dipyrimidin-7 threonine-specific protein kinase that plays a key role in many (8H)-one); U.S. Pat. No. 8,420,690 to Seefeld et al. (N-(2- cellular processes such as glucose metabolism, apoptosis, amino-1-phenylethyl)-5-(1-methyl-1H-pyrazol-5-yl)-3- cellular proliferation, transcription, and cell migration. It is thiophenecarboxamide; N-2-amino-1-(phenylmethyl) associated with tumor cell Survival, proliferation, and inva ethyl-5-(1-methyl-1H-pyrazol-5-yl)-3- siveness. The activation of Akt is frequently observed in thiophenecarboxamide; N-(1S)-2-amino-1-(2- tumor cells. Akt comprises an N-terminal pleckstrin homol (trifluoromethyl)phenyl)methylethyl)-5-(1-methyl-1H ogy (PH) domain, a kinase domain and a C-terminal “tail pyrazol-5-yl)-3-thiophenecarboxamide: N-(1S)-2-amino region. Three isoforms of human Akt kinase (Akt-1, -2 and 1-(2-fluorophenyl)methylethyl-5-(1-methyl-1H-pyrazol -3) have been reported so far. The PH domain binds 3-phos 5-yl)-3-thiophenecarboxamide; N-(1S)-2-amino-1-(2- phoinositides, which are synthesized by phosphatidylinositol chlorophenyl)methylethyl-5-(1-methyl-1H-pyrazol-5-yl)- 3-kinase (PI3K) upon stimulation by growth factors such as 3-thiophenecarboxamide: N1-(aminomethyl)-2-methyl-2- platelet derived growth factor (PDGF), nerve growth factor phenylpropyl-5-(1-methyl-1H-pyrazol-5-yl)-3- (NGF) and insulin-like growth factor (IGF-1). Lipid binding thiophenecarboxamide; N2-amino-1-(1- to the PH domain promotes translocation of Akt to the plasma naphthalenypethyl-5-(1-methyl-1H-pyrazol-5-yl)-3- membrane and facilitates phosphorylation by another PH thiophenecarboxamide: N2-amino-1-(phenylmethyl)ethyl domain-containing protein kinases, PDK1 at Thr308, 2-(3-furanyl)-5-(1-methyl-1H-pyrazol-5-yl)-3- Thr309, and Thr305 for the Akt isoforms 1, 2 and 3, respec thiophenecarboxamide; N-(1S)-2-amino-1-(2-

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diazol-3-yl)-1-ethyl-7-(3S)-3-piperidinylmethylloxy}- Publication No. 2013/0039930 by Alitalo et al.; United States 1H-imidazo[4,5-cpyridin-4-yl)-2-methyl-3-butyn-2-ol; Patent Application Publication No. 2013/0029972 by Hips 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-(2S)-2- kind et al. (4,4,4-trifluoro-N-(1S)-2-(7S)-5-(2-hydroxy thiomorpholinylmethylloxy)-1H-imidazo[4,5-cpyridin-4- ethyl)-6-oxo-7H-pyrido2.3-d3benzazepin-7-yl)amino yl)-2-methyl-3-butyn-2-ol: 4-(2-(4-amino-1,2,5-oxadiazol 1-methyl-2-oxo-ethylbutanamide); United States Patent 3-yl)-1-ethyl-7-(2S)-2-morpholinylmethyloxy)-1H Application Publication No. 2012/0328.608 by Siebel (an imidazo[4,5-cpyridin-4-yl)-2-methyl-3-butyn-2-ol; and tagonist antibodies and anti-Notch3 NRR (negative regula 4-2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-((2R)-6- tory region) antibodies); United States Patent Application methyl-2-morpholinyl)methyloxy)-1H-imidazo[4,5-cpy Publication No. 2011/0223183 by Kitajewski et al. (fusion ridin-4-yl)-2-methyl-3-butyn-2-ol); PCT Patent Application proteins as decoy inhibitors); United States Patent Applica Publication No. WO 2008/070016 by Kelly et al. (substituted tion Publication No. 2011/0178046 by Ross et al. (gamma naphthyridine compounds, including (8-4-(1-aminocy secretase inhibitors, including Semagacestat (2S)-2-Hy clobutyl)phenyl-9-phenyl 1.2.4 triazolo 3,4-f-1,6-naph droxy-3-methyl-N-(1S)-1-methyl-2-oxo-2-(1S)-2,3,4,5- thyridin-3 (2H)-one); and PCT Patent Application Publication tetrahydro-3-methyl-2-oxo-1H-3-benzazepin-1-yl)amino No. WO 2007/058850 by Heerding et al. (1H-imidazo[4,5-c. ethylbutanamide, also known as LY450139; Eli Lilly and pyridin-2-yl compounds). Co.), Compound E ((2S)-2-(3,5-difluorophenyl)acetyl 1081. The Notch signaling pathway has been identified as amino-N-(3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H playing an important role in many diverse biological func 1,4-benzodiazepin-3-ylpropanamideliavailable from Alexis 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 1082. Notch inhibitors include, but are not limited to, inhibitor IV. gamma secretase inhibitor V. gamma Secretase SemagaceStat, 7-(S)-N'(3,5-difluorophenylacetyl)-L- inhibitor VI, gamma Secretase inhibitor VII, gamma Secretase alaninyl)amino-5-methyl-5,7-dihydro-6H-dibenzb.d inhibitor IX, gamma secretase inhibitor X, gamma Secretase azepin-6-one (YO-01027), and (2R,3S)-N-(3S)-1-Methyl inhibitor XI, gamma secretase inhibitor XII, gamma Secretase 2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2, inhibitor XIII, gamma secretase inhibitor XIV. gamma secre 3-bis(3,3,3-trifluoropropyl)succinamide (BMS-906024). tase inhibitor XVI, gamma secretase inhibitor XVII, gamma 1083. 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-A- 8,377,886 to Susztak et al.; U.S. Pat. No. 8.362,075 Lewis et Sta-OCH); and PCT Patent Application Publication No. WO al.; U.S. Pat. No. 8,343,923 to Long et al. (DAPT (N-N-(3, 2012/129353 by Quesnelle et al. 5-difluorophenacetyl-L-alanyl)-S-phenylglycine t-butyl 1084. 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 US 2016/0166546 A1 Jun. 16, 2016 76 the multiprotein complex responsible for conformational equatorial domain, and the intermediate domain. Hsp60 also maturation of newly formed nascent peptides into biologi functions in the replication of mitochondrial DNA. cally active three-dimensional structures. Hsp90 is an ATP 1085 Hsp90 inhibitors include, but are not limited to, dependent protein with an ATP binding site in the N-terminal IPI-493 (17-amino-17-demethoxygeldanamycin); IPI-504 region of the active homodimer. Disruption of the ATPase (retaspimycin hydrochloride); 17-demethoxy-17-(2-propy activity of Hsp90 results in the destabilization of multiprotein lamino)-geldanamycin; AUY-922 (5-(2,4-dihydroxy-5-iso complexes and Subsequent ubiquitination of the client pro propylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl) tein, which undergoes proteasome-mediated hydrolysis. isoxazole-3-carboxamide); elesclomol; ganetispib; More specifically, in an ATP-dependent fashion, Hsp70 binds alvespimycin (17-demethoxy-17-2-(dimethylamino)ethyl to newly synthesized proteins cotranslationally and/or post aminol-geldanamycin hydrochloride); 5'-O-(4-cyanophe translationally to stabilize the nascent peptide by preventing nyl)methyl-8-II(3,4-dichlorophenyl)methylamino-ad aggregation. Stabilization of the Hsp70/polypeptide binary enosine; N1-(3-endo)-8-5-(cyclopropylcarbonyl)-2- complex is dependent upon the binding of Hsp70 interacting pyridinyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-5-II (1R)- 1-methylpropylamino-1,4-benzenedicarboxamide; (2,4- protein (“HIP”), which occurs after Hsp70 binds to the newly dihydroxy-5-isopropylphenyl)(5-(4-methylpiperazin-1-yl) formed peptide. Hsp70-Hsp90 organizing protein (“HOP) methyl)isoindolin-2-yl)methanone, 4-(6,6-dimethyl-4-OXo contains highly conserved tetratricopeptide repeats (“TPRs) 3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-1-yl)-2-((1r, that are recognized by both Hsp70 and Hsp90, promoting the 4r)-4-hydroxycyclohexylamino)benzamide: (1 r,4r)-4-(2- union of Hsp70/HIP and Hsp90, which results in a heteropro carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4.5, tein complex. In the case of telomerase and steroid hormone 6,7-tetrahydroindazol-1-yl)phenylamino)cyclohexyl receptors, the client protein is transferred from the Hsp70 2-aminoacetate; 2-amino-4-(2,4-dichloro-5-(2-(pyrrolidin system to the Hsp90 homodimer with concomitant release of 1-yl)ethoxy)phenyl)-N-ethylthieno2,3-dipyrimidine-6-car Hsp70, HIP, and HOP. Upon binding of ATP and an immu boxamide: 6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2- nophilin with cis/trans peptidyl prolyl-isomerase activity 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 1086. 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) cin (17-AAG), 17-(desmethoxy)-17-dimethylaminoethy in malignant cells; the activities of these proteins are required lamino-geldanamycin (17-DMAG), radicicol); U.S. Pat. No. to promote angiogenesis in tumor cells. Hsp90 also promotes 8.329,179 to Nietal. (17-aminogeldanamycin); U.S. Pat. No. the spread of tumors by assisting matrix metalloproteinase 8,158,638 to Ohsuki et al. (pyrazolopyrimidine derivatives); MMP2. Another heat shock protein that acts as a chaperone is U.S. Pat. No. 7,129,244 to Kasibhatla et al.; U.S. Pat. No. Hsp60. Hsp60 is implicated in mitochondrial protein import 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.

US 2016/0166546 A1 Jun. 16, 2016 protein-coupled receptors and tyrosine kinase receptors. 1090. Inhibitors of phosphatidylinositide 3-kinase (PI3K) They are heterodimeric molecules composed of a regulatory include, but are not limited to, wortmannin, LY294.002, BEZ and a catalytic subunit; they are further divided between IA 205 (2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3- and IB subsets on sequence similarity. Class IA PI3K is dihydroimidazo 4.5-cquinolin-1-yl)phenyl)propanenitrile), composed of a heterodimer between a p110 catalytic subunit GDC-0941 (2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)pip and a p85 regulatory subunit. There are five variants of the erazin-1-yl)methyl)-4-morpholinothieno3.2-dpyrimidine), p85 regulatory subunit, designated p85C, p55C. p50C., p85B, idelalisib, buparlisib, GDC-0032 (4-5,6-dihydro-2-3-me and p85y. There are also three variants of the p110 catalytic thyl-1-(1-methylethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-d subunit designated p110C., B, or 8 catalytic subunit. The first 1,4-benzoxazepin-9-yl-O.C.-dimethyl-1H-pyrazole-1-ac three regulatory subunits are all splice variants of the same etamide), SF-1126 (N2-1,4-dioxo-4-4-(4-oxo-8-phenyl gene (Pik3r1), the other two being expressed by other genes 4H-1-benzopyran-2-yl)morpholinium-4-yl)methoxybutyl (Pik3r2 and Pik3r3, p85 B, and p55Y, respectively). The most L-arginylglycyl-L-C.-aspartyl-L-serine inner salt), NU7441 highly expressed regulatory Subunit is p85C.; all three cata (8-(4-dibenzothienyl)-2-(4-morpholinyl)-4H-1-benzopyran lytic Subunits are expressed by separate genes. Class II and III 4-one), BYL-719 ((2S) N1-(4-methyl-5-2-(2.2.2-trif PI3Kare differentiated from the Class I by their structure and luoro-1,1-dimethylethyl)-4-pyridinyl-2-thiazolyl)-2-pyrro function. Class II comprises three catalytic isoforms (C2C. lidinedicarboxamide), IPI-145 (8-chloro-2-phenyl-3-(1S)- C2B, and C2Y), but, unlike Classes I and III, no regulatory 1-(9H-purin-6-ylamino)ethyl-1(2H)-isoquinolinone), proteins. Class II PI3Ks catalyze the production of PI(3)P and GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl) PI(3,4)P from PI; however, little is known about their role in phenyl)methyl-6-(4-morpholinyl)-1H-Benzimidazole-4- immune cells. The distinct feature of Class II PI3Ks is the carboxylic acid), TG-100713 (3-(2,4-diamino-6-pteridinyl)- C-terminal C2 domain. This domain lacks critical Asp resi phenol), PI3K/HDAC Inhibitor I (N-hydroxy-2-(((2-(6- dues to coordinate binding of Ca", which suggests class II methoxypyridin-3-yl)-4-morpholinothieno3.2-dpyrimidin PI3Ks bind lipids in a Ca"-independent manner. Class III 6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide), produces only PI(3)P from PI but are more similar to Class I YM201636 (6-amino-N-3-4-(4-morpholinyl)pyrido3'2': in structure, as they exist as a heterodimers of a catalytic 4.5 furo3,2-dipyrimidin-2-yl)phenyl)-3-pyridinecarboxa (Vps34) and a regulatory (Vps 15/p150) subunit. Class III mide), NVP-BGT226 (8-(6-methoxypyridin-3-yl)-3-methyl seems to be primarily involved in the trafficking of proteins 1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H and vesicles. There is, however, evidence to show that they are imidazo 4.5-cquinolin-2(3H)-one maleic acid), able to contribute to the effectiveness of several processes PF-04691502 (2-amino-8-((1r,4r)-4-(2-hydroxyethoxy)cy important to immune cells, not least phagocytosis. PI3KS can clohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido2,3- activate Akt, as in the PI3K/Akt/mTOR pathway. The various dpyrimidin-7(8H)-one), PKI-402 (1-(4-(3-ethyl-7-mor 3-phosphorylated inositides produced by the catalytic activ pholino-3H-1.2.3 triazolo 4,5-dipyrimidin-5-yl)phenyl)-3- ity of PI3Ks function in a mechanism by which various sig (4-(1-methylpiperazine-4-carbonyl)phenyl)urea), naling proteins, containing the PX domain, pleckstrinhomol CH5132799 (5-(7-(methylsulfonyl)-2-morpholino-6,7-dihy ogy domains (PH domains), FYVE domains, and other dro-5H-pyrrolo2,3-dipyrimidin-4-yl)pyrimidin-2-amine), phosphoinositide-binding domains are recruited to cell mem AS-252424 (Z)-5-((5-(4-fluoro-2-hydroxyphenyl)furan-2- branes. In general. The pleckStrin homology domain of Akt yl)methylene)thiazolidine-2,4-dione), AS-604850 ((Z)-5- binds directly to PI(3,4)P and PI(3,4,5)P, which are pro ((2,2-difluorobenzod1.3dioxol-5-yl)methylene)thiazoli duced by activated PI 3-kinase. Since PI(3,4)P, and PI(3,4,5) dine-2,4-dione), CAY10505 ((E)-5-((5-(4-fluorophenyl) Ps are restricted to the plasma membrane, this results in trans furan-2-yl)methylene)thiazolidine-2,4-dione), GSK2126458 location of Akt to the plasma membrane. Likewise, the (2,4-difluoro-N-(2-methoxy-5-(4-(pyridazin-4-yl)cquinolin phosphoinositide-dependent kinase-1 also contains a pleck 6-yl)pyridin-3-yl)benzenesulfonamide), A66 ((2S)- N1-(5- strin homology domain that binds directly to PI(3,4)P and (2-tert-butylthiazol-4-yl)-4-methylthiazol-2-yl)pyrrolidine PI(3,4,5)P, causing it to also translocate to the plasma mem 1.2-dicarboxamide), PF-05212384 (1-(4-(4- brane upon activation of PI3K. The colocalization of acti (dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4.6- vated phosphoinositide-dependent kinase-1 and Akt allows dimorpholino-1,3,5-triazin-2-yl)phenyl)urea), PIK-294 (2- Akt to become phosphorylated by phosphoinositide-depen ((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo 3,4-d dent kinase-bon threonine 308, leading to partial activation of pyrimidin-1-yl)methyl)-5-methyl-3-o-tolylcuinazolin-4 Akt. Full activation of Akt occurs upon phosphorylation of (3H)-one), PIK-293 (2-((4-amino-1H-pyrazolo 3,4-d serine 473 by the TORC2 complex of the mTOR protein pyrimidin-1-yl)methyl)-5-methyl-3-o-tolylcuinazolin-4 kinase. This signaling pathway has been shown to be required (3H)-one), XL765 (N-4-3-(3,5-dimethoxyphenyl) for an extremely diverse array of cellular activities, most amino-2-quinoxalinyl)aminosulfonylphenyl-3-methoxy notably cellular proliferation and survival. The phosphati 4-methyl-benzamide), PIK-93 (N-5-4-chloro-3-(2- dylinositol 3-kinase/protein kinase B pathway is stimulated hydroxyethyl)sulfamoylphenyl]-4-methylthiazol-2-yl) in protection of astrocytes from ceramide-induced apoptosis. acetamide), AZD6482 ((R)-2-(1-(7-methyl-2-morpholino-4- Additionally, the Class IA PI3K p110C. is mutated in many oxo-4H-pyrido 1,2-alpyrimidin-9-yl)ethylamino)benzoic malignancies; many of these mutations cause the kinase to be acid), AS-605240 ((Z)-5-(quinoxalin-6-ylmethylene)thiazo more active. These mutations have been associated with a lidine-2,4-dione), GSK105.9615 ((Z)-5-((4-(pyridin-4-yl) number of types of cancer, including ovarian cancer, cervical quinolin-6-yl)methylene)thiazolidine-2,4-dione), TG 100 cancer, breast cancer, colorectal cancer, endometrial cancer, 115 (6.7-bis(3-hydroxyphenyl)pteridine-2,4-diamine), gastric carcinomas, hepatocellular carcinoma, Small and non IC-87114 (2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3- Small cell lung cancer, thyroid carcinoma, acute myelogenous o-tolylcuinazolin-4(3H)-one), PIK-75 ((E)-N'-((6-bromoH leukemia (AML), chronic myelogenous leukemia (CML), imidazo[1,2-alpyridin-3-yl)methylene)-N,2-dimethyl-5-ni and glioblastomas. trobenzenesulfonohydrazidehydrochloride), PIK-90, XL 147

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(4-allyl-benzene-1, amino-3-methyl-1H-pyrazolo 3,4-dipyrimidin-1-yl)ethyl 2-diol (hydroxychavicol); 4.5-diallylbenzene-1,2-diol: 3,4- 6-chloro-3-ethoxy-2-(2-oxo-1,3-oxazolidin-5-yl) benzonitrile; 6-3-1-(4-amino-3-methyl-1H-pyrazolo 3,4- diallylbenzene-1,2-diol, 4-allyl-5-propylbenzene-1,2-diol; dpyrimidin-1-yl)ethyl-5-chloro-2-methoxy-6- 4.5-diallyl-1,2-phenylene diacetate, 4-allyl-1,2-phenylene methylphenylmorpholin-3-one: 5-3-1-(4-amino-3- diacetate, 4-allyl-5-propyl-1,2-phenylene diacetate; (E)- methyl-1H-pyrazolo 3,4-dpyrimidin-1-yl)ethyl-5-chloro ethyl 4-(3,4-dihydroxyphenyl)-4-methylpent-2-enoate; (E)- 2-methoxy-6-methylphenyl-1,3-oxazolidin-2-one: 4-3-1- 4-(5-ethoxy-2-methyl-5-oxopent-3-en-2-yl)-1,2-phenylene (4-amino-3-methyl-1H-pyrazolo 3,4-dpyrimidin-1-yl) diacetate; 3-allyl-benzene-1,2-diol; and 3-allyl-1,2-phe ethyl-5-chloro-2-ethoxy-6-fluorophenylpyrrolidin-2-one; nylene diacetate); United States Patent Application Publica 4-1-(4-amino-3-methyl-1H-pyrazolo 3,4-dpyrimidin-1-yl) tion No. 2012/0178736 by Castanedo et al. (bicyclic pyrim ethyl-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzoni idines); United States Patent Application Publication No. trile, 4-3-1-(4-amino-3-methyl-1H-pyrazolo 3,4-dipyri 2012/0171199 by Dotsonetal. (tricyclic compounds); United midin-1-yl)ethyl-5-chloro-2-ethoxy-6-fluorophenyl-1,3- States Patent Application Publication No. 2012/0165321 by oxazolidin-2-one; and 5-3-1-(4-amino-3-methyl-1H Adams et al. (quinoline derivatives); United States Patent pyrazolo 3,4-dpyrimidin-1-yl)ethyl-5-chloro-2-ethoxy-6- Application Publication No. 2012/0157430 by Li et al. (N- fluorophenyl-1,3-oxazolidin-2-one); United States Patent (1-(substituted-phenyl)ethyl)-9H-purin-6-amine deriva Application Publication No. 2013/0029984 by Castro et al.: tives); United States Patent Application Publication No. United States Patent Application Publication No. 2013/ 2012/0129848 by Shuttleworth et al. (benzo E1.3 oxazin 0029982 by Castro et al.: United States Patent Application 4-one derivatives); United States Patent Application Publica Publication No. 2013/0018057 by Burliet al. (quinoline and tion No. 2012/0108627 by Kumar et al. (imidazo 4.5-c. quinoxaline derivatives, substituted by a fused bicyclic pyri quinoline derivatives); United States Patent Application dine or pyrimidine moiety attached via an alkylene chain Publication No. 2012/0077815 by Allen et al. (amino-substi optionally linked to a heteroatom); United States Patent tuted fused pyridine and pyrazine derivatives); United States Application Publication No. 2013/0012517 by Allen et al. Patent Application Publication No. 2012/007 1475 by (quinoline and quinoxaline derivatives, Substituted by an Taniyama et al. (urea derivatives); United States Patent Appli optionally Substituted bicyclic heteroaryl moiety consisting cation Publication No. 2012/0053167 by Allen et al. (substi of two fused six-membered aromatic rings attached via an tuted 1.3.5 triazin-2-yl derivatives); United States Patent alkylene chain optionally linked to a heteroatom); United Application Publication No. 2012/0053166 by Hamblin et al. States Patent Application Publication No. 2012/0263712 by (4-oxadiazol-2-yl-indazoles); United States Patent Applica Fairhurst et al. (pyrrolidine-1,2-dicarboxamide derivatives): tion Publication No. 2012/0035208 by Dotson et al. (pyrazol United States Patent Application Publication No. 2012/ opyridines); and United States Patent Application Publication 0252802 by Brown et al. ((alpha-substituted aralkylamino or No. 2012/0015964 by Fowler et al. (3-(2,6-difluoro-phenyl)- heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benz 2-1-(9H-purin-6-ylamino)-ethyl-3H-quinazolin-4-one). imidazoles); United States Patent Application Publication 1092 Directed antibody conjugates, also known as anti No. 2012/0245171 by Baldwin et al. (benzpyrazole deriva body-drug conjugates, are well known in the art. Examples tives); United States Patent Application Publication No. include brentuximab vedotin and trastuzumab emtansine. 2012/0245144 by Heffron et al. (benzoxazepine com Directed antibody conjugates (antibody-drug conjugates or pounds); United States Patent Application Publication No. ADC) are described in U.S. Pat. No. 8,470,329 to Oflazoglu 2012/0238587 by Lee et al. (pyridopyrimidines); United et al., U.S. Pat. No. 8,466,260 to Elkins et al., U.S. Pat. No. States Patent Application Publication No. 2012/0238571 by 8,461,117 to Sufi et al., U.S. Pat. No. 8,436,147 to Dennis et Baldwin et al. (indazole derivatives); United States Patent al., U.S. Pat. No. 8,420,086 to Govindan et al., and U.S. Pat. Application Publication No. 2012/0232072 by Kumar et al. No. 8.394.967 to Ebens, Jr. et al., all of which are incorpo (imidazopyridine derivatives); United States Patent Applica rated by this reference. In a directed antibody conjugate (an tion Publication No. 2012/0225859 by Burger et al. (pyrimi tibody-drug conjugate), typically, the therapeutic agent and dine derivatives); United States Patent Application Publica antibody are covalently joined by a cleavable linker. A num tion No. 2012/0220587 by Emde et al. (pyridinylimidazolone ber of cleavable linkers are known in the art. US 2016/0166546 A1 Jun. 16, 2016

1093. Adjuvants are well known in the art and are dosage kit and packaging possesses increased therapeutic described above. efficacy or reduced side effects as compared with an unmodi 1094 Kinase inhibitors are well known in the art. Kinase fied therapeutic agent; and inhibitors block the phosphorylation of one or more serine, 1102 (v) a therapeutically effective quantity of a thera threonine, tyrosine, or in Some cases, histidine residues in peutic agent, a modified therapeutic agent, or a derivative, proteins that are the Substrates of kinases. Many kinases regu analog, or prodrug of a therapeutic agent or modified thera late cell proliferation and represent targets for chemotherapy. peutic agent that is Subjected to a bulk drug product improve Kinase inhibitors can be either Small molecules, monoclonal ment, wherein the therapeutic agent, the modified therapeutic antibodies, or RNA aptamers. Small-molecule kinase inhibi agent, or the derivative, analog, or prodrug of a therapeutic tors include, but are not limited to, afatinib, axitinib, bosu agent or modified therapeutic agent Subject to the bulk drug tinib, crizotinib, dasatinib, erlotinib, fostamatinib, gefitinib, product improvement possesses increased therapeutic effi ibrutinib, lapatinib, lenvatinib, mulbritinib, nilotinib, pazo cacy or reduced side effects as compared with an unmodified panib, ruxolitinib, Sorafenib, Sunitinib, SU6656 ((3Z) N.N- therapeutic agent; Dimethyl-2-oxo-3-(4,5,6,7-tetrahydro-1H-indol-2-ylmeth 1103 (vi) a therapeutically effective quantity of a thera ylidene)-2,3-dihydro-1H-indole-5-sulfonamide)), peutic agent or a derivative, analog, or prodrug of a therapeu tofacitinib, Vandetanib, and Vemurafenib. Monoclonal anti tic agent, wherein the therapeutic agent or the derivative, body kinase inhibitors include, but are not limited to, bevaci analog, or prodrug of the therapeutic agent is optimized for Zumab, cetuximab, panitumumab, ranibizumab, and trastu increasing an immunologic response; and Zumab. RNA aptamer kinase inhibitors include, but are not 1104 (vii) a composition comprising: limited to, pegaptinib. 1105 (a) a therapeutically effective quantity of a thera 1095) Another aspect of the present invention is a compo peutic agent or a derivative, analog, or prodrug of a sition to improve the efficacy and/or reduce the side effects of therapeutic agent; and Suboptimally administered drug therapy comprising an alter 1106 (b) at least one immune adjuvant for stimulating native selected from the group consisting of an immune response; 1096 (i) a therapeutically effective quantity of a modified wherein the therapeutic agent, the modified therapeutic agent, therapeutic agent or a derivative, analog, or prodrug of a or the derivative, analog, or prodrug of a therapeutic agent or therapeutic agent or modified therapeutic agent, wherein the modified therapeutic agent Subject to the bulk drug product modified therapeutic agent or the derivative, analog or pro improvement possesses increased therapeutic efficacy or drug of the therapeutic agent or modified therapeutic agent reduced side effects as compared with an unmodified thera possesses increased therapeutic efficacy or reduced side peutic agent; wherein the unmodified therapeutic agent is effects as compared with an unmodified therapeutic agent; bisantrene or a derivative or analog of bisantrene, the modi fied therapeutic agent is a modification of bisantrene or a 1097 (ii) a composition comprising: derivative or analog of bisantrene, and the derivative, analog, 1098 (a) a therapeutically effective quantity of a thera or prodrug is a derivative, analog, or prodrug of bisantrene or peutic agent, a modified therapeutic agent or a deriva of a derivative or analog of bisantrene. tive, analog, or prodrug of a therapeutic agent or modi 1107. In one alternative, the composition comprises a fied therapeutic agent; and composition to improve the efficacy and/or reduce the side 1099 (b) at least one additional therapeutic agent, effects of Suboptimally administered drug therapy compris therapeutic agent Subject to chemosensitization, thera ing a therapeutically effective quantity of a therapeutic agent peutic agent Subject to chemopotentiation, diluent, or modified therapeutic agent or a derivative, analog, or pro excipient, Solvent system, drug delivery system, or agent drug of a therapeutic agent or modified therapeutic agent, for enhancing the activity or efficacy of the therapeutic wherein the therapeutic agent or modified therapeutic agent agent, the modified therapeutic agent or the derivative, or the derivative, analog or prodrug of the therapeutic agent or analog, or prodrug of a therapeutic agent or modified modified therapeutic agent possesses increased therapeutic therapeutic agent of (a), wherein the composition pos efficacy or reduced side effects, wherein the composition: sesses increased therapeutic efficacy or reduced side 1108 (a) includes at least one bulk drug product effects as compared with an unmodified therapeutic improvement; agent, 1109 (b) is produced in a specified dosage form; 1100 (iii) a therapeutically effective quantity of a thera 1110 (c) includes a drug conjugate form; peutic agent, a modified therapeutic agent, or a derivative, 1111 (d) includes a compound analog; or analog, or prodrug of a therapeutic agent or modified thera 1112 (e) includes a prodrug; peutic agent that is incorporated into a dosage form, wherein wherein the therapeutic agent, the modified therapeutic agent, the therapeutic agent, the modified therapeutic agent, or the or the derivative, analog, or prodrug of a therapeutic agent or derivative, analog, or prodrug of a therapeutic agent or modi modified therapeutic agent Subject to the bulk drug product fied therapeutic agent incorporated into the dosage form pos improvement possesses increased therapeutic efficacy or sesses increased therapeutic efficacy or reduced side effects reduced side effects as compared with an unmodified thera as compared with an unmodified therapeutic agent; peutic agent; wherein the unmodified therapeutic agent is 1101 (iv) a therapeutically effective quantity of a thera bisantrene or a derivative or analog of bisantrene, the modi peutic agent, a modified therapeutic agent, or a derivative, fied therapeutic agent is a modification of bisantrene or a analog, or prodrug of a therapeutic agent or modified thera derivative or analog of bisantrene, and the derivative, analog, peutic agent that is incorporated into a dosage kit and pack or prodrug is a derivative, analog, or prodrug of bisantrene or aging, wherein the therapeutic agent, the modified therapeu of a derivative or analog of bisantrene. tic agent, or the derivative, analog, or prodrug. ofatherapeutic 1113. In another alternative, the composition comprises a agent or modified therapeutic agent incorporated into the composition to improve the efficacy and/or reduce the side US 2016/0166546 A1 Jun. 16, 2016 effects of Suboptimally administered drug therapy compris prising a therapeutically effective quantity of a therapeutic ing a therapeutically effective quantity of a therapeutic agent agent or modified therapeutic agent, wherein the composition or modified therapeutic agent, wherein the composition: further comprises: 1114 (a) is formulated for use in a program of dose 1140 (a) an additional therapeutic agent; modification; 1141 (b) a therapeutic agent Subject to chemosensitiza 1115 (b) is formulated for use in a program of alteration tion; or modification of route of administration; 1142 (c) a therapeutic agent Subject to chemopotentia 1116 (c) is formulated for use in a program of alteration tion; or modification of schedule of administration; 1143 (d) a second therapeutic agent that forms a mul 1117 (d) is formulated for use in a program of selecting tiple drug system; appropriate indications for use; 1144 (e) an agent that enhances the activity of the thera 1118 (e) is formulated for use in a program of selecting peutic agent or modified therapeutic agent; appropriate disease stages for use: 1145 (f) at least one survivin modulator or inhibitor; 1119 (f) is formulated for use in a program of selecting 1146 (g) at least one multidrug resistance reversal appropriate additional indications for use; agent, 1120 (g) is formulated for use in a program of selecting 1147 (h) at least one directed antibody conjugate; appropriate patients for use of the composition; 1148 (i) at least one adjuvant; or 1121 (h) is formulated for use in a program of selecting 1149 () an additional therapeutic agent suitable for use appropriate patient or disease phenotypes for use of the with the therapeutic agent in a combinatorial regime, composition; wherein the quantities of the therapeutic agent and the 1122 (i) is formulated for use in a program of selecting additional therapeutic agent are chosen to provide effec appropriate patient or disease genotypes for use of the tive activity of both the therapeutic agent and the addi composition; tional therapeutic agent, wherein the therapeutic agent or the modified therapeutic agent in the composition 1123 () 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 1124 (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 1125 (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 1126 (m) is formulated for use in a program of bio modification of bisantrene or a derivative or analog of therapeutic resistance modulation; bisantrene. 1127 (n) is formulated for use in a program of radiation 1150. When the composition is formulated for use in a therapy enhancement; program of dose modification or in a program of alteration or 1128 (o) is formulated for use to employ novel mecha modification of schedule of administration, one of ordinary nisms of action in its therapeutic activity; skill in the art would be able to formulate the composition 1129 (p) is formulated for use in a program of selective according to the intended dosage or range of dosages or the target cell population therapeutics; intended schedule of administration, taking into account Such 1130 (q) is formulated for use in a program of modu variables as the status or progress of the disease or condition lating DNA methylation: for which the composition is to be used, other therapeutic 1131 (r) is formulated for use in a program of inhibiting agents the sex, age, and weight of the patient, and pharmaco telomerase or inducing telomere dysfunction; kinetic considerations such as liver or kidney function. When 1132 (s) is formulated for use in a program of inhibiting the composition is formulated for use in a program of alter Surv1V1n; ation or modification of route of administration, one of ordi nary skill in the art would be able to formulate the composi 1133 (t) further comprises a diluent; tion according to the physical properties of the composition, 1134 (u) further comprises a solvent system; such as physical form, flowability, and compatibility of the 1135 (v) further comprises an excipient; composition with the intended route of administration. When 1136 (w) is incorporated into a dosage kit and packag the composition is formulated for use in a program of select 1ng ing appropriate indications for use, appropriate disease stages 1137 (x) comprises a drug delivery system; or for use, appropriate additional indications for use, or appro 1138 (y) is formulated to optimize an immunological priate patients for use of the composition, one of ordinary response; skill in the art would be able to formulate the composition wherein the therapeutic agent or the modified therapeutic according to the intended requirements, including the targets agent in the composition possesses increased therapeutic effi of therapeutic treatment, the possibility of side effects or cacy or reduced side effects as compared with the therapeutic toxicity, and the severity or stage of disease intended to be agent or unmodified therapeutic agent as administered indi treated. When the composition is formulated for use in a vidually and not in the composition, wherein the unmodified program of selecting appropriate patient or disease pheno therapeutic agent is bisantrene or a derivative or analog of types or genotypes for use of the composition, one of ordinary bisantrene, and the modified therapeutic agent is a modifica skill in the art would be able to formulate the composition tion of bisantrene or a derivative or analog of bisantrene. according to the intended requirements, including the par 1139. In yet another alternative, the composition com ticular phenotypes or genotypes involved, the possibility of prises a composition to improve the efficacy and/or reduce the Somatic mutation in target cells, and the potential for the side effects of Suboptimally administered drug therapy com occurrence of drug resistance in target cells. When the com US 2016/0166546 A1 Jun. 16, 2016

position is formulated for use in a program of prefpost-treat United States Patent Application Publication No. 2014/ ment preparation or a program of alternative medicine/thera 0179768 by Bettencourt (emulsions); PCT Patent Applica peutic support, one of ordinary skill in the art would be able to tion Publication No. WO 2007/136219 by Kim et al. (doc formulate the composition according to the intended require etaxel for injection); United States Patent Application ments, including compatibility and lack of deleterious inter Publication No. 2014/0179738 by Singh et al. (formulations actions with additional agents being administered or methods for oral administration); United States Patent Application being used. When the composition is formulated for use in a Publication No. 2014/0179732 by Jaroskova et al.; United program of biotherapeutic enhancement or biotherapeutic States Patent Application Publication No. 2014/0179624 by resistance modulation, one of ordinary skill in the art would Gutterman et al., PCT Patent Application Publication No. be able to formulate the composition according to the WO 2008/107452 by German et al.; United States Patent intended requirements, including the compatibility with the Application Publication No. 2014/0186447 by Desai (nano biotherapeutic agents and the lack of side effects or deleteri particulate compositions); United States Patent Application ous interactions. When the composition is formulated for use Publication No. 2014/0186430 by Gould-Fougerite etal. (co in a program of radiation therapy enhancement, one of ordi chleate pharmaceutical compositions); United States Patent nary skill in the art would be able to formulate the composi Application Publication No. 2014/0186361 by Manning et al. tion according to the intended requirements, including com (stable aqueous formulations); United States Patent Applica 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 1152 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 1153 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 1154 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 1155 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 1156. 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 1157 (i) bisantrene or a derivative or analog of bisantrene: account by one of ordinary skill in the art. and 1151. Manufacturing methods for compositions are well 1158 (ii) an additional therapeutic agent selected from the known in the art. Such manufacturing methods are disclosed group consisting of: in United States Patent Application Publication No. 2014/ 1159 (a) fraudulent nucleosides; 0179749 by Lorenz et al.; United States Patent Application 1160 (b) fraudulent nucleotides; Publication No. 2014/01797.12 by Baker et al. (tablets): U.S. 1161 (c) thymidylate synthetase inhibitors; Pat. No. 7,094.545 to Lomryd et al. (solid dosage forms): 1162 (d) signal transduction inhibitors; US 2016/0166546 A1 Jun. 16, 2016 87

1163 (e) cisplatin or platinum analogs; 1212 (bb) inhibitors of CXCR4; 1164 (f) alkylating agents; 1213 (bc) pyruvate dehydrogenase kinase (PDK1) 1165 (g) anti-tubulin agents: inhibitors; 1166 (h) antimetabolites; 1214 (bd) epherin receptor targeting agents; 1167 (i) berberine; 1215 (be) binding proteins for Axl; 1168 (j) apigenin: 1216 (bf) Wnt pathway inhibitors together with MAPK 1169 (k) colchicine or an analog thereof; pathway inhibitors; 1170 (1) genistein: 1217 (bg) TEC family kinase inhibitors; 1171 (m) etoposide; 1218 (bh) substituted macrocyclic compounds with 1172 (n) cytarabine; proteasome activity; 1173 (o) camptothecins: 1219 (bi) peptide-based PACE4 inhibitors; 1174 (p) vinca alkaloids; 1220 (b) azaindole derivatives as JAK3 inhibitors; 1175 (d) topoisomerase inhibitors; 1221 (bk) inhibitors of Myc; 1176 (r) 5-fluorouracil; 1222 (bl) inhibitors of furin and other pro-protein con 1177 (s) curcumin; Vertases; 1178 (t) rosmarinic acid; 1223 (bm) GPBP-1 inhibitors, optionally together with 1179 (u) mitoguaZone: a p21 inhibitor; and 1180 (v) meiso indigo; 1224) (bn) PGE inhibitors. 1181 (w) imatinib; 1225 Typically, in this composition, the bisantrene or a 1182 (x) dasatinib; derivative or analog of bisantrene is bisantrene. 1183 (y) nilotinib; 1226. In another alternative, the composition comprises: 1184 (Z) epigenetic modulators; 1227 (i) bisantrene or a derivative or analog of bisantrene 1185 (aa) transcription factor inhibitors; and 1186 (ab) taxol; 1228 (ii) a therapeutic agent Subject to chemosensitiza 1187 (ac) homoharringtonine: tion selected from the group consisting of: 1188 (ad) pyridoxal; 1229 (a) topoisomerase inhibitors; 1189 (ae) spirogermanium; 1230 (b) fraudulent nucleosides; 1190 (af) caffeine: 1231 (c) fraudulent nucleotides: 1191 (ag) nicotinamide: 1232 (d) thymidylate synthetase inhibitors; 1192 (ah) methylglyoxalbisguanylhydrazone: 1233 (e) signal transduction inhibitors; 1193 (ai) PARP inhibitors: 1234 (f) cisplatin or platinum analogs; 1194 (a) EGFR inhibitors; 1235 (g) alkylating agents; 1195 (ak) Bruton's tyrosine kinase (BTK) inhibitors: 1236 (h) anti-tubulin agents; 1196 (al) bis-thio-hydrazide amides; 1237 (i) antimetabolites: 1197 (am) succinimide or maleimide derivatives as 1238 () berberine; inhibitors of topoisomerase II; 1239 (k) apigenin: 1198 (an) histone deacetylase (HDAC) inhibitors; 1240 (1) colchicine or an analog of colchicine; 1199 (ao) immunostimulants; 1241 (m) genistein; 1200 (ap) telomerase inhibitors; 1242 (n) etoposide; 1201 (aq) inhibitors of the expression or activity of 1243 (o) cytarabine; Her2: 1244 (p) camptothecin, 1202 (at) inhibitors of the expression of activity of 1245 (q) Vinca alkaloids; estrogen receptors; 1246 (r) 5-fluorouracil; 1203 (as) inhibitors of the expression or activity of an 1247 (s) curcumin; antigen associated with a specific tumor targets; 1248 (t) rosmarinic acid; and 1204 (at) G-quadruplex ligands; 1249 (u) mitoguaZone. 1205 (au) polycyclic lysophosphatidic receptor 1250 Typically, in this composition, the bisantrene or a antagonists; derivative or analog of bisantrene is bisantrene. 1206 (av) anti-CTGF agents: 1251. InN another- 0 alternative, the composition comprises: 1207 (aw) myeloid differentiation inducing agents: 1252 (i) bisantrene or a derivative or analog of bisantrene 1208 (ax) covalent diabodies binding to a tumor-asso- and ciated antigen; 1253 (ii) a therapeutic agent subject to chemopotentiation 1209 (ay)9. bispecific antibodies that have a cell-pen- selected from the group consisting- - - - of:- etrating determinant and an intracellular target-binding 1254 (a) topoisomerase inhibitorS; determinant; 1255 (b) fraudulent nucleosides; 1210 (az) multidomain molecules that comprise a cell 1256 (c) fraudulent nucleotides; - - - - - binding ligand that binds to cells in the tumor Stroma 1257 (d) thymidylate synthetase inhibitorS; such as endothelial cells, fibroblasts, or immune cells 1258 (e) signal transduction inhibitors; and an oligonucleotide that inhibits the nonsense-medi- 1259 (f) cisplatin or platinum analogs; ated decay pathway; 1260 (g) alkylating agents; 1211 (ba) tumor-specific antibodies binding to a por- 1261 (h) anti-tubulin agents; tion of the CD44 protein or a binding protein derived 1262 (i) antimetabolites: from the light-chain or heavy-chain complementary-de- 1263 () berberine; termining regions of Such antibodies; 1264 (k) apigenin, US 2016/0166546 A1 Jun. 16, 2016 88

1265 (1) colchicine or an analog of colchicine; 1311 Typically, in this composition, the bisantrene or a 1266 (m) genistein; derivative or analog of bisantrene is bisantrene. 1267 (n) etoposide: 1312. In yet another alternative, the therapeutic agent is 1268 (o) cytarabine; bisantrene or a derivative or analog of bisantrene and the 1269 (p) camptothecin: composition comprises an excipient, wherein the excipient is 1270 (q) Vinca alkaloids; selected from the group consisting of: 1271 (r) 5-fluorouracil; 1313 (a) mannitol; 1272 (s) curcumin; 1314 (b) albumin; 1273 (t) rosmarinic acid; and 1315 (c) EDTA; 1274 (u) mitoguaZone. 1316 (d) sodium bisulfite: 1275 Typically, in this composition, the bisantrene or a 1317 (e) benzyl alcohol: derivative or analog of bisantrene is bisantrene. 1318 (f) carbonate buffers: 1276. In yet another alternative, the therapeutic agent is 1319 (g) phosphate buffers; bisantrene or a derivative or analog of bisantrene, and the 1320 (h) PEG: amonafide orderivative oranalog of bisantrene is subjected to 1321 (i) vitamin A; a bulk drug product improvement, wherein the bulk drug 1322 () vitamin D; product improvement is selected from the group consisting 1323 (k) vitamin E: of: 1324 (1) esterase inhibitors; 1277 (a) preparation as a free base form: 1325 (m) cytochrome P450 inhibitors: 1278 (b) salt formation; 1326 (n) multi-drug resistance (MDR) inhibitors; 1279 (c) preparation as a homogeneous crystalline 1327 (o) organic resins; and Structure: 1328 (p) detergents. 1280 (d) amorphous structure; 1329. Typically, in this composition, the bisantrene or 1281 (e) preparation as a pure isomer; derivative or analog of bisantrene is bisantrene. 1282 (f) increased purity; 1330. In yet another alternative, the therapeutic agent is 1283 (g) preparation with lower residual solvent con bisantrene or a derivative or analog of bisantrene, and the tent; and bisantrene or derivative or analog of bisantrene is incorpo 1284 (h) preparation with lower residual heavy metal rated into a dosage form selected from the group consisting COntent. of: 1285 Typically, in this composition, the bisantrene or a 1331 (a) tablets; 1332 (b) capsules; derivative or analog of bisantrene is bisantrene. 1333 (c) topical gels: 1286. In still another alternative, the therapeutic agent is 1334 (d) topical creams: bisantrene or a derivative or analog of bisantrene and the 1335 (e) patches: composition comprises a diluent, wherein the diluent is 1336 (f) suppositories: selected from the group consisting of: 1337 (g) lyophilized dosage fills; 1287 (a) an emulsion; 1338 (h) immediate-release formulations; 1288 (b) dimethylsulfoxide (DMSO); 1339 (i) slow-release formulations: 1289 (c) N-methylformamide (NMF) 1340 () controlled-release formulations: 1290 (d) dimethylformamide (DMF) 1341 (k) liquid in capsules; and 1291 (e) dimethylacetamide (DMA); 1342 (1) liposomal formulations. 1292 (f)ethanol: 1343. Typically, in this composition, the bisantrene or 1293 (g) benzyl alcohol; derivative or analog of bisantrene is bisantrene. 1294 (h) dextrose-containing water for injection; 1344. In yet another alternative, the therapeutic agent is 1295 (i) Cremophor; bisantrene or a derivative or analog of bisantrene and the 1296) () cyclodextrins; and bisantrene or derivative or analog of bisantrene is incorpo 1297 (k) PEG. rated into a dosage kit and packaging selected from the group 1298 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. 1299. In still another alternative, the therapeutic agent is 1345 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 1346. 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 1300 (a) an emulsion; composition comprises a drug delivery system selected from 1301 (b) DMSO; the group consisting of 1302 (c) NMF; 1347 (a) oral dosage forms: 1303 (d) DMF; 1348 (b) nanocrystals: 1304 (e) DMA; 1349 (c) nanoparticles: 1305 (f)ethanol: 1350 (d) cosolvents: 1306 (g) benzyl alcohol; 1351 (e) slurries: 1307 (h) dextrose-containing water for injection; 1352 (f) syrups: 1308 (i) Cremophor; 1353 (g) bioerodible polymers: 1309 (i) PEG; and 1354 (h) liposomes; 1310 (k) salt systems. 1355 (i) slow-release injectable gels: US 2016/0166546 A1 Jun. 16, 2016 89

1356 () microspheres; 1389 (w) conjugates including a modified amino acid 1357 (k) amphiphilic block copolymer systems; incorporating an azido group: 1358 (1) emulsion vehicles comprising an emulsion of 1390 (x) conjugates to albumin; and C-tocopherol stabilized by biocompatible surfactants; 1391 (y) conjugates to folate. 1359 (m) biodegradable polymer compositions con 1392 Typically, in this composition, the bisantrene or taining phosphorus and desaminotyrosyl L-tyrosine derivative or analog of bisantrene is bisantrene. linkages in the polymer backbone; 1393. In yet another alternative, the therapeutic agent is a 1360 (n) substantially anhydrous injectable semi-solid modified bisantrene or a modified derivative or analog of compositions comprising a water immiscible fatty acid bisantrene and the modification is selected from the group matrix and a cytostatic agent; consisting of: 1394 (a) alteration of side chains to increase or 1361 (o) lipophilic vehicles: decrease lipophilicity; 1362 (p) pH-dependent carriers that include a com 1395 (b) addition of an additional chemical function pound that includes at least one ionizable group; ality to alter a property selected from the group consist 1363 (q) pH-dependent carriers that include a mono ing of reactivity, electron affinity, and binding capacity; carboxylic acid having at least 8 carbons and less than and about 10% by weight of Zwitterionic phospholipids; and 1396 (c) alteration of salt form. 1364 (r) liposomes comprising the bisantrene or the 1397. 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. 1398. In still another alternative of a composition accord 1365 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 1366. 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 1399 (a) enzyme sensitive esters; group consisting of 1400 (b) dimers: 1367 (a) a polymer system; 1401 (c) Schiffbases: 1368 (b) polylactides; 1402 (d) pyridoxal complexes: 1369 (c) polyglycolides: 1403 (e) caffeine complexes; 1404 (f) plasmin-activated prodrugs; and 1370 (d) amino acids; 1405 (g) drug targeting complexes comprising a target 1371 (e) peptides; ing carrier molecule that is selectively distributed to a 1372 (f) multivalent linkers; specific cell type or tissue containing the specific cell 1373 (g) conjugates to fatty acids; type; a linker which is acted upon by a molecule that is 1374 (h) conjugates to fatty alcohols; present at an effective concentration in the environs of 1375 (i) conjugates to elastin-like peptide; the specific cell type; and a therapeutically active agent 1376 () conjugates with polyclonal or monoclonal to be delivered to the specific cell type; and antibodies, proteins, or peptides; 1406 (h) a prodrug molecule comprising a conjugate of 1377 (k) conjugates with cell-binding agents through a bisantrene or a derivative or analog of bisantrene, a charged or pro-charged cross-linker, protease-specific cleavable peptide, and optionally, a 1378 (1) conjugates to antibodies targeted to tumor targeting peptide, with the prodrug molecule being Sub markers; stantially inactive prior to degradation of the protease 1379 (m) biodegradable polymer-bioactive moiety specific cleavable peptide by a proteolytic enzyme conjugates: within or in close proximity to the cancer cell. 1380 (n) conjugates with 2-nitroimidazole compounds 1407 Typically, in this composition, the bisantrene or with a secondary basic nitrogen atom and a linker; derivative or analog of bisantrene is bisantrene. 1408. In yet another alternative, the therapeutic agent is 1381 (o) conjugates with ladder frame polyether com bisantrene or a derivative or analog of bisantrene and the pounds, including those derived from brevenal, brevisin, composition further comprises at least one additional thera tamulamide, brevetoxins, hemibrevetoxins, gambierols, peutic agent to form a multiple drug system, wherein the at and gambieric acids; least one additional therapeutic agent is selected from the 1382 (p) conjugates to antibodies having one or more group consisting of: non-natural amino acid residues at specific positions in 1409 (a) inhibitors of multi-drug resistance: the heavy or light chains; 1410 (b) specific drug resistance inhibitors; 1383 (q) conjugates to a sialoadhesin binding moiety; 1411 (c) specific inhibitors of selective enzymes; 1384 (r) pheophorbide-C conjugates; 1412 (d) signal transduction inhibitors; 1385 (s) conjugates to multi-component nanochains: 1413 (e) meiso indigo; 1386 (t) conjugates to activatable antibodies that 1414 (f) imatinib; include a masking moiety, a cleavable moiety, and an 1415 (g) hydroxyurea; antibody binding specifically to interleukin-6: 1416 (h) dasatinib; 1387 (u) conjugates including hydrophilic linkers; 1417 (i) capecitabine; 1388 (V) conjugates to antibodies specific for p97; 1418 () nilotinib; US 2016/0166546 A1 Jun. 16, 2016 90

1419 (k) repair inhibition agents: 1449 Typically, in this composition, the bisantrene or 1420 (1) topoisomerase inhibitors with non-overlap derivative or analog of bisantrene is bisantrene. ping side effects; 1450 Typically, in this composition, the additional thera 1421 (m) PARP inhibitors: peutic agent is selected from the group consisting of 1422 (n) a taxane; 1451 (a) an agent inducing immunoactivity, wherein 1423 (o) cytarabine; the bisantrene or derivative or analog thereof acts as a 1424 (p) microtubule inhibitors; chemotherapeutic agent; 1425 (q) EGFR inhibitors; and 1452 (b) an agent inducing macrophage activation, 1426 (r) HDAC inhibitors. wherein the bisantrene or derivative or analog thereof 1427 Typically, in this composition, the bisantrene or acts as a chemotherapeutic agent; derivative or analog of bisantrene is bisantrene. 1453 (c) a cytokine, wherein the bisantrene or deriva 1428. In still another alternative, the therapeutic agent is tive or analog thereofacts as a chemotherapeutic agent; bisantrene or a derivative or analog of bisantrene and the 1454 (d) an agent inhibiting telomerase, wherein the composition further comprises at least one agent for enhanc bisantrene or derivative or analog thereofacts as a che ing the activity or efficacy of the bisantrene or derivative or motherapeutic agent; analog of bisantrene, wherein the at least one agent for 1455 (e) an agent inhibiting surviving, wherein the enhancing the activity or efficacy of the bisantrene or deriva bisantrene or derivative or analog thereofacts as a che tive or analog of bisantrene is selected from the group con motherapeutic agent; sisting of: 1456 (f) an agent inducing demethylation, wherein the bisantrene or derivative or analog thereofacts as a che 1429 (i) nicotinamide: motherapeutic agent; 1430 (ii) caffeine: 1457 (g) an adjuvant, wherein the bisantrene or deriva 1431 (iii) tetandrine; and tive or analog thereofacts as a chemotherapeutic agent; 1432 (iv) berberine. 1458 (h) an antibody, wherein the bisantrene or deriva 1433) Typically, in this composition, the bisantrene or tive or analog thereofacts as a chemotherapeutic agent; derivative or analog of bisantrene is bisantrene. 1459 (i) an innate or adaptive immune stimulator, 1434. In still another alternative, the composition com wherein the bisantrene or derivative or analog thereof prises a therapeutically effective quantity of bisantrene or a acts as a chemotherapeutic agent; derivative, analog, or prodrug of bisantrene, wherein the 1460) () a checkpoint inhibitor, wherein the bisantrene bisantrene or the derivative, analog, or prodrug of bisantrene or derivative or analog thereofacts as a chemotherapeu is optimized for increasing an immunologic response. tic agent; 1435 Typically, in this composition, the bisantrene or 1461 (k) an mTOR antagonist, wherein the bisantrene derivative or analog of bisantrene is bisantrene. or derivative or analog thereofacts as a chemotherapeu 1436. In still another alternative, the composition com tic agent; prises: 1462 (1) an Akt inhibitor, wherein the bisantrene or 1437 (a) a therapeutically effective quantity of bisant derivative or analog thereofacts as a chemotherapeutic rene or a derivative, analog, or prodrug of bisantrene; agent, and 1463 (m) a notch inhibitor, wherein the bisantrene or 1438 (b) at least one immune adjuvant for stimulating derivative or analog thereofacts as a chemotherapeutic an immune response. agent, 1439 Suitable immune adjuvants are as described above. 1464) (n) an HSP inhibitor, wherein the bisantrene or 1440 Typically, in this composition, the bisantrene or derivative or analog thereofacts as a chemotherapeutic derivative or analog of bisantrene is bisantrene. agent, 1441. In still another alternative, the composition com 1465 (o) a phosphatidylinositide 3-kinase inhibitor, prises: wherein the bisantrene or derivative or analog thereof 1442 (a) a therapeutically effective quantity of bisant acts as a chemotherapeutic agent; rene or a derivative or analog of bisantrene; and 1466 (p) a kinase inhibitor, wherein the bisantrene or 1443 (b) a multidrug resistance reversal agent. derivative or analog thereofacts as a chemotherapeutic 1444 Typically, the multidrug resistance reversal agent is agent, Verapamil. 1467 (q) an agent inducing telomerase inhibition, 1445 Typically, in this composition, the bisantrene or wherein the bisantrene or derivative or analog thereof derivative or analog of bisantrene is bisantrene. acts as an agent inducing macrophage activation; 1446. In yet another alternative, the composition com 1468 (r) a cytokine, wherein the bisantrene or deriva prises: tive or analog thereofacts as an agent inducing macroph 1447 (a) a therapeutically effective quantity of bisant age activation; rene or a derivative or analog of bisantrene; and 1469 (s) an agent inhibiting survivin, wherein the 1448 (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; 1470 (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 1471 (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; US 2016/0166546 A1 Jun. 16, 2016 91

1472 (v) an antibody, wherein the bisantrene or deriva compound with a mineral or organic acid or an inorganic tive or analog thereofacts as an agent inducing macroph base. Such as Salts including Sulfates, pyrosulfates, bisulfates, age activation; Sulfites, bisulfites, phosphates, monohydrogenphosphates, 1473 (w) an innate or adaptive immune stimulator, dihydrogenphosphates, metaphosphates, pyrophosphates, wherein the bisantrene or derivative or analog thereof chlorides, bromides, iodides, acetates, propionates, acts as an agent inducing macrophage activation; decanoates, caprylates, acrylates, formates, isobutyrates, 1474 (x) a checkpoint inhibitor, wherein the bisantrene caproates, heptanoates, propiolates, oxalates, malonates, suc or derivative or analog thereofacts as an agent inducing cinates, Suberates, sebacates, fumarates, maleates, butyne-1, macrophage activation; 4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, 1475 (y) an mTOR antagonist, wherein the bisantrene methyl benzoates, dinitrobenzoates, hydroxybenzoates, or derivative or analog thereofacts as an agent inducing methoxybenzoates, phthalates, Sulfonates, Xylenesulfonates, macrophage activation; phenylacetates, phenylpropionates, phenylbutyrates, citrates, 1476 (Z) an Akt inhibitor, wherein the bisantrene or lactates, B-hydroxybutyrates, glycolates, tartrates, methane derivative or analog thereof acts as an agent inducing Sulfonates, propanesulfonates, naphthalene-1-sulfonates, macrophage activation; naphthalene-2-sulfonates, and mandelates. If the pharmaco 1477 (aa) a notch inhibitor, wherein the bisantrene or logically active compound has one or more basic functional derivative or analog thereof acts as an agent inducing groups, the desired pharmaceutically acceptable salt may be macrophage activation; prepared by any suitable method available in the art, for 1478 (ab) an HSP inhibitor; wherein the bisantrene or example, treatment of the free base with an inorganic acid, derivative or analog thereof acts as an agent inducing Such as hydrochloric acid, hydrobromic acid, Sulfuric acid, macrophage activation; nitric acid, phosphoric acid and the like, or with an organic 1479 (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 1480 (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 1481 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 1482 In one alternative, the composition is formulated for tertiary), an alkali metal hydroxide or alkaline earth metal intravenous, intraperitoneal, or Subcutaneous administration. hydroxide, or the like. Illustrative examples of suitable salts The composition can alternatively be formulated for other include organic salts derived from amino acids, such as gly routes of administration, Such as, but not limited to, central or cine and arginine, ammonia, primary, secondary, and tertiary peripheral venous administration, intravesicular administra amines, and cyclic amines, such as piperidine, morpholine tion (particularly for use in treating bladder cancer), intrath and piperazine, and inorganic salts derived from Sodium, ecal administration, and intra-arterial administration. calcium, potassium, magnesium, manganese, iron, copper, 1483. When a pharmaceutical composition according to Zinc, aluminum and lithium. the present invention includes a prodrug, prodrugs and active 1485. In the case of agents that are solids, it is understood metabolites of a compound may be identified using routine by those skilled in the art that the inventive compounds and techniques known in the art. See, e.g., Bertolini et al., J. Med. salts may exist in different crystal or polymorphic forms, all Chem., 40, 2011-2016 (1997); Shan et al., J. Pharm. Sci., 86 of which are intended to be within the scope of the present (7), 765-767: Bagshawe, Drug Dev. Res., 34,220-230 (1995); invention and specified formulas. Bodor, Advances in Drug Res., 13, 224-331 (1984); Bund 1486 The amount of a given pharmacologically active gaard, Design of Prodrugs (Elsevier Press 1985); Larsen, agent that is included in a unit dose of a pharmaceutical Design and Application of Prodrugs, Drug Design and Devel composition according to the present invention will vary opment (Krogsgaard-Larsen et al., eds., Harwood Academic depending upon factors such as the particular compound, Publishers, 1991); Dearet al., J. Chromatogr. B, 748,281-293 disease condition and its severity, the identity (e.g., weight or (2000); Spraulet al., J. Pharmaceutical & Biomedical Analy Surface area) of the Subject in need of treatment, but can sis, 10, 601-605 (1992); and Proxet al., Xenobiol. 3, 103-112 nevertheless be routinely determined by one skilled in the art. (1992), all incorporated herein by this reference. Typically, such pharmaceutical compositions include athera 1484. When the pharmacologically active compound in a peutically effective quantity of the pharmacologically active pharmaceutical composition according to the present inven agent and an inert pharmaceutically acceptable carrier or tion possesses a Sufficiently acidic, a Sufficiently basic, or diluent. Typically, these compositions are prepared in unit both a sufficiently acidic and a sufficiently basic functional dosage form appropriate for the chosen route of administra group, these group or groups can accordingly react with any tion, Such as oral administration or parenteral administration. of a number of inorganic or organic bases, and inorganic and A pharmacologically active agent as described above can be organic acids, to form a pharmaceutically acceptable salt. administered in conventional dosage form prepared by com Exemplary pharmaceutically acceptable salts include those bining a therapeutically effective amount of Such a pharma salts prepared by reaction of the pharmacologically active cologically active agent as an active ingredient with appro US 2016/0166546 A1 Jun. 16, 2016 92 priate pharmaceutical carriers or diluents according to experimental data for an agent. For oral administration, an conventional procedures. These procedures may involve mix exemplary daily dose generally employed is from about 0.001 ing, granulating and compressing or dissolving the ingredi to about 3000 mg/kg of body weight, with courses of treat ents as appropriate to the desired preparation. The pharma ment repeated at appropriate intervals. In some embodiments, ceutical carrier employed may be either a solid or liquid. the daily dose is from about 1 to 3000 mg/kg of body weight. Exemplary of Solid carriers are lactose. Sucrose, talc, gelatin, 1490 Methods and compositions according to the present agar, pectin, acacia, magnesium Stearate, Stearic acid and the invention are Suitable for use in treating diseases and condi like. Exemplary of liquid carriers are syrup, peanut oil, olive tions of both humans and non-humans, including treatment of oil, water and the like. Similarly, the carrier or diluent may Socially and economically important animals such as dogs, include time-delay or time-release material known in the art, cats, cows, horses, sheep, pigs, goats, and other species. Such as glyceryl monostearate or glyceryl distearate alone or Unless specified, methods and compositions according to the with a wax, ethylcellulose, hydroxypropylmethylcellulose, present invention are not limited to treatment of humans. methylmethacrylate and the like. 1491 Typical daily doses in a patient may be anywhere 1487. A variety of pharmaceutical forms can be employed. between about 500 mg to about 3000 mg, given once or twice Thus, if a solid carrier is used, the preparation can be tableted, daily, e.g., 3000 mg can be given twice daily for a total dose placed in a hard gelatin capsule in powder or pellet form or in of 6000 mg. In one embodiment, the dose is between about the form of a troche or lozenge. The amount of solid carrier 1000 to about 3000 mg. In another embodiment, the dose is may vary, but generally will be from about 25 mg to about 1 between about 1500 to about 2800 mg. In other embodiments, g. If a liquid carrier is used, the preparation will be in the form the dose is between about 2000 to about 3000 mg. In particu 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 1488 To obtain a stable water-soluble dose form, a phar particularly suitable for bisantrene. maceutically acceptable salt of a pharmacologically active 1492 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 1493 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 1489. 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 1494. 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 US 2016/0166546 A1 Jun. 16, 2016

be used. Also, chelators such as EDTA can be used. Other pounds well, and itself produces low toxicity upon systemic ingredients that are conventional in the area of pharmaceuti administration. Naturally, the proportions of a co-solvent sys cal compositions and formulations, such as lubricants in tab tem may be varied considerably without destroying its solu lets or pills, coloring agents, or flavoring agents, can be used. bility and toxicity characteristics. Furthermore, the identity of Also, conventional pharmaceutical excipients or carriers can the co-solvent components may be varied: for example, other be used. The pharmaceutical excipients can include, but are low-toxicity nonpolar surfactants may be used instead of not necessarily limited to, calcium carbonate, calcium phos polysorbate 80; the fraction size of polyethylene glycol may phate, various Sugars or types of starch, cellulose derivatives, be varied; other biocompatible polymers may replace poly gelatin, vegetable oils, polyethylene glycols and physiologi ethylene glycol, e.g. polyvinyl pyrrolidone; and other Sugars cally compatible solvents. Other pharmaceutical excipients or polysaccharides may be substituted for dextrose. are well known in the art. Exemplary pharmaceutically 1499 Alternatively, other delivery systems for hydropho acceptable carriers include, but are not limited to, any and/or bic pharmaceutical compounds may be employed. Lipo all of solvents, including aqueous and non-aqueous solvents, Somes and emulsions are known examples of delivery dispersion media, coatings, antibacterial and/or antifungal vehicles or carriers for hydrophobic drugs. Certain organic agents, isotonic and/or absorption delaying agents, and/or the Solvents such as dimethylsulfoxide also may be employed, like. The use of Such media and/or agents for pharmaceuti although usually at the cost of greater toxicity. Additionally, cally active substances is well known in the art. Exceptinsofar the compounds may be delivered using a Sustained-release as any conventional medium, carrier, or agent is incompatible system, Such as semipermeable matrices of Solid hydropho with the active ingredient or ingredients, its use in a compo bic polymers containing the therapeutic agent. Various Sus 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. 1500. The pharmaceutical compositions also may com 1495. 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 1501. 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 1496 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, 1497 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 1498. 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 1502 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 US 2016/0166546 A1 Jun. 16, 2016 94 are preferably manufactured under GMP conditions. Formu typically takes into account physicochemical properties of lations for parenteral administration may, for example, con the pharmacologically active agent, such as aqueous solubil tain excipients, sterile water, or saline, polyalkylene glycols ity, partition coefficient, molecular size, stability, and nonspe Such as polyethylene glycol, oils of vegetable origin, or cific binding to proteins and other biological macromol hydrogenated naphthalenes. Biocompatible, biodegradable ecules. This process of preparation also takes into account lactide polymers, lactide/glycolide copolymers, or polyoxy biological factors, such as absorption, distribution, metabo ethylene-polyoxypropylene copolymers may be used to con lism, duration of action, the possible existence of side effects, trol the release of the compounds. Other potentially useful and margin of safety, for the pharmacologically active agent. parenteral delivery systems for molecules of the invention Accordingly, one of ordinary skill in the art could modify the include ethylene-vinyl acetate copolymer particles, osmotic formulations into a formulation having the desirable proper pumps, and implantable infusion systems. Formulations for ties described above for a particular application. inhalation may contain excipients, for example, lactose, or 1508 U.S. Pat. No. 6,573.292 by Nardella, U.S. Pat. No. may be acqueous Solutions containing, e.g., polyoxyethylene 6,921,722 by Nardella, U.S. Pat. No. 7,314,886 to Chao et al., 9-lauryl ether, glycocholate and deoxycholate, or can be oily and U.S. Pat. No. 7,446,122 by Chao et al., which disclose Solutions for administration or gels. methods of use of various pharmacologically active agents 1503 Pharmaceutical compositions according to the and pharmaceutical compositions in treating a number of present invention are usually administered to the Subjects on diseases and conditions, including cancer, and methods of multiple occasions. Intervals between single dosages can be determining the therapeutic effectiveness of Such pharmaco weekly, monthly or yearly. Intervals can also be irregular as logically active agents and pharmaceutical compositions, are indicated by therapeutic response or other parameters well all incorporated herein by this reference. known in the art. Alternatively, the pharmaceutical composi tion can be administered as a Sustained release formulation, in Advantages of the Invention which case less frequent administration is required. Dosage 1509. The present invention provides more effective and and frequency vary depending on the half-life in the Subject of efficient methods of using therapeutic drugs that have previ the pharmacologically active agent included in a pharmaceu ously been evaluated for treatment of a number of diseases tical composition. The dosage and frequency of administra and conditions, especially hyperproliferative disorders, but tion can vary depending on whether the treatment is prophy whose evaluations resulted in a premature conclusion of lack lactic ortherapeutic. In prophylactic applications, a relatively of sufficient efficacy or of occurrence of side effects sufficient low dosage is administered at relatively infrequent intervals to prevent the use of the therapeutic drug. Such more effective over a long period of time. Some Subjects may continue to and efficient methods of therapeutic drugs will improve effi receive treatment for the rest of their lives. In therapeutic cacy, prevent or reduce the occurrence of significant side applications, a relatively high dosage at relatively short inter effects, and will identify categories of patients and situations vals is sometimes required until progression of the disease is in which Such drugs can be effectively employed. Such drugs reduced or terminated, and preferably until the subject shows particularly include bisantrene and derivatives and analogs partial or complete amelioration of symptoms of disease. thereof. Thereafter, the subject can be administered a prophylactic 1510 Methods according to the present invention possess regime. industrial applicability for the preparation of a medicament 1504 For the purposes of the present application, treat for the treatment of a number of diseases and conditions, ment can be monitored by observing adverse events or one or especially hyperproliferative diseases, and compositions more of the improving symptoms associated with the disease, according to the present invention possess industrial applica disorder, or condition being treated, or by observing one or bility as pharmaceutical compositions. more of the improving clinical parameters associated with the 1511. Where methods are referred to, the methods of the disease, disorder, or condition being treated, as described present invention provide specific method steps that are more above. than general applications of laws of nature and require that 1505 Sustained-release formulations or controlled-re those practicing the method steps employ steps other than lease formulations are well-known in the art. those conventionally known in the art, in addition to the 1506. The pharmacokinetic principles of controlled drug specific applications of laws of nature recited or implied in the delivery are described, for example, in B. M. Silber et al., claims, and thus confine the scope of the claims to the specific "Pharmacokinetic/Pharmacodynamic Basis of Controlled applications recited therein. In some contexts, these claims Drug Delivery” in Controlled Drug Delivery: Fundamentals are directed to new ways of using an existing drug. and Applications (J. R. Robinson & V. H. L. Lee, eds, 2d ed., 1512. The inventions illustratively described herein can Marcel Dekker, New York, 1987), ch.5, pp. 213-251, incor suitably be practiced in the absence of any element or ele porated herein by this reference. ments, limitation or limitations, not specifically disclosed 1507 One of ordinary skill in the art can readily prepare herein. Thus, for example, the terms “comprising.” “includ formulations for controlled release or Sustained release com ing.” “containing, etc. shall be read expansively and without prising a pharmacologically active agent according to the limitation. Additionally, the terms and expressions employed present invention by modifying the formulations described herein have been used as terms of description and not of above, such as according to principles disclosed in V. H. K. Li limitation, and there is no intention in the use of Such terms et al., “Influence of Drug Properties and Routes of Drug and expressions of excluding any equivalents of the future Administration on the Design of Sustained and Controlled shown and described or any portion thereof, and it is recog Release Systems” in Controlled Drug Delivery. Fundamen nized that various modifications are possible within the scope tals and Applications (J. R. Robinson & V. H. L. Lee, eds. 2d of the invention claimed. Thus, it should be understood that ed., Marcel Dekker, New York, 1987), ch. 1, pp. 3-94, incor although the present invention has been specifically disclosed porated herein by this reference. This process of preparation by preferred embodiments and optional features, modifica US 2016/0166546 A1 Jun. 16 , 2016

tion and variation of the inventions herein disclosed can be (b) the bisantrene analog of Formula (III) resorted by those skilled in the art, and that such modifica tions and variations are considered to be within the scope of the inventions disclosed herein. The inventions have been (III) H described broadly and generically herein. Each of the nar N rower species and Subgeneric groupings falling within the Scope of the generic disclosure also form part of these inven Il-4, D o2HCI tions. This includes the generic description of each invention N N with a proviso or negative limitation removing any subject n matter from the genus, regardless of whether or not the excised materials specifically resided therein. 1513. In addition, where features or aspects of an inven tion are described in terms of the Markush group, those schooled in the art will recognize that the invention is also thereby described in terms of any individual member or sub group of members of the Markush group. It is also to be understood that the above description is intended to be illus cH trative and not restrictive. Many embodiments will be appar HN N 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 O) be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are (c) the bisantrene analog of Formula (IV) entitled. The disclosures of all articles and references, includ (IV) ing patent publications, are incorporated herein by reference. What is claimed is: HN N 1. A method to improve the efficacy and/or reduce the side Y NH effects of Suboptimally administered drug therapy compris N H ing the steps of: f i-g D (a) identifying at least one factor or parameter associated N N N with the efficacy and/or occurrence of side effects of the N n drug therapy, wherein the factor or parameter is addi tionally associated with at least one of: (i) the specific disease or condition being treated; (ii) the stage of the disease or condition being treated; (iii) selection of an appropriate patient for treatment; (iv) selection of an appropriate phenotype of the patient or the disease or (d) the bisantrene analog of Formula (V) condition being treated; and (v) selection of an appro (V) priate phenotype of the patient or the disease or condi tion being treated; and (b) modifying the factor or parameter to improve the effi cacy and/or reduce the side effects of the drug therapy: N wherein the drug therapy comprises administration of bisant HNN rene or a derivative or analog thereof. N 2. The method of claim 1 wherein the drug therapy com prises administration of bisantrene. 3. The method of claim 1 wherein the drug therapy com prises administration of a derivative or analog of bisantrene. 4. The method of claim 3 wherein the derivative or analog of bisantrene is selected from the group consisting of (e) the bisantrene analog of Formula (VI) (a) the analog of Formula (II) (II) (VI) H N t & D o2HCI HN N N N n / \ Y HN N HN 0 I N C US 2016/0166546 A1 Jun. 16, 2016 96

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

(VII) (XII) HN N NH Y N1 NH & D HN NN o2HCI

(g) the bisantrene analog of Formula (VIII)

(VIII) H N NH N i-CDN 2 o2HCI

(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)

(X)

(j) the bisantrene analog of Formula (XI)

(XI) R CHEN-N

ci=n- R4 US 2016/0166546 A1 Jun. 16, 2016 97 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: ent can be ortho, meta, or para and is fluoro, nitro, C-C alkyl, (n) the bisantrene analog 9,10-bis(2-hydroxyethyl)imi C-C alkoxy, or cyano), pentafluorophenyl, naphthyl, fura nomethyllanthracene; nyl, (o) the bisantrene analog 9,10-bis(2-(-2-hydroxyethy lamino)ethyliminomethyl)anthracene; (p) the bisantrene analog 9,10-bis(2-(-2-hydroxyethy lamino)ethyliminomethyl)anthracene; t th (q) the bisantrene analog 9,10-bis(2-(morpholin-4-yl) -CHNHCOOC(CH), -CHNH2, -CH2CHCOOH, ethyliminomethyl)anthracene: -OC(CH), -CHOCH, -(CH2)COOH, (r) the bisantrene analog 9,10-bis(2-hydroxyethyl)ami COOH nomethyllanthracene; (s) the bisantrene analog 9,10-bis(2-(2-hydroxyethy -(CH2)2SOH lamino)ethylaminomethyl)anthracene tetrahydrochlo s O ride; (t) the bisantrene analog 9,10-bis(2-(piperazin-1-yl) ethylaminomethyl)anthracene hexahydrochloride; (u) the bisantrene analog 9,10-bis(2-(morpholin-4-yl) ethylaminomethyl)anthracene tetrahydrochloride; (v) N,N'-bis(2-(dimethylamino)ethyl-9,10-anthracene bis(methylamine); --(). -o-()-ch O (w) N,N'-bis(1-ethyl-3-piperidinyl)-9,10-anthracene-bis (methylamine); and (X) derivatives and salt forms of the compounds of (a)-(w). —SOH; wherein only one of R and R may be hydrogen or 5. The method of claim 1 wherein the drug therapy is C-C alkyl; R and Ra are the same or different and are: administered to treat a hyperproliferative disease. hydrogen, C-C alkyl or—C(O)—R, where R is hydrogen, 6. The method of claim 5 wherein the hyperproliferative C-C alkyl, phenyl, mono-Substituted phenyl (wherein the disease is cancer. Substituent may be in the ortho, meta, or para position and is 7. The method of claim 6 wherein the cancer is a form of fluoro, nitro, C-C alkyl, C-C alkoxy, or cyano), pentafluo cancer selected from the group consisting of refractory breast rophenyl, naphthyl, furanyl, or —CHOCH. The com cancer, triple-negative breast cancer, acute myelocytic leuke pounds can have the schematic structure B(O), wherein B is mia, and acute leukemias of childhood. the residue formed by removal of a hydrogen atom from one 8. The method of claim 1 wherein the improvement is made or more basic nitrogen atoms of an amine, amidine, guani by an indication for use. dine, isourea, isothiourea, or biguanide-containing pharma 9. The method of claim 8 wherein the drug therapy com ceutically active compound, and Q is hydrogen or A, wherein prises administration of bisantrene. A is 10. The method of claim 8 wherein the drug therapy com prises administration of a derivative or analog of bisantrene. 11. The method of claim 8 wherein the indication for use is selected from the group consisting of: (a) use for treatment of refractory breast cancer; (b) use for treatment of triple-negative breast cancer, (c) use for treatment of acute myelocytic leukemia (AML); (d) use for treatment of acute myelocytic leukemia (AML) such that RandR" are the same or different and are R (where and acute lymphocytic leukemia (ALL) of childhood; R is C-C alkyl, aryl, aralkyl, heteroalkyl, NC CHCH . (e) use for treatment of myelodysplastic syndrome; (f) use for treatment of chronic myelocytic leukemia (CML), either subsequent to or in combination with the administration of tyrosine kinase inhibitors or homohar D-CH- s ringtonine: (g) use for treatment of chronic lymphocytic leukemia; (h) use for treatment of Hodgkin’s lymphoma; ClC-C , or ROCH2CH2—, where R, is hydrogen or (i) use for treatment of non-Hodgkin’s lymphoma; C-C alkyl, hydrogen, or a pharmaceutically acceptable cat () use for treatment of mycosis fungoides; ion or Rand R" are linked to forma —CH-CH group or (k) use for treatment of prostate cancer, especially andro a gen-resistant prostate cancer, (l) use for treatment of lung Small-cell carcinoma, either Subsequent to or in combination with the administration of an EGFR inhibitor, wherein the lung small-cell car cinoma is characterized by either wild-type or mutated EGFR, (m) use for treatment of lung non-Small cell carcinoma, subsequent to or in combination with an EGFR inhibitor, US 2016/0166546 A1 Jun. 16, 2016 98

wherein the lung non-Small cell carcinoma is character the group consisting of histone deacetylase, protein ized by either wild-type or mutated EGFR: kinases, and ornithine decarboxylase; (n) use for treatment of breast cancer characterized by (b) selecting patients with a disease condition character overexpressed Her-2-neu: ized by a low level of a metabolic enzyme selected from (o) use for treatment of glioblastoma that is resistant to one the group consisting of histone deacetylase, protein or both of the following therapeutic agents: temozolo kinases, and ornithine decarboxylase; mide (Temodar) or bevacizumab (Avastin), or is charac (c) selecting patients with a low or high Susceptibility to a terized by EGFR variant III, either alone or in combina condition selected from the group consisting of throm tion with other therapeutic agents; bocytopenia and neutropenia; (p) use for treatment of malignancies characterized by (d) selecting patients intolerant of GI toxicities; overexpressed topoisomerase II; and (e) selecting patients characterized by over- or under-ex (q) use for treatment of malignancies characterized by pression of a gene selected from the group consisting of overexpressed and/or mutated EGFR. jun, GPCRs, signal transduction proteins, VEGF, pros 12. The method of claim 1 wherein the improvement is tate specific genes, protein kinases, and telomerase; made by selection of disease stage. (f) selecting patients as the result of immune screening; 13. The method of claim 12 wherein the drug therapy (g) selecting patients as the result of DNA methylation comprises administration of bisantrene. Screening: 14. The method of claim 12 wherein the drug therapy comprises administration of a derivative or analog of bisant (h) selecting patients with recurrent disease characterized C. by the duration of their initial response: 15. The method of claim 12 wherein the disease stage is (i) selecting patients without mutations in p53; and selected from the group consisting of: () selecting for patients without extensive prior treatment. (a) use for the treatment of localized polyp stage colon 24. The method of claim 1 wherein the improvement is Cancer, made by analysis of patient or disease phenotype. (b) use for the treatment of leukoplakia in the oral cavity; 25. The method of claim 24 wherein the drug therapy (c) use to induce angiogenesis inhibition to prevent or limit comprises administration of bisantrene. metastatic spread; 26. The method of claim 24 wherein the drug therapy (d) use against HIV with AZT, DDI, or reverse tran comprises administration of a derivative or analog of bisant scriptase inhibitors; ele. (e) use for recurrent leukemia; and 27. The method of claim 24 wherein the analysis of patient (f) use for recurrent breast cancer. or disease phenotype is carried out by a method selected from 16. The method of claim 1 wherein the improvement is the group consisting of made by other indications. (a) use of a diagnostic tool, a diagnostic technique, a diag 17. The method of claim 16 wherein the drug therapy nostic kit, or a diagnostic assay to confirm a patients comprises administration of bisantrene. particular phenotype; 18. The method of claim 16 wherein the drug therapy (b) use of a method for measurement of a marker selected comprises administration of a derivative or analog of bisant from the group consisting of histone deacetylase, orni C. thine decarboxylase, VEGF, a protein that is a gene 19. The method of claim 16 wherein the other indication is product of a prostate specific gene, a protein that is a selected from the group consisting of: gene product of jun, and a protein kinase; (a) use as an anti-infective agent; (c) Surrogate compound dosing: (b) use as an antiviral agent; (d) low dose pre-testing for enzymatic status; (c) use as an antibacterial agent; (e) determination of the multi-drug resistance activity of (d) use for control of pleural effusions; cells; (e) use as an antifungal agent; (f) determining expression or activation of a signaling or (f) use as an antiparasitic agent; metabolic protein, where an alteration in the level of (g) use for treatment of eczema: expression or activation of the signaling or metabolic (h) use for treatment of shingles; protein indicates the therapeutic potential of a chemo (i) use for treatment of condylomata; therapeutic agent; () use for treatment of human papilloma virus (HPV); and (g) detection or assay of expression of biomarkers indicat (k) use for treatment of herpes simplex virus (HSV). ing sensitivity to apoptosis-inducing agents; 20. The method of claim 1 wherein the improvement is (h) use of an in vitro human tumor clonal assay to deter made by patient selection. mine patients with enhanced responses; 21. The method of claim 20 wherein the drug therapy comprises administration of bisantrene. (i) use of an immunohistochemical assay to determine 22. The method of claim 20 wherein the drug therapy overexpression of HIF-1C.; comprises administration of a derivative or analog of bisant () assessment of p53 mutation; and C. (k) determination of the quantity or activity of topoi 23. The method of claim 20 wherein the patient selection is Somerase 2B in cardiac cells. a patient selection carried out by a criterion selected from the 28. The method of claim 1 wherein the improvement is group consisting of made by analysis of patient or disease genotype. (a) selecting patients with a disease condition character 29. The method of claim 28 wherein the drug therapy ized by a high level of a metabolic enzyme selected from comprises administration of bisantrene. US 2016/0166546 A1 Jun. 16, 2016 99

30. The method of claim 28 wherein the drug therapy 35. The method of claim 34 wherein the derivative or comprises administration of a derivative or analog of bisant analog of bisantrene is selected from the group consisting of C. (a) the analog of Formula (II) 31. The method of claim 28 wherein the analysis of patient or disease genotype is carried out by a method selected from (II) H the group consisting of N (a) genetic tests to determine the absence or nonfunction ality of ABCG2: (b) genetic tests to determine the presence or functionality of FABP7; (c) use of a diagnostic tool, a diagnostic technique, a diag nostic kit, or a diagnostic assay to confirm a patients particular genotype; (d) use of a gene chip; (b) the bisantrene analog of Formula (III) (e) use of gene expression analysis; (III) (f) use of single nucleotide polymorphism (SNP) analysis: (g) measurement of the level of a metabolite or a metabolic enzyme; (h) determination of the presence of one or more specific genetic variants of the MDR1 gene associated with increased efficacy of an antineoplastic drug transported by MDR1 protein: (i) identification of one or more biomarkers associated with sensitivity or resistance to bisantrene, derivatives orana logs thereof, or other intercalating agents or topoi Somerase II inhibitors; and (j) determination of the presence or absence of the single nucleotide polymorphisms (SNPs) rs229.109 and/or 72552784 associated with sensitivity to bisantrene. ) (c) the bisantrene analog of Formula (IV) 32. A method to improve the efficacy and/or reduce the side effects of Suboptimally administered drug therapy compris (IV) ing the steps of HN (a) identifying at least one factor or parameter associated H with the efficacy and/or occurrence of side effects of the N drug therapy, wherein the factor or parameter is addi NH tionally associated with at least one of: (i) the chemical " –{D composition of the drug being administered; (ii) the physical form of the drug being administered or a phar maceutical composition including the drug being administered; (iii) the makeup of a pharmaceutical com position including the drug being administered; (iv) the specific use of the drug being administered; (v) the target cell, organ, or receptor targeted by the drug being admin (d) the bisantrene analog of Formula (V) istered; or (vi) additional agents administered with the drug being administered; and (b) modifying the factor or parameter to improve the effi (V) cacy and/or reduce the side effects of the drug therapy: wherein the drug therapy comprises administration of bisant rene or a derivative or analog thereof. NHNS 33. The method of claim 32 wherein the drug therapy N comprises administration of bisantrene. 34. The method of claim 32 wherein the drug therapy comprises administration of a derivative or analog of bisant C.