US 20100311751A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0311751A1 Schmitt et al. (43) Pub. Date: Dec. 9, 2010

(54) SOLID DISPERSIONS CONTAINING AN Related U.S. Application Data APOPTOSS-PROMOTINGAGENT (60) Provisional application No. 61/185,105, filed on Jun. (75) Inventors: Eric A. Schmitt, Libertyville, IL 8, 2009. (US); Ping Tong, Libertyville, IL Publication Classification (US); Katherine Heemstra, (51) Int. Cl. Chicago, IL (US); Cristina M. A 6LX 3/5.377 (2006.01) Fischer, Wadsworth, IL (US); A6IP35/00 (2006.01) Huailiang Wu, Long Grove, IL (US); Jonathan Mark Miller, (52) U.S. Cl...... S14/235.8 Lindenhurst, IL (US); Yanxia Li, (57) ABSTRACT Grayslake, IL (US); Justin S. A pro-apoptotic Solid dispersion comprises, in essentially Lafountaine, Chicago, IL (US) non-crystalline form, a Bcl-2 family protein inhibitory com pound, e.g., ABT-263, dispersed in a solid matrix that com Correspondence Address: prises (a) a pharmaceutically acceptable water-soluble poly PAUL. D. YASGER meric carrier and (b) a pharmaceutically acceptable ABBOTT LABORATORIES Surfactant. A process for preparing Such a solid dispersion 100 ABBOTT PARK ROAD, DEPT. 377/AP6A comprises dissolving the compound, the polymeric carrier ABBOTT PARK, IL 60064-6008 (US) and the Surfactant in a Suitable solvent, and removing the Solvent to provide a solid matrix comprising the polymeric (73) Assignee: ABBOTT LABORATORIES, carrier and the Surfactant and having the compound dispersed Abbott Park, IL (US) in essentially non-crystalline form therein. The solid disper sion is suitable for oral administration to a subject in need (21) Appl. No.: 12/796,061 thereof for treatment of a disease characterized by overex pression of one or more anti-apoptotic Bcl-2 family proteins, (22) Filed: Jun. 8, 2010 for example . Patent Application Publication Dec. 9, 2010 Sheet 1 of 2 US 2010/0311751A1

100

80

: 60 -0- Tween TM 20 SSe 40 -- TP GS -A- SpanTM20

2O

O O 20 40 60 8O 1OO 120 140 160 Time (min) Fig. 1

1 OO

80

60 A / SS 40

-- Tween TM 20 2O -- TPGS

-A- SpanTM20

O 20 40 60 80 100 120 140 160 Time (min)

Fig. 2 Patent Application Publication Dec. 9, 2010 Sheet 2 of 2 US 2010/0311751A1

100 -X-powidone only --50% povidone + 50% copovidone 8O -A-25% powidone + 75% copovidone -O-CopOvidone only

60

40

O 20 40 60 8O 1OO 120 140 160 Time (min)

Fig. 3 US 2010/03 11751 A1 Dec. 9, 2010

SOLID DISPERSIONS CONTAINING AN pounds, are disclosed in U.S. Patent Application Publication APOPTOSS-PROMOTINGAGENT No. 2007/0072860 of Bruncko et al. 0006 More recently, a further series of compounds has been identified having high binding affinity to Bcl-2 family 0001. This application claims priority benefit of U.S. pro proteins. These compounds, and methods to make them, are visional application Ser. No. 61/185,105 filed on Jun. 8, 2009. disclosed in U.S. Patent Application Publication No. 2007/ 0027135 of Bruncko et al. (herein “the 135 publication'), FIELD OF THE INVENTION incorporated by reference herein in its entirety, and can be 0002 The present invention relates to solid dispersions seen from their formula below to be structurally related to comprising an apoptosis-promoting agent, to pharmaceutical ABT-737. dosage forms comprising such dispersions, to processes for 0007. The 135 publication states that while inhibitors of preparing Such dispersions and dosage forms and to methods Bcl-2 family proteins previously known may have either of use thereof for treating diseases characterized by overex potent cellular efficacy or high systemic exposure after oral pression of anti-apoptotic Bcl-2 family proteins. administration, they do not possess both properties. A typical measure of cellular efficacy of a compound is the concentra BACKGROUND OF THE INVENTION tion eliciting 50% cellular effect (ECs). A typical measure of 0003) Evasion of apoptosis is a hallmark of cancer (Hana systemic exposure after oral administration of a compound is han & Weinberg (2000) Cell 100:57-70). Cancer cells must the area under the curve (AUC) resulting from graphing overcome a continual bombardment by cellular stresses Such plasma concentration of the compound versus time from oral as DNA damage, oncogene activation, aberrant administration. Previously known compounds, it is stated in progression and harsh microenvironments that would cause the 135 publication, have a low AUC/ECso ratio, meaning normal cells to undergo apoptosis. One of the primary means that they are not orally efficacious. Compounds of the above by which cancer cells evade apoptosis is by up-regulation of formula, by contrast, are stated to demonstrate enhanced anti-apoptotic proteins of the Bcl-2 family. properties with respect to cellular efficacy and systemic expo 0004 Compounds that occupy the BH3 binding groove of Sure after oral administration, resulting in a AUC/ECso ratio Bcl-2 proteins have been described, for example by Bruncko significantly higher than that of previously known com et al. (2007) J. Med. Chem. 50:641-662. These compounds pounds. have included N-(4-(4-(4-chloro-(1,1'-biphenyl)-2-yl)me 0008. One compound, identified as “Example 1 in the thyl)piperazin-1-yl)benzoyl)-4-(1R)-3-(dimethylamino)-1- 135 publication, is N-(4-(4-(2-(4-chlorophenyl)-5,5-dim ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene-Sul ethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)ben fonamide, otherwise known as ABT-737, which has the Zoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)me formula: thyl)propyl)amino)-3-((trifluoromethyl)sulfonyl) benzenesulfonamide, otherwise known as ABT-263. This compound has a molecular weight of 974.6 g/mol and has the formula: NO H N S H O Ns H MV N O O N S 1 'N H O N / \, N O O CC CN 0005 ABT-737 binds with high affinity (K,<1 nM) to pro teins of the Bcl-2 family (specifically Bcl-2, Bcl-X, and Bcl w). It exhibits single-agent activity against Small-cell lung C cancer (SCLC) and lymphoid malignancies, and potentiates pro-apoptotic effects of other chemotherapeutic agents. ABT 0009. ABT-263 binds with high affinity (<1 nM) to Bcl-2 737 and related compounds, and methods to make Such com and Bcl-X, and is believed to have similarly high affinity for US 2010/03 11751 A1 Dec. 9, 2010

Bcl-w. Its AUC/ECs ratio is reported in the 135 publication 0016 A particular type of disease for which improved as 56, more than an order of magnitude greater than that are needed is non-Hodgkin’s lymphoma (NHL). reported for ABT-737 (4.5). For determination of AUC NHL is the sixth most prevalent type of new cancer in the U.S. according to the 135 publication, each compound was and occurs primarily in patients 60-70 years of age. NHL is administered to rats in a single 5 mg/kg dose by oral gavage as not a single disease but a family of related diseases, which are a 2 mg/ml solution in a vehicle of 10% DMSO (dimethyl classified on the basis of several characteristics including sulfoxide) in PEG-400 (polyethylene glycol of average clinical attributes and histology. molecular weight about 400). 0017. One method of classification places different histo 0010 Oral bioavailability (as expressed, for example, by logical Subtypes into two major categories based on natural AUC after oral administration as a percentage of AUC after history of the disease, i.e., whether the disease is indolent or intravenous administration) is not reported in the 135 publi aggressive. In general, indolent Subtypes grow slowly and are cation, but can be concluded therefrom to be substantially generally incurable, whereas aggressive Subtypes grow rap greater for ABT-263 than for ABT-737. idly and are potentially curable. Follicular lymphomas are the 0011 Recently, Tse et al. (2008) Cancer Res.68(9):3421 most common indolent Subtype, and diffuse large-cell lym 3428, reported in Supplementary data thereto that, in a dog phomas constitute the most common aggressive Subtype. The model, oral bioavailability of an ABT-263 solution in PEG oncoprotein Bcl-2 was originally described in non-Hodgkin’s 400/DMSO was 22.4%, and that of an ABT-263 solution in B-cell lymphoma. 60% PhosalTM PG (phosphatidylcholine--propylene glycol), 0018 Treatment of follicular lymphoma typically consists 30% PEG-400 and 10% ethanol was 47.6%. of biologically-based or combination . Combi 0012. Oxidation reactions represent an important degra nation with , , doxorubi dation pathway of pharmaceuticals, especially when formu cin, and prednisone (R-CHOP) is routinely used, lated in Solution. Oxidation can occur by a number of path as is combination therapy with rituximab, cyclophospha ways, including uncatalyzed autoxidation of a Substrate by mide, Vincristine and prednisone (RCVP). Single-agent molecular oxygen, photolytic initiation, hemolytic thermal therapy with rituximab (targeting CD20, a phosphoprotein cleavage, and metal catalysis. Various functional groups show uniformly expressed on the surface of B-cells) or particular sensitivity towards oxidation. In particular, thioet is also used. Addition of rituximab to chemotherapy regimens hers can degrade via hydrogen abstraction at the C-position to can provide improved response rate and increased progres the sulfur atom or by addition of an O-peroxyl radical directly sion-free survival. or via a one-electron transfer process, which transforms a 0019 Radioimmunotherapy agents, high-dose chemo sulfide to a sulfine, sulfone, or sulfoxide (Hovorka & Scho therapy and stem cell transplants can be used to treat refrac neich (2001).J. Pharm. Sci. 90:253-269). tory or relapsed NHL. Currently, there is not an approved 0013 The (phenylsulfanyl)methyl group possessed by treatment regimen that produces a cure, and current guide compounds disclosed in the 135 publication, including ABT lines recommend that patients be treated in the context of a 263, is seen to have a thioether linkage, which is susceptible , even in a first-line setting. to oxidation, for example in presence of oxygen or reactive 0020 First-line treatment of patients with aggressive large oxygen species Such as Superoxide, hydrogen peroxide or B-cell lymphoma typically consists of rituximab, cyclophos hydroxyl radicals. The 135 publication includes antioxidants phamide, , Vincristine and prednisone in an extensive list of excipients said to be useful for admin (R-CHOP), or dose-adjusted , prednisone, Vincris istering the compounds disclosed therein. tine, cyclophosphamide, doxorubicin and rituximab (DA-EP 0014. However, pharmaceutical compositions that are less OCH-R). susceptible to oxidation of the active ingredient would be 0021 Most lymphomas respond initially to any one of advantageous. Additionally, compositions capable of higher these therapies, but tumors typically recur and eventually active ingredient loading than the Solution compositions of become refractory. As the number of regimens patients the 135 publication or of Tse et al. (2008), supra would be receive increases, the more chemotherapy-resistant the dis advantageous. Further, liquid formulations as disclosed in the ease becomes. Average response to first-line therapy is 135 publication and in Tse et al. (2008), supra can be approximately 75%, 60% to second-line, 50% to third-line, unpleasant to take orally for taste or other reasons and can and about 35-40% to fourth-line therapy. Response rates present patient compliance problems for these reasons; thus a approaching 20% with a single agent in a multiple relapsed solid-state composition would be beneficial. setting are considered positive and warrant further study. 0015 The very low aqueous solubility of compounds of 0022. Current chemotherapeutic agents elicit their antitu the 135 publication including ABT-263 raises challenges for mor response by inducing apoptosis through a variety of the formulator, especially where there is a need to maintain mechanisms. However, many tumors ultimately become acceptable oral bioavailability, which is strongly dependent resistant to these agents. Bcl-2 and Bcl-X, have been shown on solubility in the aqueous medium of the gastrointestinal to confer chemotherapy resistance in short-term Survival tract. Various solutions to the challenge of low oral bioavail assays in vitro and, more recently, in vivo. This Suggests that ability have been proposed in the art. For example, Sharma & if improved therapies aimed at Suppressing the function of Joshi (2007) Asian Journal of Pharmaceutics 1(1):9-19 dis Bcl-2 and Bcl-X can be developed, such chemotherapy cuss various solubility enhancement strategies in preparing resistance could be successfully overcome. Solid dispersions. A solvent evaporation method for preparing 0023 Apoptosis-promoting drugs that target Bcl-2 family Solid dispersions is described therein, mentioning as an proteins such as Bcl-2 and Bcl-X are best administered example a solid dispersion of etoricoxib, prepared by a pro according to a regimen that provides continual, for example cess that includes dissolving polyethylene glycol (PEG), daily, replenishment of the plasma concentration, to maintain polyvinylpyrrolidone (PVPorpovidone) and the active ingre the concentration in a therapeutically effective range. This dient in 2-propanol. can be achieved by daily parenteral, e.g., intravenous (i.v.) or US 2010/03 11751 A1 Dec. 9, 2010

intraperitoneal (i.p.) administration. However, daily 0031. Or parenteral administration is often not practical in a clinical I0032 (2)X is azepan-1-yl, morpholin-4-ylpyrrolidin setting, particularly for outpatients. To enhance clinical utility 1-yl, - N(CH)(CH(CH)) or 7-azabicyclo[2.2.1]hep of an apoptosis-promoting agent, for example as a chemo tan-7-yl; and R' is therapeutic in cancer patients, a solid dosage form with acceptable oral bioavailability would be highly desirable. Such a dosage form, and a regimen for oral administration thereof, would represent an important advance in treatment of many types of cancer, including NHL, and would more readily enable combination therapies with other chemothera peutics.

SUMMARY OF THE INVENTION 0024. There is now provided a solid dispersion compris ing, in essentially non-crystalline, for example amorphous, form, a compound of Formula I: 0033 where X, X7 and X are as above; or I0034) (3)X is morpholin-4-ylor N(CH); and Ris CFX SO H N S H O N. /MV \, X4 r44 X8 0035 where X is as above: or a pharmaceutically acceptable salt, prodrug, salt of a pro drug or metabolite thereof; dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble CN polymeric carrier and (b) a pharmaceutically acceptable Sur R0 factant. 0036. There is further provided a solid orally deliverable dosage form comprising such a solid dispersion, optionally where: together with one or more additional excipients. 0025 X is chloro or fluoro; and 0037. There is still further provided a process for prepar (0026 (1) X is azepan-1-yl, morpholin-4-yl, 1,4-ox ing a solid dispersion as described above. This process com aZepan-4-yl, pyrrolidin-1-yl, —N(CH), —N(CH) prises: (CH(CH)), 7-azabicyclo[2.2.1]heptan-7-yl or 2-oxa 0.038 (a) dissolving an active pharmaceutical ingredi 5-azabicyclo[2.2.1]hept-5-yl; and R' is ent (API) comprising (i) a compound of Formula I or a pharmaceutically acceptable salt, prodrug, salt of a pro drug or metabolite thereof, (ii) a pharmaceutically acceptable water-soluble polymeric carrier and (iii) a pharmaceutically acceptable Surfactant in a Suitable sol vent; and 0.039 (b) removing the solvent to provide a solid matrix comprising the polymeric carrier and the Surfactant and having the compound or a salt, prodrug, salt of a prodrug or metabolite thereof dispersed in an essentially non crystalline form therein. 0040. The compound present in the finished solid disper sion can be in the same chemical form (e.g., a free base or a salt) as in the API used to prepare it. Alternatively, the process comprises one or more additional steps wherein the com 0027 where pound is converted from free base to salt or vice versa. In a I0028 X is —CH2—, —C(CH), or particular embodiment, the API is a salt, for example a crys —CHCH: talline salt, of a compound of Formula I, and the finished solid 0029 X and X’ are both -H or both methyl; and dispersion contains the compound in free base form. Accord 0030 X is fluoro, chloro, bromo or iodo; ing to this embodiment, the process further comprises, prior US 2010/03 11751 A1 Dec. 9, 2010

to removing the solvent, adding a base for conversion of the herein encompasses systems having Small solid-state par salt to the free base, and optionally extracting a by-product of ticles of one phase dispersed in another solid-state phase. Such conversion (e.g., a salt by-product) from the resulting More particularly, the present Solid dispersions comprise one mixture. or more active ingredients dispersed in an inert carrier or matrix in Solid State, and can be prepared by melting or 0041. There is still further provided a solid dispersion Solvent methods or by a combination of melting and solvent prepared by the process described above. methods. According to the present invention a solvent method 0042. There is still further provided a method for treating as described herein is particularly favored, avoiding the risk a disease characterized by apoptotic dysfunction and/or over of thermal decomposition of the active ingredient by expo expression of an anti-apoptotic Bcl-2 family protein, com Sure to temperatures required to melt the polymeric carrier. prising orally administering to a subject having the disease a 0050. An “amorphous form” refers to a particle without therapeutically effective amount of a Solid dispersion as definite structure, i.e., lacking crystalline structure. described above, or one or more solid dosage forms compris 0051. The term “essentially non-crystalline' herein means that no more than about 5%, for example no more than about ing Such a dispersion. Examples of Such a disease include 2% or no more than about 1% crystallinity is observed by many neoplastic diseases including . A specific illus X-ray diffraction analysis. In a particular embodiment, no trative type of cancer that can be treated according to the detectable crystallinity is observed by one or both of X-ray present method is non-Hodgkin’s lymphoma (NHL). Another diffraction analysis or polarization microscopy. specific illustrative type of cancer that can be treated accord 0.052 Compounds of Formula I, including salts, prodrugs, ing to the present method is chronic lymphocytic leukemia. salts of prodrugs and metabolites thereof, useful herein typi Yet another specific illustrative type of cancer that can be cally have very low solubility in water, for example less than treated according to the present method is acute lymphocytic about 100 ug/ml, in most cases less than about 30 ug/ml. The leukemia, for example in a pediatric patient. present invention can be especially advantageous for drugs that are essentially insoluble in water, i.e., having a solubility 0043. According to any of the embodiments of the inven of less than about 10 ug/ml, since a process of the invention tion described above, the compound of Formula I is illustra increases the apparent solubility of Such a poorly-soluble tively ABT-263 or a pharmaceutically acceptable salt, pro active ingredient. Examples of such active ingredients are, for drug, salt of a prodrug or metabolite thereof, for example example, Biopharmaceutics Classification System (BCS) ABT-263 free base or ABT-263 bis-hydrochloride salt (ABT Class IV drug substances that are characterized by low solu 263 bis-HCl). bility and low permeability (see “Waiver of in vivo bioavail 0044) There is still further provided a method for main ability and bioeduivalence studies for immediate-release taining in bloodstream of a human cancer patient, for example Solid oral dosage forms based on a biopharmaceutics classi a patient having NHL, a therapeutically effective plasma con fication system'. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug centration of ABT-263 and/or one or more metabolites Evaluation and Research (CDER), August 2000). It will be thereof, comprising orally administering to the Subject a solid recognized that aqueous solubility of many compounds is dispersion of ABT-263 or a pharmaceutically acceptable salt, pH-dependent; in the case of Such compounds the Solubility prodrug, salt of a prodrug or metabolite thereof (for example of interest herein is at a physiologically relevant pH, for ABT-263 free base or ABT-263 bis-HCl) in essentially non example a pH of about 1 to about 8. Thus, in various embodi crystalline form in a matrix that comprises a pharmaceuti ments, the drug has a solubility in water, at least at one point cally acceptable water-soluble polymeric carrier and a phar in a pH range from about 1 to about 8, of less than about 100 maceutically acceptable Surfactant, in a dosage amount ug/ml, for example less than about 30 ug/ml, or less than about 10 ug/ml. Illustratively, ABT-263 has a solubility in equivalent to about 50 to about 500 mg ABT-263 free base water at pH 2 of less than 4 Jug/ml. equivalent per day, at an average dosage interval of about 3 0053 Solid dispersions of the present invention comprise hours to about 7 days. as active ingredient a compound of Formula I as defined 0045. Additional embodiments of the invention, including above, or a pharmaceutically acceptable salt, prodrug, salt of more particular aspects of those provided above, will be a prodrug or metabolite of such a compound. Optionally they found in, or will be evident from, the detailed description that may further comprise a second active ingredient, for example follows. a therapeutic agent useful in combination therapy with the compound of Formula I as indicated hereinbelow. 0054. In one embodiment, the compound has Formula I BRIEF DESCRIPTION OF THE DRAWINGS where X is fluoro. 0046 FIG. 1 is a graphical representation of effects of 0055. In a further embodiment, the compound has For various Surfactants on dissolution rates of Solid dispersions mula I where X is morpholin-4-yl. containing ABT-263 bis-HCl as described in Example 3. 0056. In a still further embodiment, the compound has 0047 FIG. 2 is a graphical representation of effects of Formula I where R is various Surfactants on dissolution rates of Solid dispersions containing ABT-263 free base as described in Example 3. 0048 FIG. 3 is a graphical representation of effects of various polymeric carriers on dissolution rates of Solid dis persions containing ABT-263 bis-HCl as described in Example 4.

DETAILED DESCRIPTION 0049. A solid dispersion in accordance with the present disclosure comprises an active ingredient in an essentially non-crystalline or amorphous form, which is usually more soluble than the crystalline form. The term "solid dispersion” US 2010/03 11751 A1 Dec. 9, 2010

where X is O—, CH2—, C(CH) O this embodiment X can be —C(CH), and/or each of X —CH2CH2 : X and X’ are both —H or both methyl; and and X7 can be —H and/or X can be chloro. X is fluoro, chloro, bromo or iodo. Illustratively according to 0061. In a still further embodiment, the compound has this embodiment X can be C(CH) and/or each of X Formula I where X is fluoro, X is morpholin-4-yland R is and X’ can be Hand/or X can be chloro. 0057. In a still further embodiment, the compound has Formula I where R is

X8

where X is O—, CH , C(CH), O X8 —CHCH. : X and X’ are both —H or both methyl; and X is fluoro, chloro, bromo or iodo. Illustratively according to where X is O—, CH2—, C(CH) O this embodiment X can be —C(CH), and/or each of X —CHCH. : X and X’ are both —H or both methyl; and and X’ can be Hand/or X can be chloro. X is fluoro, chloro, bromo or iodo. Illustratively according to 0062 Compounds of Formula I may contain asymmetri this embodiment X can be C(CH) and/or each of X cally Substituted carbon atoms in the R- or S-configuration; and X’ can be Hand/or X can be chloro. Such compounds can be present as racemates or in an excess 0058. In a still further embodiment, the compound has of one configuration over the other, for example in an enan Formula I where X is fluoro and X* is morpholin-4-yl. tiomeric ratio of at least about 85:15. The compound can be 0059. In a still further embodiment, the compound has Substantially enantiomerically pure, for example having an Formula I where X is fluoro and R is enantiomeric ratio of at least about 95:5, or in some cases at least about 98.2 or at least about 99:1. 0063 Compounds of Formula I may alternatively or addi tionally contain carbon-carbon double bonds or carbon-nitro gen double bonds in the Z- or E-configuration, the term “Z” denoting a configuration wherein the larger Substituents are on the same side of such a double bond and the term “E” denoting a configuration wherein the larger Substituents are on opposite sides of the double bond. The compound can alternatively be present as a mixture of Z- and E-isomers. 0064 Compounds of Formula I may alternatively or addi X8 tionally exist as tautomers or equilibrium mixtures thereof wherein a proton shifts from one atom to another. Examples where X is O—, CH2—, C(CH), O of tautomers illustratively include keto-enol, phenol-keto, —CHCH. : X and X’ are both —H or both methyl; and oXime-nitroso, nitro-aci, imine-enamine and the like. X is fluoro, chloro, bromo or iodo. Illustratively according to 0065. In some embodiments, a compound of Formula I is this embodiment X can be C(CH), and/or each of X present in the Solid dispersion in its parent-compound form, and X’ can be Hand/or X can be chloro. alone or together with a salt or prodrug form of the compound. 0060. In a still further embodiment, the compound has 0.066 Compounds of Formula I may form acid addition Formula I where X is morpholin-4-yland R' is salts, basic addition salts or Zwitterions. Salts of compounds of Formula I can be prepared during isolation or following purification of the compounds. Acid addition salts are those derived from reaction of a compound of Formula I with an acid. For example, salts including the acetate, adipate, algi nate, bicarbonate, citrate, aspartate, benzoate, benzene Sulfonate (besylate), bisulfate, butyrate, camphorate, cam phorsulfonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hex anoate, hydrochloride, hydrobromide, hydroiodide, lacto bionate, lactate, maleate, mesitylenesulfonate, methane Sulfonate, naphthylenesulfonate, nicotinate, oxalate, X8 pamoate, pectinate, persulfate, phosphate, picrate, propi onate. Succinate, tartrate, thiocyanate, trichloroacetate, trif where X is O—, CH2—, C(CH) O luoroacetate, para-toluenesulfonate and undecanoate salts of —CH2CH2 : X and X’ are both —H or both methyl; and a compound of Formula I can be used in a composition of the X is fluoro, chloro, bromo or iodo. Illustratively according to invention. Basic addition salts, including those derived from US 2010/03 11751 A1 Dec. 9, 2010

reaction of a compound with the bicarbonate, carbonate, ABT-263 bis-HCl salt. The Solution is heated to about 45° C. hydroxide or phosphate of cations such as lithium, Sodium, with stirring and seeds are added as a slurry in EtOH. After potassium, calcium and magnesium, can likewise be used. about 6 hours, the resulting slurry is cooled to about 20° C. 0067. A compound of Formula I typically has more than over about 1 hour and is mixed at that temperature for about one protonatable nitrogen atom and is consequently capable 36 hours. The slurry is filtered to recover a crystalline solid, of forming acid addition salts with more than one, for which is an ethanol solvate of ABT-263 bis-HC1. Drying of example about 1.2 to about 2, about 1.5 to about 2 or about 1.8 this solid under vacuum and nitrogen with mild agitation for to about 2, equivalents of acid per equivalent of the com about 8 days yields white desolvated ABT-263 bis-HCl crys pound. tals. This material is suitable as an API for preparation of an 0068 ABT-263 can likewise form acid addition salts, ABT-263 bis-HCl or (by inclusion of a salt-to-base conver basic addition salts or Zwitterions. Salts of ABT-263 can be sion step in the solid dispersion process) ABT-263 free base prepared during isolation or following purification of the formulation of the present invention. compound. Acid addition salts derived from reaction of ABT 0072. The term “free base' is used for convenience herein 263 with an acid include those listed above. Basic addition to refer to the parent compound, while recognizing that the salts including those listed above can likewise be used. ABT parent compound is, strictly speaking, Zwitterionic and thus 263 has at least two protonatable nitrogen atoms and is con sequently capable of forming acid addition salts with more does not always behave as a true base. than one, for example about 1.2 to about 2, about 1.5 to about 0073 Compounds of Formula I, and methods of prepara 2 or about 1.8 to about 2, equivalents of acid per equivalent of tion of Such compounds, are disclosed in above-cited U.S. the compound. Patent Application Publication No. 2007/0027135 and/or in 0069 Illustratively in the case of ABT-263, bis-salts can above-cited U.S. Patent Application Publication No. 2007/ be formed including, for example, bis-hydrochloride (bis 0072860, each of which is incorporated herein by reference in HCl) and bis-hydrobromide (bis-HBr) salts. its entirety. Terms for substituents used herein are defined 0070 For example, ABT-263 bis-HCl, which has a exactly as in those publications. molecular weight of 1047.5 g/mol and is represented by the 0074 Compounds of Formula I having —NH, —C(O) formula OH, -OH or —SH moieties may have attached thereto pro drug-forming moieties which can be removed by metabolic processes in vivo to release the parent compound having free CF - NH, -C(O)OH, -OH or -SH moieties. Salts of pro drugs can also be used. SO (0075. Without being bound by theory, it is believed that H N s the therapeutic efficacy of compounds of Formula I is due at S least in part to their ability to bind to a Bcl-2 family protein such as Bcl-2, Bcl-X, or Bcl-w in a way that inhibits the O N anti-apoptotic action of the protein, for example by occupy ing the BH3 binding groove of the protein. It will generally be / \, N found desirable to select a compound having high binding affinity for a Bcl-2 family protein, for example a K, not greater than about 5 nM, preferably not greater than about 1 nM. O 0076 A solid dispersion as provided herein comprising any specific compound disclosed in the 135 publication is expressly contemplated as an embodiment of the present C (HCl) invention. 0077. In a more particular embodiment, the composition N comprises ABT-263 or a salt, prodrug, salt of a prodrug or metabolite thereof. In a still more particular embodiment, the composition comprises ABT-263 parent compound (i.e., free base) or a salt, prodrug or salt of a prodrug thereof. In a still more particular embodiment, the composition comprises ABT-263 free base or a salt thereof. In an even more particular embodiment, the composition comprises ABT-263 free base C or ABT-263 bis-HC1. (0078 ABT-263 bis-HCl, by virtue of its crystalline nature, can be prepared by a variety of processes, for example a is typically more convenient to use as an API than ABT-263 process that can be outlined as follows. free base, which as prepared according to the 135 publication (0071 ABT-263 free base is prepared, illustratively as is an amorphous or glassy Solid. However, there may be described in Example 1 of above-cited U.S. Patent Applica advantages in providing a solid dispersion formulation of tion Publication No. 2007/0027135, the entire disclosure of ABT-263 wherein the ABT-263 is in free base form, as the which is incorporated by reference herein. A suitable weight drug will be less susceptible to crystallization within the of ABT-263 free base is dissolved in ethyl acetate. A solution formulation or immediately upon release therefrom. Thus in ofhydrochloric acid in ethanol (for example about 4.3 kg HCl a yet more particular embodiment, the composition com in 80 g EtOH) is added to the ABT-263 solution in an amount prises ABT-263 free base. It is emphasized that, in this providing at least 2 mol HCl per mol ABT-263 and sufficient embodiment, it is not necessarily the free base form of ABT EtOH (at least about 20 vol) for crystallization of the resulting 263 that is used as the API in preparing the composition. US 2010/03 11751 A1 Dec. 9, 2010

0079 A compound of Formula I or a salt, prodrug, salt of alkyl-celluloses such as hydroxypropylmethylcellulose a prodrug or metabolite thereof) is present in a solid disper (HPMC or hypromellose), cellulose phthalates and suc sion of the invention in an amount that can be therapeutically cinates Such as cellulose acetate phthalate, hydroxypro effective when the composition is administered to a subject in pylmethylcellulose phthalate, hydroxypropylmethyl need thereof according to an appropriate regimen. Dosage cellulose Succinate and hydroxypropylmethylcellulose amounts are expressed herein as parent-compound-equiva acetate succinate (HPMC-AS); lent (free base equivalent) amounts unless the context 0085 high molecular weight polyalkylene oxides such requires otherwise. Typically, a unit dose (the amount admin as polyethylene oxide, polypropylene oxide and copoly istered at a single time), which can be administered at an mers of ethylene oxide and propylene oxide (poloxam appropriate frequency, e.g., twice daily to once weekly, is ers); about 10 to about 1,000 mg. depending on the compound in I0086 polyacrylates and polymethacrylates such as question. Where frequency of administration is once daily methacrylic acid/ethyl acrylate copolymers, meth (q.d.), unit dose and daily dose are the same. Illustratively, for acrylic acid/methyl methacrylate copolymers, butyl example where the drug is ABT-263, the unit dose is typically methacrylate/2-dimethylaminoethyl methacrylate about 25 to about 1,000 mg, more typically about 50 to about copolymers, poly(hydroxyalkyl acrylates) and poly(hy 500 mg, for example about 50, about 100, about 150, about droxyalkyl methacrylates); 200, about 250, about 300, about 350, about 400, about 450 or 0.087 polyacrylamides; about 500 mg. Where the dosage form comprises a capsule 0088 vinyl acetate polymers such as copolymers of shell enclosing the solid dispersion, or a tablet wherein the vinyl acetate and crotonic acid, partially hydrolyzed Solid dispersion is formulated with other ingredients, a unit polyvinyl acetate (also referred to as partially saponified dose can be deliverable in a single dosage form or a plurality "polyvinyl alcohol) and polyvinyl alcohol; of dosage forms, most typically 1 to about 10 dosage forms. 0089 oligo- and polysaccharides such as carrageenans, 0080. The higher the unit dose, the more desirable it galactomannans and Xanthan gum, becomes to prepare a solid dispersion having a relatively high and mixtures of two or more thereof. concentration of the drug therein. Typically, the concentration 0090. In one embodiment, the solid dispersion matrix of drug in the Solid dispersion is at least about 1%, e.g., about comprises one or more polymeric carriers selected from the 1% to about 50%, by free base equivalent weight, but lower group consisting of copovidone, povidone and HPMC-AS. A and higher concentrations can be acceptable or achievable in particular example of a useful copovidone is one consisting of specific cases. Illustratively, for example where the drug is about 60% N-vinyl pyrrolidone and about 40% vinyl acetate ABT-263, the drug concentration in various embodiments is monomers. A particular example of a useful povidone is one at least about 2%, e.g., about 2% to about 50%, or at least having a K-value (a measure of viscosity of an aqueous solu about 5%, e.g., about 5% to about 40%, for example about tion of the povidone) of about 30. 5%, about 10%, about 15%, about 20%, about 25%, about 0091. One or more polymeric carriers typically constitute 30%, about 35% or about 40%, by free base equivalent in total about 20% to about 90%, for example about 40% to weight. about 85%, by weight of the solid dispersion. 0081. The major component of the matrix of a solid dis 0092. Upon oral administration and exposure to GI fluid, it persion product is a polymer that is hydrophilic or water is believed without being bound by theory that, through inter soluble at least in a part of the pH scale, more particularly at play between the polymeric carrier and a surfactant compo a pH occurring in the gastrointestinal (GI) tract, or a combi nent of the Solid dispersion, a Suitable release rate and inhi nation of Such polymers. A polymer or polymer mixture bition of crystallization or recrystallization of the active useful herein is solid at ambient temperature and, in the ingredient are provided, thereby permitting bioabsorption. interests of good storage stability at a range of temperatures, 0093 Particularly useful as surfactants herein are pharma should remain Solid even at the highest temperatures typically ceutically acceptable non-ionic Surfactants, especially those experienced during storage, transport and handling of the having a hydrophilic-lipophilic balance (HLB) value of about product. A useful property of a polymer determining its use 12 to about 18, for example about 13 to about 17, or about 14 fulness herein is therefore its glass transition temperature to about 16. The HLB system (see Fiedler (2002) Encyclope (T). Suitable water-soluble polymers include, but are not dia of Excipients, 5th edition, Aulendorf. ECV-Editio-Can limited to, those having a T of at least about 50° C., more tor-Verlag) attributes numeric values to surfactants, with lipo particularly about 80° C. to about 180° C. Methods for deter philic substances receiving lower HLB values and mining T values of organic polymers are described for hydrophilic substances receiving higher HLB values. example in Sperling, ed. (1992) Introduction To Physical 0094. Non-limiting examples of non-ionic surfactants Polymer Science, 2nd edition, John Wiley & Sons, Inc. useful herein include: 0082) Non-limiting examples of polymeric carriers useful 0.095 polyoxyethylene castor oil derivatives such as herein include: PEG-35 castor oil (e.g., Cremophor ELTM of BASF I0083 homopolymers and copolymers of N-vinyl lac Corp. or equivalent product), PEG-40 hydrogenated tams, especially homopolymers and copolymers of castor oil (e.g., Cremophor RHTM40 or equivalent prod N-Vinyl pyrrolidone, e.g., the homopolymer polyvi uct) and PEG-60 hydrogenated castor oil (e.g., Cremo nylpyrrolidone (PVPorpovidone) and copolymers such phor RHTM60 or equivalent product): as those comprising monomers of N-vinyl pyrrolidone 0.096 fatty acid monoesters of sorbitan, for example and vinyl acetate (copovidone) or N-vinyl pyrrolidone sorbitan monooleate (e.g., SpanTM 80 or equivalent and vinyl propionate; product), sorbitan monostearate (e.g., SpanTM 60 or I0084 cellulose esters and cellulose ethers, in particular equivalent product), Sorbitan monopalmitate (e.g., methylcellulose, ethylcellulose, (hydroxyalkyl)cellulo SpanTM 40 or equivalent product) and sorbitan monolau ses such as hydroxypropylcellulose, (hydroxyalkyl) rate (e.g., SpanTM 20 or equivalent product): US 2010/03 11751 A1 Dec. 9, 2010

0097 fatty acid monoesters of polyoxyethylene sorbi 0104. In the dissolving step, the various components can tan (polysorbates) such as PEG-20 sorbitan monooleate be added in any order. For example, each ingredient can be (polysorbate 80, e.g., TweenTM 80 or equivalent product) added to the solvent separately and then dissolved therein. PEG-20 sorbitan monostearate (polysorbate 60, e.g., Alternatively, the polymeric carrier and/or Surfactant can be TweenTM 60 or equivalent product), PEG-20 sorbitan pre-mixed with the API, and the resulting mixture then added monopalmitate (polysorbate 40, e.g., TweenTM 40 or to the solvent. However, it will generally be found convenient, equivalent product), or PEG-20 sorbitan monolaurate when the process includes in situ Salt-to-free base conversion, (polysorbate 20, e.g., TweenTM 20 or equivalent prod to first add the API salt and the base to the solvent, then uct); (optionally after extraction of a salt by-product) add the poly 0.098 poloxamers such as poloxamer 124, poloxamer meric carrier and Surfactant. 188, poloxamer 237, poloxamer 388 or poloxamer 407; 0105. In principle any solvent can be used so long as it is 0099 C-tocopheryl polyethylene glycol succinate effective to dissolve the active ingredient, polymer carrier and (TPGS or vitamin E polyethylene glycol succinate, see Surfactant. Non-limiting examples of solvents that can be U.S. National Formulary); useful include methanol, ethanol, acetone and mixtures and mixtures of two or more thereof. thereof. Optionally a cosolvent can be included. 0100. One or more surfactants typically constitute in total 0106 Where it is desired to extract a salt by-product such about 2% to about 25%, for example about 5% to about 20%, as NaCl, KCl or NHCl prior to solvent removal, a solvent can by weight of the solid dispersion. be selected wherein the salt by-product is insoluble, thereby 0101. A dosage form of the invention can consist of, or permitting extraction of the salt by-product by filtration. consist essentially of a solid dispersion as described above. 0107 Solvent removal can be accomplished using heat, However, in Some embodiments a dosage form contains addi vacuum or a combination thereof. If heat is used, it is gener tional excipients and requires additional processing of the ally preferable to avoid exceeding the glass transition tem Solid dispersion. For example, the solid dispersion can be perature (T) of the polymeric matrix. For most purposes ground to a powder and filled into a capsule shell or molded or heating at a temperature of about 50° C. to about 80°C., for compressed to form a tablet, with additional excipients as example about 55° C. to about 75°C., will be found suitable. may be conventionally used in Such dosage forms. After solvent removal, the resulting product is cooled (if 0102 Thus orally deliverable solid dosage forms of the necessary) to ambient temperature. invention include but are not limited to capsules, dragees, 0.108 Further process details can be found in the illustra granules, pills, powders and tablets. Excipients commonly tive processes of Examples 1 and 2 below. used to formulate such dosage forms include encapsulating 0109. The terms “orally deliverable”, “oral administra materials or formulation additives such as absorption accel tion' and "orally administered herein refer to administration erators, antioxidants, binders, buffers, coating agents, color to a subject per os (p.o.), that is, administration wherein the ing agents, diluents, disintegrating agents, emulsifiers, composition is immediately Swallowed, for example with the extenders, fillers, flavoring agents, humectants, lubricants, aid of a suitable volume of water or other potable liquid. “Oral preservatives, propellants, releasing agents, Sterilizing administration' is distinguished herein from intraoral admin agents, Sweeteners, solubilizers and mixtures thereof. istration, e.g., Sublingual or buccal administration or topical Examples of specific excipients include agar, alginic acid, administration to intraoral tissues such as periodontal tissues, aluminum hydroxide, benzyl benzoate, 1,3-butylene glycol, that does not involve immediate Swallowing of the composi castor oil, cellulose, cellulose acetate, cocoa butter, corn tion. starch, corn oil, cottonseed oil, ethanol, ethyl acetate, ethyl 0110. The active ingredient form (e.g., free base or salt), carbonate, ethylcellulose, ethyl laureate, ethyl oleate, gelatin, the polymeric carrier(s), Surfactant(s) and other optional germ oil, glucose, glycerol, groundnut oil, isopropanol, iso ingredients should be selected, and relative amounts of these tonic saline, lactose, magnesium hydroxide, magnesium components should be used, to provide a solid dispersion or Stearate, malt, olive oil, peanut oil, potassium phosphate salts, dosage form having acceptable bioabsorption when adminis potato starch, propylene glycol, talc, tragacanth, water, saf tered orally. Such bioabsorption can be evidenced, for flower oil, Sesame oil, Sodium carboxymethyl cellulose, example, by the pharmacokinetic (PK) profile of the solid Sodium lauryl Sulfate, Sodium phosphate salts, soybean oil, dispersion or dosage form, more particularly by the C or sucrose, tetrahydrofurfuryl alcohol, and mixtures thereof. AUC, for example AUC or AUCo. at a particular dose or 0103) A solvent process for preparing a solid dispersion as over a range of doses. Illustratively, bioavailability can be described above comprises dissolving the API, the polymeric expressed as a percentage, for example using the parameter F. carrier and the Surfactant in a Suitable solvent; and removing which computes AUC for oral delivery of a test composition the solvent to provide the solid dispersion. Optionally, where as a percentage of AUC for intravenous (i.v.) delivery of the the API is in salt form and it is desired to provide a solid drug in a suitable solvent, taking into account any difference dispersion of the drug in free base form, a base is added before between oral and i.v. doses. solvent removal to effect conversion of the API to its corre 0111 Bioavailability can be determined by PK studies in sponding free base. For example, where the API is ABT-263 humans or in any suitable model species. For present pur bis-HCl, addition of a base such as sodium hydroxide poses, a dog model, as illustratively described in Example 5 (NaOH), potassium hydroxide (KOH), sodium bicarbonate below, is generally suitable. In various illustrative embodi (NaHCO), potassium bicarbonate (KHCO) or ammonium ments, where the drug is ABT-263, compositions of the inven bicarbonate (NHHCO) in an amount of at least 2 moles per tion exhibit oral bioavailability of at least about 15%, at least mole of API can result in conversion of the API to ABT-263 about 20%, at least about 25% or at least about 30%, up to or free base. The inorganic salt by-product, illustratively NaCl, exceeding about 50%, in a dog model, when administered as KCl or NHCl, can remain in the product or is optionally a single dose of about 2.5 to about 10 mg/kg to fasting or extracted before solvent removal. non-fasting animals. US 2010/03 11751 A1 Dec. 9, 2010

0112 Compositions embraced herein, including compo days, or about 12 hours to about 2 days. In most cases a sitions described generally or with specificity herein, are use once-daily (q.d.) administration regimen is Suitable. ful for orally delivering a drug that is a compound of Formula 0117. An “average dosage interval herein is defined as a I or a pharmaceutically acceptable salt, prodrug, salt of a span of time, for example one day or one week, divided by the prodrug or metabolite thereof to a Subject. Accordingly, a number of unit doses administered over that span of time. For method of the invention for delivering Such a drug to a subject example, where a drug is administered three times a day, comprises orally administering a composition as described around 8 am, around noon and around 6 pm, the average above. dosage interval is 8 hours (a 24-hour time span divided by 3). 0113. The Subject can be human or non-human (e.g., a If the drug is formulated as a discrete dosage form Such as a farm, Zoo, work or companion animal, or a laboratory animal tablet or capsule, a plurality (e.g., 2 to about 10) of dosage used as a model) but in an important embodiment the Subject forms administered at one time is considered a unit dose for is a human patient in need of the drug, for example to treat a the purpose of defining the average dosage interval. disease characterized by apoptotic dysfunction and/or over 0118 Where the drug compound is ABT-263, for example expression of an anti-apoptotic Bcl-2 family protein. A in the form of ABT-263 free base or ABT-263 bis-HCl, a daily human Subject can be male or female and of any age. The dosage amount and dosage interval can, in Some embodi patient is typically an adult, but a method of the invention can ments, be selected to maintain a plasma concentration of be useful to treat a childhood cancer such as leukemia, for ABT-263 in a range of about 0.5 to about 10 ug/ml. Thus, example acute lymphocytic leukemia, in a pediatric patient. during a course of ABT-263 therapy according to Such 0114. The composition is normally administered in an embodiments, the steady-state peak plasma concentration amount providing atherapeutically effective daily dose of the (C) should in general not exceed about 10 ug/ml, and the drug. The term “daily dose herein means the amount of drug steady-state trough plasma concentration (C) should in administered per day, regardless of the frequency of admin general not fall below about 0.5ug/ml. It will further be found istration. For example, if the subject receives a unit dose of desirable to select, within the ranges provided above, a daily 150 mg twice daily, the daily dose is 300 mg. Use of the term dosage amount and average dosage interval effective to pro "daily dose” will be understood not to imply that the specified vide a C/C, ratio not greater than about 5, for example dosage amount is necessarily administered once daily. How not greater than about 3, at steady-state. It will be understood ever, in a particular embodiment the dosing frequency is once that longer dosage intervals will tend to result in greater daily (q.d.), and the daily dose and unit dose are in this C/C, ratios. Illustratively, at steady-state, an ABT-263 embodiment the same thing. C of about 3 to about 8 g/ml and C of about 1 to about 0115 What constitutes a therapeutically effective dose 5 g/ml can be targeted by the present method. Steady-state depends on the particular compound, the Subject (including values of C and C can be established in a human PK species and body weight of the Subject), the disease (e.g., the study, for example conducted according to standard protocols particular type of cancer) to be treated, the stage and/or sever including but not limited to those acceptable to a regulatory ity of the disease, the individual subject's tolerance of the agency Such as the U.S. Food and Drug Administration compound, whether the compound is administered in mono (FDA). therapy or in combination with one or more other drugs, e.g., 0119 Where the composition is in the form of a capsule, other chemotherapeutics for treatment of cancer, and other one to a small plurality of capsules can be Swallowed whole, factors. Thus the daily dose can vary within wide margins, for typically with the aid of water or other imbibable liquid to example from about 10 to about 1,000 mg. Greater or lesser help the Swallowing process. Suitable capsule shell materials daily doses can be appropriate in specific situations. It will be include, without limitation, gelatin (in the form of hard gela understood that recitation herein of a “therapeutically effec tin capsules or Soft elastic gelatin capsules), starch, carrag tive' dose herein does not necessarily require that the drug be eenan and HPMC. therapeutically effective if only a single such dose is admin 0.120. As compositions of the present invention are istered; typically therapeutic efficacy depends on the compo believed to exhibit only a minor food effect, administration sition being administered repeatedly according to a regimen according to the present embodiment can be with or without involving appropriate frequency and duration of administra food, i.e., in a non-fasting or fasting condition. It is generally tion. It is strongly preferred that, while the daily dose selected preferred to administer the present compositions to a non is sufficient to provide benefit in terms of treating the cancer, fasting patient. it should not be sufficient to provoke an adverse side-effect to I0121 Compositions of the invention are suitable for use in an unacceptable or intolerable degree. A Suitable therapeuti monotherapy or in combination therapy, for example with cally effective dose can be selected by the physician of ordi other chemotherapeutics or with ionizing radiation. A par nary skill without undue experimentation based on the dis ticular advantage of the present invention is that it permits closure herein and on art cited herein, taking into account once-daily oral administration, a regimen which is convenient factors such as those mentioned above. The physician may, for the patient who is undergoing treatment with other orally for example, start a cancer patient on a course of therapy with administered drugs on a once-daily regimen. Oral adminis a relatively low daily dose and titrate the dose upwards over a tration is easily accomplished by the patient him/herself or by period of days or weeks, to reduce risk of adverse side-effects. a caregiver in the patient's home; it is also a convenient route 0116 Illustratively, suitable doses of ABT-263 are gener of administration for patients in a hospital or residential care ally about 25 to about 1,000 mg/day, more typically about 50 Setting. to about 500 mg/day or about 200 to about 400 mg/day, for 0.122 Combination therapies illustratively include admin example about 50, about 100, about 150, about 200, about istration of a composition of the present invention, for 250, about 300, about 350, about 400, about 450 or about 500 example Such a composition comprising ABT-263, concomi mg/day, administered at an average dosage interval of about 3 tantly with one or more of , , , hours to about 7 days, for example about 8 hours to about 3 cyclophosphamide, , dexamethasone, , US 2010/03 11751 A1 Dec. 9, 2010

doxorubicin, etoposide, fludarabine, , , of nucleotides on each Strand (bluntends) or asymmetric ends rapamycin, rituximab, Vincristine and the like, for example (overhangs). The overhang of 1-2 nucleotides can be present with a polytherapy such as CHOP (cyclophosphamide+doxo on the sense and/or the antisense Strand, as well as present on rubicin--Vincristine-prednisone), RCVP (rituximab+cyclo the 5’- and/or the 3'-ends of a given strand. For example, phosphamide--Vincristine--prednisone), R-CHOP (ritux siRNAs targeting Mcl-1 have been shown to enhance the imab--CHOP) or DA-EPOCH-R (dose-adjusted etoposide, activity of ABT-263 or ABT-737 in various tumor cell lines prednisone, Vincristine, cyclophosphamide, doxorubicin and (Tse et al. (2008) Cancer Res. 68:3421-3428 and references rituximab). therein). 0123. A composition of the invention, for example such a 0.126 Multivalent binding proteins are binding proteins composition comprising ABT-263, can be administered in comprising two or more antigen binding sites. Multivalent combination therapy with one or more therapeutic agents that binding proteins are engineered to have the three or more include, but are not limited to, alkylating agents, angiogenesis antigen binding sites and are generally not naturally occur inhibitors, antibodies, , antimitotics, antipro ring antibodies. The term “multispecific binding protein’ liferatives, antivirals, aurora kinase inhibitors, other apopto means a binding protein capable of binding two or more sis promoters (for example, Bcl-XL, Bcl-w and Bfl-1 inhibi related or unrelated targets. Dual variable domain (DVD) tors), activators of a death receptor pathway, Bcr-Abl kinase binding proteins are tetravalent or multivalent binding pro inhibitors, BiTE (bi-specific T-cell engager) antibodies, anti teins binding proteins comprising two or more antigen bind body-drug conjugates, biological response modifiers, cyclin ing sites. Such DVDs may be monospecific (i.e., capable of dependent kinase (CDK) inhibitors, cell cycle inhibitors, binding one antigen) or multispecific (i.e., capable of binding cyclooxygenase-2 (COX-2) inhibitors, dual variable domain two or more antigens). DVD binding proteins comprising two binding proteins (DVDs), human epidermal growth factor heavy-chain DVD polypeptides and two light-chain DVD receptor 2 (ErbB2 or HER/2neu) receptor inhibitors, growth polypeptides are referred to as DVD Ig's. Each half of a DVD factor inhibitors, heat shock protein (HSP)-90 inhibitors, his Ig comprises a heavy-chain DVD polypeptide, a light-chain tone deacetylase (HDAC) inhibitors, hormonal therapies, DVD polypeptide, and two antigen binding sites. Each bind immunologicals, inhibitors of apoptosis proteins (IAPB), ing site comprises a heavy-chain variable domain and a light intercalating antibiotics, kinase inhibitors, kinesin inhibitors, chain variable domain with a total of 6 CDRs involved in JAK2 inhibitors, mammalian target of rapamycin (mTOR) antigen binding per antigen binding site. inhibitors, microRNAS, mitogen-activated extracellular sig I0127. Alkylating agents include , AMD-473, nal-regulated kinase (MEK) inhibitors, multivalent binding AP-5280, apaziquone, , brostallicin, , proteins, non-steroidal anti-inflammatory drugs (NSAIDs), , (BCNU), , Clore poly-ADP (adenosine diphosphate)-ribose polymerase tazineTM (laromustine, VNP 40101M), cyclophosphamide, (PARP) inhibitors, platinum chemotherapeutics, polo-like dacarbazine, estramustine, , , ifos kinase (Plk) inhibitors, phosphoinositide-3 kinase (PI3K) famide, KW-2170, (CCNU), , mel inhibitors, proteasome inhibitors, purine analogs, pyrimidine phalan, , mitolactol, , analogs, receptor tyrosine kinase inhibitors, , del N-oxide, , , , , toids, plant alkaloids, small inhibitory ribonucleic acids (siR and the like. NAS), topoisomerase inhibitors, ubiquitin ligase inhibitors, I0128 Angiogenesis inhibitors include epidermal growth and the like. factor receptor (EGFR) inhibitors, endothelial-specific recep 0.124 BiTE antibodies are bi-specific antibodies that tor tyrosine kinase (Tie-2) inhibitors, insulin growth factor-2 direct T-cells to attack cancer cells by simultaneously binding receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 the two cells. The T-cell then attacks the target cancer cell. (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) Examples of BiTE antibodies include, but are not limited to, inhibitors, platelet-derived growth factor receptor (PDGFR) (Micromet MT201), (Mi inhibitors, thrombospondin analogs, vascular endothelial cromet MT103) and the like. Without being limited by theory, growth factor receptor tyrosine kinase (VEGFR) inhibitors one of the mechanisms by which T-cells elicit apoptosis of the and the like. target cancer cell is by exocytosis of cytolytic granule com I0129. Antimetabolites include AlimtaTM ( ponents, which include perforin and granzyme B. In this disodium, LY231514, MTA), 5-, XelodaTM regard, Bcl-2 has been shown to attenuate the induction of (), , Leustatt M (), , apoptosis by both perforin and granzyme B. These data Sug , cytarabine ocfosfate, cytosine arabinoside, decit gest that inhibition of Bcl-2 could enhance the cytotoxic abine, deferoxamine, , efornithine, EICAR effects elicited by T-cells when targeted to cancer cells (Sut (5-ethynyl-1-?3-D-ribofuranosylimidazole-4-carboxamide), ton et al. (1997).J. Immunol. 158:5783-5790). enocitabine, ethenylcytidine, fludarabine, 5- 0.125 siRNAs are molecules having endogenous RNA (5-FU) alone or in combination with leucovorin, GemzarTM bases or chemically modified nucleotides. The modifications (), hydroxyurea, AlkeranTM (), mer do not abolish cellular activity, but rather impart increased captopurine, 6- riboside, , stability and/or increased cellular potency. Examples of mycophenolic acid, , nolatrexed, ocfosfate, pelitr chemical modifications include phosphorothioate groups, exol, , , ribavirin, S-1, triapine, trimetr 2'-deoxynucleotide, 2'-OCH-containing ribonucleotides, exate, TS-1, , , Vidarabine, UFT and the like. 2'-F-ribonucleotides. 2'-methoxyethyl ribonucleotides, com 0.130 Antivirals include , hydroxychloroquine binations thereof and the like. The siRNA can have varying and the like. lengths (e.g., 10-200 bps) and structures (e.g., hairpins, 0131 Aurora kinase inhibitors include ABT-348, AZD single/double strands, bulges, nickS/gaps, mismatches) and 1152, MLN-8054, VX-680, aurora A-specific kinase inhibi are processed in cells to provide active gene silencing. A tors, aurora B-specific kinase inhibitors, pan-aurora kinase double-stranded siRNA (dsRNA) can have the same number inhibitors and the like. US 2010/03 11751 A1 Dec. 9, 2010

(0132 Bcl-2 family protein inhibitors other than ABT-263 (ibuprofen), OrudisTM (ketoprofen), RelafenTM (nabume or compounds of Formula I herein include AT-101 ((-)gos tone), FeldeneTM (piroxicam), ibuprofen cream, AleveTM and sypol), Genasense M Bcl-2-targeting antisense oligonucle NaprosyntM (naproxen), VoltarenTM (diclofenac), IndocinTM otide (G3139 or ), IPI-194, IPI-565, ABT-737, (indomethacin), ClinoriltM (sulindac), TolectinTM (tolimetin), GX-070 (obatoclax) and the like. LodineTM (etodolac), ToradolTM (ketorolac), DayproTM (ox 0133) Bcr-Abl kinase inhibitors include dasatinib (BMS aprozin) and the like. 354825), GleevecTM () and the like. 0148 PDGFR inhibitors include CP-673451, CP-868596 0134. CDK inhibitors include AZD-5438, BMI-1040, and the like. BMS-387032, CVT-2584, flavopyridol, GPC-286199, MCS 0149 Platinum chemotherapeutics include cisplatin, 5A, PD0332991, PHA-690509, (CYC-202 or EloxatinTM (), eptaplatin, lobaplatin, medaplatin, R-roscovitine), ZK-304709 and the like. ParaplatinTM (carboplatin), picoplatin, and the 0135 COX-2 inhibitors include ABT-963, ArcoxiaTM like. (etoricoxib), BextraTM (valdecoxib), BMS-347070, Cele 0150 Polo-like kinase inhibitors include BI-2536 and the brexTM (), COX-189 (lumiracoxib), CT-3, Dera like. maxXTM (deracoxib), JTE-522, 4-methyl-2-(3,4-dimeth 0151. Phosphoinositide-3 kinase inhibitors include wort ylphenyl)-1-(4-sulfamoylphenyl)-1H-pyrrole, MK-663 mannin, LY-294.002, XL-147, CAL-120, ONC-21, AEZS (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, 127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, SD-8381, SVT-2016, S-2474, T-614, VioxxTM (rofecoxib) XL765 and the like. and the like. 0152 Thrombospondin analogs include ABT-510, ABT 0.136 EGFR inhibitors include ABX-EGF, anti-EGFR 567, ABT-898, TSP-1 and the like. immunoliposomes, EGF-vaccine, EMD-7200, ErbituxTM (O153 VEGFR inhibitors include AvastinTM (bevaci (), HR3, IgA antibodies, IressaTM (gefitinib), Zumab), ABT-869, AEE-788, AngiozymeTM (a ribozyme that TarcevaTM (erlotinib or OSI-774), TP-38, EGFR fusion pro inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, tein, TykerbTM (lapatinib) and the like. Colo.) and Chiron (Emeryville, Calif.)), axitinib (AG 0137 ErbB2 receptor inhibitors include CP-724714, 13736), AZD-2171, CP-547632, IM-862, MacugenTM (pe CI-1033 (canertinib), HerceptinTM (), TykerbTM gaptainib), NexavarTM (Sorafenib, BAY43-9006), pazopanib (lapatinib), OmnitargTM (2C4, petuzumab), TAK-165, (GW-786034), (PTK-787 or ZK-222584), SutentTM GW-572016 (ionafamib), GW-282974, EKB-569, PI-166, (sunitinib or SU-11248), VEGF trap, ZactimaTM (vandetanib dHER2 (HER2 vaccine), APC-8024 (HER2 vaccine), anti or ZD-6474) and the like. HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 tri 0154 Antibiotics include intercalating antibiotics such as functional bispecific antibodies, mAB AR-209, mAB 2B-1 , actinomycin D, , annamycin, Adria and the like. mycinTM (doxorubicin), BlenoxaneTM (), daunoru 0.138. Histone deacetylase inhibitors include depsipep bicin, CaelyxTM and MyocetTM (liposomal doxorubicin), tide, LAQ-824, MS-275, trapoxin, suberoylanilide hydrox , , glarubicin, , mitomycin amic acid (SAHA), TSA, valproic acid and the like. C, memorubicin, neocarzinostatin, peplomycin, , 0139. HSP-90 inhibitors include 17 AAG, CNF-101, rebeccamycin, stimalamer, streptozocin, ValstarTM (valrubi CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, cin), Zinostatin and the like. KOS-953, Mycograb TM (human recombinant antibody to 0155 Topoisomerase inhibitors include aclarubicin, HSP-90), nab-17AAG, NCS-683664, PU24FC1, PU-3, 9-aminocamptothecin, amonafide, , becatecarin, radicicol, SNX-2112, STA-9090, VER-49009 and the like. , BN-80915, CamptosarTM (irinotecan hydrochlo 0140. Inhibitors of apoptosis proteins include HGS-1029, ride), , CardioxaneTM (dexrazoxane), diflomo GDC-0145, GDC-0152, LCL-161, LBW-242 and the like. tecan, edotecarin, EllenceTM and PharmorubicinTM (epirubi 0141 Antibody-drug conjugates include anti-CD22-MC cin), etoposide, , 10-hydroxycamptothecin, MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, gimatecan, , , orathecin, pirarbucin, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19A, , , Sobuzoxane, SN-38, tafluposide, topo SGN-35, SGN-75 and the like. tecan and the like. 0142 Activators of death receptor pathway include 0156 Antibodies include AvastinTM (), TRAIL and antibodies or other agents that target TRAIL or CD40-specific antibodies, chTNT-1/B, denosumab, death receptors (e.g., DR4 and DR5) Such as apomab, cona ErbituxTM (cetuximab), Humax-CD4TM (Zanolimumab), tumumab, ETR2-ST01, GDC0145 (), HGS IGF1R-specific antibodies, , PanorexTM (edreco 1029, LBY-135, PRO-1762, trastuzumab and the like. lomab), RencarexTM (WX G250), RituxanTM (rituximab), 0143 Kinesin inhibitors include Eg5 inhibitors such as ticilimumab, trastuzumab, CD20 antibodies types I and II and AZD-4877 and ARRY-520, CENPE inhibitors such as GSK the like. 923295A, and the like. 0157 Hormonal therapies include ArimidexTM (anastro 0144) JAK2 inhibitors include CEP-701 (lesaurtinib), zole). AromasinTM (exemestane), arzoxifene, CasodexTM (bi XL019, NCB-018424 and the like. calutamide), Cetrotide TM (cetrorelix), degarelix, deslorelin, (0145 MEK inhibitors include ARRY-142886, ARRY DesopanTM (trilostane), dexamethasone, Drogenil M (fluta 438162, PD-325901, PD-98.059 and the like. mide), EvistaTM (raloxifene), AfemaTM (fadrozole), Far 0146 mTOR inhibitors include AP-23573, CC1-779, estonTM (toremifene), FaslodexTM (fulvestrant), FemaraTM everolimus, RAD-001, rapamycin, temsirolimus, ATP-com (letrozole), formestane, glucocorticoids, HectorolTM (doxer petitive TORC1/TORC2 inhibitors, including PI-103, PP242, calciferol), RenagelTM (sevelamer carbonate), lasofoxifene, PP30 and Torin 1, and the like. leuprolide acetate, MegaceTM (megestrol), MifeprexTM (mife 0147 Non-steroidal anti-inflammatory drugs include pristone), NilandronTM (nilutamide), tamoxifen including AmigesicTM (salsalate), DolobidTM (diflunisal), MotrinTM NolvadexTM (tamoxifen citrate), PlenaxisTM (abarelix), pred US 2010/03 11751 A1 Dec. 9, 2010 nisone, PropeciaTM (finasteride), rilostane, SuprefactTM external beam radiotherapy (XBRT), teletherapy, brachy (buserelin), luteinizing hormone releasing hormone (LHRH) therapy, sealed-source radiotherapy, unsealed-source radio including TrelstarTM (triptorelin), histrelin including Van therapy and the like. tasTM (histrelin implant), ModrastaneTM (trilostane), Zola 0168 Additionally or alternatively, a composition of the dexTM (goserelin) and the like. present invention can be administered in combination therapy 0158 Deltoids and retinoids include seocalcitol (EB1089 with one or more antitumor or chemotherapeutic agents or CB1093), lexacalcitol (KH1060), fenretinide, PanretinTM selected from AbraxaneTM (ABI-007), ABT-100 (farnesyl (), including AtragenTM (liposomal tret transferase inhibitor), AdvexinTM (Ad5CMV-p53 vaccine or inoin), TargretinTM (), LGD-1550 and the like. contusugene ladenovec). AltocorTM or MevacorTM (lovasta 0159 PARP inhibitors include ABT-888, , tin), AmpligenTM (poly(I)-poly(C12U), a synthetic RNA), KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, AptosynTM (), ArediaTM (pamidronic acid), arglabin, INO-1001, ONO-2231 and the like. L-, atamestane (1-methyl-3,17-dione-androsta 1,4-diene), AvageTM (tazarotene), AVE-8062 (combretastatin 0160 Plant alkaloids include Vincristine, , Vin derivative), BEC2 (mitumomab), cachectin or cachexin (tu desine, and the like. mor necrosis factor), Canvaxin TM ( vaccine), (0161 Proteasome inhibitors include VelcadeTM (bort CeaVacTM (cancer vaccine), CeleukTM (celmoleukin), hista ezomib), MG132, NPI-0052, PR-171 and the like. mine including CepleneTM (histamine dihydrochloride), Cer 0162 Examples of immunologicals include interferons varixTM (AS04 adjuvant-adsorbed human papilloma virus and other immune-enhancing agents. Interferons include (HPV) vaccine), CHOP (CytoxanTM (cyclophosphamide)+ interferon alpha, interferon alpha-2a, interferon alpha-2b. AdriamycinTM (doxorubicin)+OncovinTM (Vincristine)+ interferon beta, interferon gamma-1a, ActimmuneTM (inter prednisone), combretastatin A4P. Cypat'TM (cyproterone), feron gamma-1b), interferon gamma-nl, combinations DAB(389)EGF (catalytic and translocation domains of diph thereofand the like. Other agents include Alfaferone (IFN-O.), theria toxin fused via a His-Ala linker to human epidermal BAM-002 (oxidized glutathione), BeromunTM (tasonermin), growth factor), dacarbazine, , DimericineTM BexxarTM (to situmomab), CampathTM (), (T4N5 liposome lotion), 5,6-dimethylxanthenone-4-acetic CTLA4 (cytotoxic lymphocyte antigen 4), dacarbazine, acid (DMXAA), discodermolide, DX-8951 f(exatecan mesy denileukin, epratuzumab, GranocyteTM (lenograstim), len late), eniluracil (ethynyluracil), squalamine including Evi tinan, leukocyte alpha interferon, imiquimod, MDX-010 ZonTM (squalamine lactate), enzastaurin, EPO-906 (anti-CTLA-4), melanoma vaccine, mitumomab, molgra ( B), Gardasil TM (quadrivalent human papilloma mostim, MylotargTM (), Neupo virus (Types 6, 11, 16, 18) recombinant vaccine), Gastrim genTM (filgrastim). OncoVAC-CL, OvarexTM (), muneTM, GenasenseTM (oblimersen), GMK (ganglioside con (Y-muHMFG1), ProvengeTM (sipuleucel-T), jugate vaccine), GVAXTM (prostate cancer vaccine), sargaramostim, sizofuran, teceleukin, TheracysTM (BCG or halofuginone, histerelin, hydroxycarbamide, ibandronic Bacillus Calmette-Guerin), ubenimex, VirulizinTM (immuno acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin therapeutic, Lorus Pharmaceuticals), Z-100 (Specific Sub besudotox), IL-13-pseudomonas exotoxin, interferon-C. stance of Maruyama or SSM), WF-10 (tetrachlorodecaoxide interferon-Y, JunovanTM and MepactTM (mi?amurtide), lona or TCDO), ProleukinTM (aldesleukin), ZadaxinTM (thymalfa farnib, 5,10-methylenetetrahydrofolate, miltefo sine (hexa sin), ZenapaxTM (daclizumab), ZevalinTM (90Y-ibritumomab decylphosphocholine), NeovastatTM (AE-941), NeutrexinTM tiuxetan) and the like. Biological response modifiers are (trimetrexate glucuronate), NipentTM (pentostatin). Oncon agents that modify defense mechanisms of living organisms aseTM (ranpirinase, a ribonuclease enzyme). OncophageTM or biological responses, such as Survival, growth or differen (vitespen, melanoma vaccine treatment). OncoVAXTM (IL-2 tiation of tissue cells to direct them to have anti-tumor activ vaccine), OrathecinTM (rubitecan), OsidemTM (antibody ity, and include krestin, lentinan, sizofuran, picibanil, based cell drug), OvarexTMMAb (murine monoclonal anti PF-3512676 (CpG-8954), ubenimex and the like. body), paclitaxel albumin-stabilized nanoparticle, paclitaxel, 0163 Pyrimidine analogs include cytarabine (cytosine PandimeXTM (aglycone saponins from ginseng comprising arabinoside, ara Cor arabinoside C), doxifluridine, FludaraTM 20(S)-protopanaxadiol (aPPD) and 200S)-protopanaxatriol (fludarabine), 5-FU (5-fluorouracil), , GemzarTM (aPPT)), , PanvacTM-VF (investigational cancer (gemcitabine), TomudexTM (raltitrexed), triacetyluridine, vaccine), , peginterferon alfa (PEG interferon TroxatylTM (troxacitabine) and the like. A), phenoxodiol, , rebimastat, RemovabM (ca 0164 Purine analogs include LanvisTM (thioguanine), tumaxomab), RevlimidTM (lenalidomide), RSR13 (efaprox iral). SomatulineTMLA (lanreotide), SoriataneTM (acitretin), PurinetholTM (mercaptopurine) and the like. staurosporine (Streptomyces staurospores), tallabostat 0.165 Antimitotic agents includebatabulin, epothilone D (PT100), TargretinTM (bexarotene), TaxoprexinTM (docosa (KOS-862), N-(2-((4-hydroxy-phenyl)amino)pyridin-3-yl)- hexaenoic acid (DHA)+paclitaxel), TelcytaTM (canfosfamide, 4-methoxybenzenesulfonamide, (BMS TLK-286), TemodarTM (temozolomide), tesmilifene, tetran 247550), paclitaxel, TaxotereTM (docetaxel), (PNU drine, thalidomide. Theratope TM (STn-KLH Vaccine), 100940, RPR-109881 or XRP-9881), patupilone, , Thymitaq TM (nolatrexed dihydrochloride), TNFeradeTM (ad ZK-EPO (synthetic epothilone) and the like. enovector: DNA carrier containing the gene for tumor necro 0166 Ubiquitin ligase inhibitors include MDM2 inhibi sis factor-O.), TracleerTM or ZavescaTM (bosentan), Trans tors such as nutlins, NEDD8 inhibitors such as MLN4924, MID-107RTM (KSB-311, diphtheria toxins), tretinoin (retin and the like. A), TrisenoxTM (), UkrainTM (derivative of 0167 Compositions of this invention can also be used as alkaloids from the greater celandine plant), VirulizinTM, radiosensitizers that enhance the efficacy of radiotherapy. VitaxinTM (anti-CVB3 antibody), XcytrinTM (motexafin gado Examples of radiotherapy include, but are not limited to, linium), XinlayTM (), XyotaxTM (paclitaxel poli US 2010/03 11751 A1 Dec. 9, 2010

glumex), YondelisTM (), ZD-6126 (N-acetyl cancer, colon cancer, rectal cancer, cancer of the anal region, colchinol-O-phosphate), Zinecard TM (dexraZoxane), stomach cancer, gastrointestinal (gastric, colorectal and/or Zoledronic acid, and the like. duodenal) cancer, chronic lymphocytic leukemia, acute lym 0169. In one embodiment, a composition of the invention, phocytic leukemia, esophageal cancer, cancer of the Small for example Such a composition comprising ABT-263, is intestine, cancer of the endocrine system, cancer of the thy administered in a therapeutically effective amount to a Sub roid gland, cancer of the parathyroid gland, cancer of the ject in need thereof to treat a disease during which is overex adrenal gland, sarcoma of Soft tissue, cancer of the urethra, pressed one or more of antiapoptotic Bcl-2 protein, antiapo cancer of the penis, testicular cancer, hepatocellular (hepatic ptotic Bcl-X protein and antiapoptotic Bcl-w protein. and/or biliary duct) cancer, primary or secondary central ner 0170 In another embodiment, a composition of the inven Vous system tumor, primary or secondary brain tumor, tion, for example such a composition comprising ABT-263, is Hodgkin's disease, chronic or acute leukemia, chronic administered in a therapeutically effective amount to a Sub myeloid leukemia, lymphocytic lymphoma, lymphoblastic ject in need thereof to treat a disease of abnormal cell growth leukemia, follicular lymphoma, lymphoid malignancies of and/or dysregulated apoptosis. T-cell or B-cell origin, melanoma, multiple myeloma, oral 0171 Examples of such diseases include, but are not lim cancer, non-Small-cell lung cancer, prostate cancer, Small ited to, cancer, mesothelioma, bladder cancer, pancreatic can cell lung cancer, cancer of the kidney and/or ureter, renal cell cer, skin cancer, cancer of the head or neck, cutaneous or carcinoma, carcinoma of the renal pelvis, neoplasms of the intraocular melanoma, ovarian cancer, breast cancer, uterine central nervous system, primary central nervous system lym cancer, carcinoma of the fallopian tubes, carcinoma of the phoma, non-Hodgkin's lymphoma, spinal axis tumors, brain endometrium, carcinoma of the cervix, carcinoma of the stem glioma, pituitary adenoma, adrenocortical cancer, gall vagina, carcinoma of the Vulva, bone cancer, colon cancer, bladder cancer, cancer of the spleen, cholangiocarcinoma, rectal cancer, cancer of the anal region, stomach cancer, gas fibrosarcoma, neuroblastoma, retinoblastoma or a combina trointestinal (gastric, colorectal and/or duodenal) cancer, tion thereof in a Subject comprises administering to the Sub chronic lymphocytic leukemia, acute lymphocytic leukemia, ject therapeutically effective amounts of (a) a composition of esophageal cancer, cancer of the Small intestine, cancer of the the invention, for example Such a composition comprising endocrine system, cancer of the thyroid gland, cancer of the ABT-263, and (b) one or more of etoposide, Vincristine, parathyroid gland, cancer of the adrenal gland, sarcoma of CHOP. rituximab, rapamycin, R-CHOP RCVP, DA-EP Soft tissue, cancer of the urethra, cancer of the penis, testicular OCH-R or bortezomib. cancer, hepatocellular (hepatic and/or biliary duct) cancer, (0175. In particular embodiments, a composition of the primary or secondary central nervous system tumor, primary invention, for example Such a composition comprising ABT or secondary brain tumor, Hodgkin's disease, chronic oracute 263, is administered in a therapeutically effective amount to a leukemia, chronic myeloid leukemia, lymphocytic lym subject in need thereof in combination therapy with etopo phoma, lymphoblastic leukemia, follicular lymphoma, lym side, Vincristine, CHOP. rituximab, rapamycin, R-CHOP, phoid malignancies of T-cell or B-cell origin, melanoma, RCVP, DA-EPOCH-R or bortezomib in a therapeutically multiple myeloma, oral cancer, non-Small-cell lung cancer, effective amount, for treatment of a lymphoid malignancy prostate cancer, Small-cell lung cancer, cancer of the kidney Such as B-cell lymphoma or non-Hodgkin's lymphoma. and/or ureter, renal cell carcinoma, carcinoma of the renal 0176). In other particular embodiments, a composition of pelvis, neoplasms of the central nervous system, primary the invention, for example Such a composition comprising central nervous system lymphoma, non-Hodgkin's lym ABT-263, is administered in a therapeutically effective phoma, spinal axis tumors, brain stem glioma, pituitary amount to a Subject in need thereof in monotherapy or in adenoma, adrenocortical cancer, gallbladder cancer, cancer combination therapy with etoposide, Vincristine, CHOP, rit of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblas uximab, rapamycin, R-CHOP RCVP, DA-EPOCH-Rorbort toma, retinoblastoma or a combination thereof. eZomib in a therapeutically effective amount, for treatment of 0172. In a more particular embodiment, a composition of chronic lymphocytic leukemia or acute lymphocytic leuke the invention, for example Such a composition comprising a 18. ABT-263-containing Solid dispersion, is administered in a 0177. The present invention also provides a method for therapeutically effective amount to a subject in need thereof maintaining in bloodstream of a human cancer patientathera to treat bladder cancer, brain cancer, breast cancer, bone mar peutically effective plasma concentration of ABT-263 and/or row cancer, , chronic lymphocytic leukemia, one or more metabolites thereof, comprising administering to acute lymphocytic leukemia, colorectal cancer, esophageal the subject a solid dispersion of ABT-263 or a pharmaceuti cancer, hepatocellular cancer, lymphoblastic leukemia, folli cally acceptable salt, prodrug, salt of a prodrug or metabolite cular lymphoma, lymphoid malignancies of T-cell or B-cell thereof (for example ABT-263 free base or ABT-263 bis-HCl) origin, melanoma, myelogenous leukemia, myeloma, oral in essentially non-crystalline form in a matrix that comprises cancer, ovarian cancer, non-Small-cell lung cancer, prostate a pharmaceutically acceptable water-soluble polymeric car cancer, Small-cell lung cancer or spleen cancer. rier and a pharmaceutically acceptable Surfactant, in a dosage 0173 According to any of these embodiments, the com amount equivalent to about 50 to about 500 mg ABT-263 per position is administered in monotherapy or in combination day, at an average dosage interval of about 3 hours to about 7 therapy with one or more additional therapeutic agents. days. 0.174 For example, a method for treating mesothelioma, 0.178 What constitutes a therapeutically effective plasma bladder cancer, pancreatic cancer, skin cancer, cancer of the concentration depends inter alia on the particular cancer head or neck, cutaneous or intraocular melanoma, ovarian present in the patient, the stage, severity and aggressiveness cancer, breast cancer, uterine cancer, carcinoma of the fallo of the cancer, and the outcome sought (e.g., stabilization, pian tubes, carcinoma of the endometrium, carcinoma of the reduction in tumor growth, tumor shrinkage, reduced risk of cervix, carcinoma of the vagina, carcinoma of the Vulva, bone metastasis, etc.). It is strongly preferred that, while the plasma US 2010/03 11751 A1 Dec. 9, 2010

concentration is sufficient to provide benefit in terms of treat (0191 10.8% ABT-263 salt (10% free base equivalent); ing the cancer, it should not be sufficient to provoke an 10% surfactant: 79.2% polymer adverse side-effect to an unacceptable or intolerable degree. (0192. 21.5% ABT-263 salt (20% free base equivalent); 0179 For treatment of cancer in general and of alymphoid 10% surfactant: 68.5% polymer malignancy such as non-Hodgkin’s lymphoma in particular, (0193 32.3% ABT-263 salt (30% free base equivalent); the plasma concentration of ABT-263 should in most cases be 10% surfactant: 57.7% polymer maintained in a range of about 0.5 to about 10 ug/ml. Thus, (0194 43% ABT-263 salt (40% free base equivalent); 10% during a course of ABT-263 therapy, the steady-state C, surfactant: 47% polymer should in general not exceed about 10 ug/ml, and the steady (0195 The surfactant in different series was TPGS, SpanTM state C should in general not fall below about 0.5ug/ml. It 20 or TweenTM 20. The polymer in different series was cop will further be found desirable to select, within the ranges ovidone (KollidonTM VA64), povidone K-30 or HPMC-AS. provided above, a daily dosage amount and average dosage 0196. The mixture of ingredients in each case was dis interval effective to provide a C/C, ratio not greater than solved in methanol. The methanol was removed at 65° C. in about 5, for example not greater than about 3, at steady-state. vacuo using a GenevacTM system, and the resulting Solid It will be understood that longer dosage intervals will tend to dispersion was allowed to cool to ambient temperature. result in greater C/C, ratios. Illustratively, at steady 0197) The solid dispersion in each case was sieved through state, an ABT-263 C of about 3 to about 8 g/ml and C, a 40-mesh screen to provide a powder of reduced particle size. of about 1 to about 5 ug/ml can be targeted by the present The resulting powders were used for determination of T by method. differential scanning calorimetry (DSC), residual solvent and 0180 A daily dosage amount effective to maintain a thera moisture determination by thermogravimetric analysis peutically effective ABT-263 plasma level is, according to the present embodiment, about 50 to about 500 mg. In most cases (TGA), characterization of crystallinity or lack thereof by a suitable daily dosage amount is about 200 to about 400 mg. powder X-ray diffraction (PXRD), and determination of Illustratively, the daily dosage amount can be for example physical stability when stored at 25°C./60% relative humid about 50, about 100, about 150, about 200, about 250, about ity (RH) and at 40° C./75% RH. 300, about 350, about 400, about 450 or about 500 mg. 0198 The solid dispersion powder in each case was 0181 An average dosage interval effective to maintain a blended with ProSolvTM HD90, croscarmellose sodium and therapeutically effective ABT-263 plasma level is, according sodium stearyl fumarate at a weight ratio of 82:15:2:1. The to the present embodiment, about 3 hours to about 7 days. In resulting blend was filled into hard gelatin capsules of a size, most cases a Suitable average dosage interval is about 8 hours depending on drug loading, to provide a 50 mg unit dose of to about 3 days, or about 12 hours to about 2 days. A once ABT-263. The capsules were tested for dissolution in a pH 6.5 daily (q.d.) administration regimen is often suitable. buffer medium containing 7.6 mM TweenTM 80, using USP 0182 For the present embodiment, ABT-263 is illustra apparatus II (see Example 3 below). tively present in the pharmaceutical composition in the form (0199 All tested solid dispersions of ABT-263 bis-HCl of ABT-263 free base or ABT-263 bis-HCl, more particularly prepared as above were found to have a T in the range of ABT-263 free base. Any ABT-263 composition of the present 70-110° C. TGA showed that the copovidone/HPMC-AS invention, as defined more fully above, can be used. dispersions had the lowest moisture content (2-4%) and the 0183. As in other embodiments, administration according poVidone dispersions, regardless of Surfactant used, had the to the present embodiment can be with or without food, i.e., in highest moisture content (8-10%). PXRD showed no crystal a non-fasting or fasting condition. It is generally preferred to linity, i.e., the ABT-263 bis-HCl was amorphous in all solid administer the present compositions to a non-fasting patient. dispersions. Only the ABT-263 bis-HCl solid dispersions pre pared with HPMC-AS as the polymeric carrier showed EXAMPLES acceptable storage stability for one month. Where povidone 0184 The following examples are merely illustrative, and or copovidone was used, a tendency for deliquescence was do not limit this disclosure in any way. Trademarked ingre observed in open-dish storage stability testing at both at 25° dients used in the examples, which can be substituted with C. f60% RH and at 40° C. (75% RH. comparable ingredients from other Suppliers, include: 0185. ProSolviMHD90 of JRSPharma: siliconized micro Example 2 cystalline cellulose 0186 SpanTM 20 of Croda International PLC: sorbitan Preparation of Solid Dispersions of ABT-263 Free monolaurate Base 0187 TweenTM 20 of Uniqema: polysorbate 20 surfactant; 0188 TweenTM 80 of Uniqema: polysorbate 80 surfactant. (0200. ABT-263 bis-HCl crystalline salt was dissolved in 0189 All ABT-263 amounts, including concentrations acetone, and NaOH was added to convert the ABT-263 bis and doses, given in the examples are expressed as free base HCl to free base. The NaCl by-product precipitated and was equivalent doses unless expressly stated otherwise. Where removed by filtration. ABT-263 is administered as bis-HCl salt, 1.076 mg ABT-263 0201 To the resulting ABT-263 free base solution in bis-HCl provides 1 mg ABT-263 free base equivalent. acetone were added a surfactant and a water-soluble polymer in the following weight ratios: Example 1 (0202 10% ABT-263 free base; 10% surfactant: 80% poly Preparation of Solid Dispersions of ABT-263 bis C HC1 (0203 20% ABT-263 free base; 10% surfactant: 70% poly (0190. ABT-263 bis-HC1 crystalline salt was mixed with a C Surfactant and a water-soluble polymer in the following (0204 30% ABT-263 free base; 10% surfactant: 60% poly weight ratios: C US 2010/03 11751 A1 Dec. 9, 2010

0205 40% ABT-263 free base; 10% surfactant; 50% poly ment of 5% copovidone with HPMC-AS showed slower drug C release in presence of HPMC-AS. 0206. The surfactant in different series was TPGS, SpanTM 20 or TweenTM 20. The polymer in different series was cop Example 4 ovidone (KollidonTMVA 64) or HPMC-AS. 0207. The acetone was removed at 65°C. in vacuousing a Effect of Polymeric Carrier on Dissolution Profile of GenevacTM system, and the resulting solid dispersion was ABT-263 Bis-HCl Dispersions allowed to cool to ambient temperature. 0217 Solid dispersions with different polymeric carriers 0208. The solid dispersion in each case was sieved through were tested to observe impact of the polymeric carriers on a 40-mesh screen to provide a powder of reduced particle size. dissolution rates. Four solid dispersions were prepared with The resulting powders, as in Example 1, were used for deter ABT-263 bis-HCl salt (20% free base equivalent), 10%TPGS mination of T by DSC, residual solvent and moisture deter and the following polymeric carriers: mination by TGA, characterization of crystallinity or lack 0218 povidone only thereof by PXRD, and determination of physical stability 0219 50% povidone+50% copovidone when Stored at 25° C. f60% RH and at 40° C.F75% RH. 0220 25% povidone+75% copovidone 0209. The solid dispersion powder in each case was 0221 copovidone only blended with ProSolviM, croscarmellose sodium and sodium 0222 Dissolution profiles of the four solid dispersions are stearyl fumarate at a weight ratio of 82:15:2:1. The resulting shown in FIG. 3. Drug release rate increased with increasing blend was filled into hard gelatin capsules of a size, depend levels of povidone. ing on drug loading, to provide a 50mg unit dose of ABT-263. The capsules were tested for dissolution in a pH 6.5 buffer Example 5 medium containing 7.6 mM TweenTM 80 (see Example 3 below). of ABT-263 bis-HCl Dispersions 0210 All tested solid dispersions of ABT-263 free base in a Dog Model prepared as above were found to have a T in the range of 70-110° C. TGA showed that the copovidone and HPMC-AS 0223 Single-dose pharmacokinetics of two ABT-263 dispersions had low moisture content (2-4%). PXRD showed Solid dispersions were evaluated in non-fasted beagle dogs no crystallinity, i.e., the ABT-263 free base was amorphousin (n-6) after a 50 mg/kg oral dose followed by 10 ml water. all solid dispersions. The ABT-263 free base solid dispersions Serial heparinized blood samples were obtained from a jugu prepared with copovidone or HPMC-AS as the polymeric lar vein of each animal prior to dosing and 0.25, 0.5, 1, 1.5, 2. carrier showed acceptable storage stability for one month 3, 4, 6, 9, 12, 15 and 24 hours after administration. Plasma without any sign of deliquescence. was separated by centrifugation (2,000 rpm for 10 minutes at approximately 4°C.) and ABT-263 was isolated using protein Example 3 precipitation with acetonitrile. 0224. Two ABT-263 bis-HCl solid dispersions (those of Dissolution Profiles of Solid Dispersions Example 4 containing povidone only or copovidone only) were compared. The powdered dispersions were blended 0211 Representative dissolution (drug release) profiles in with ProSolvTM HD90, croscarmellose sodium and sodium apH 6.5 buffered medium containing 7.6 mMTweenTM80 are stearyl fumarate in an 82:15:2:1 weight ratio and the blend shown in FIG. 1 (ABT-263 bis-HCl) and FIG. 2 (ABT-263 filled into capsules. free base). 0225. ABT-263 and an internal standard were separated 0212. As shown in FIG. 1, at a 20% drug-loading level, the from each other and from co-extracted contaminants on a ABT-263 bis-HCl solid dispersions with 68.5% copovidone 50x3 mm Keystone Betasil CNTM 5 um column with an and 10% TPGS showed a moderate rate of drug release that acetonitrile/0.1% trifluoroacetic acid mobile phase (50:50 by plateaued at about 80% release. Release from similar disper volume) at a flow rate of 0.7 ml/min. Analysis was performed sions having SpanTM 20 or, especially, TweenTM 20 as the on a Sciex API3000TM biomolecular mass analyzer with a Surfactant was much slower. heated nebulizer interface. ABT-263 and internal standard 0213. By contrast, as shown in FIG. 2, at the same 20% peak areas were determined using Sciex MacQuanTM soft drug-loading level, the ABT-263 free base solid dispersions ware. The plasma drug concentration of each sample was with 70% copovidone and 10% of either TweenTM 20 or calculated by least squares linear regression analysis (non TPGS showed rapid dug release. Only the SpanTM20 surfac weighted) of the peak area ratio (parent/internal standard) of tant resulted in much slower release in the case of the free base the spiked plasma standards versus concentration. The dispersion. plasma concentration data were Submitted to multi-exponen 0214) Release rate was drug-loading-dependent in both tial curve fitting using WinNonlin 3 (Pharsight). ABT-263 bis-HCl and free base dispersion formulations, the 0226. The area under the plasma concentration-time curve 20% dispersions showing faster release than the 30% or 40% from 0 to thours (time of the last measured plasma concen dispersions in both cases. tration) after dosing (AUC) was calculated using the linear 0215. Unlike the analogous solid dispersion prepared trapezoidal rule for the plasma concentration-time profiles. from the ABT-263 free base, the solid dispersion containing The residual area extrapolated to infinity, determined as the ABT-263 bis-HCl, copovidone and TweenTM20 showed shell final measured plasma concentration (C) divided by the ter formation. This shell formation is believed to be caused by minal elimination rate constant (B), was added to AUCo. to precipitation of the drug on the Surface of the capsule fill plug. produce the total area under the curve (AUC). The bio 0216. In a separate study, solid dispersions of ABT-263 availability was calculated as the dose-normalized AUCo. bis-HCl in a copovidone matrix with and without replace from oral dosing divided by the corresponding value derived US 2010/03 11751 A1 Dec. 9, 2010

fromi.V. (intravenous) dosing, administered as a slow bolus to a jugular vein under light ether anesthetic. 0227 PK parameters for the povidone-only and copovi I done-only dispersions are presented in Table 1. CFX SO TABLE 1. H N PK parameters of solid dispersion compositions in dog (n = 6 S H Crna D AUCD Crna Lig/ml per Tax AUC Ig himl F O N Composition Ig/ml mg/kg h Ig himl per mg/kg 96 / \, X4 powidone S.6 1.16 9.8 39.3 7.9 16.4 copovidone 9.6 1.78 4.5 64.9 11.9 24.7

0228. Although the ABT-263 bis-HCl dispersion prepared with povidone was shown in Example 4 to provide a better release rate than copovidone, it had poorer bioavailability in this dog study than a comparable dispersion prepared with CN copovidone. R0 Example 6 where Pharmacokinetics of Illustrative Solid Dispersions in X is chloro or fluoro; and a Dog Model (1) X* is azepan-1-yl, morpholin-4-yl, 1,4-oxazepan-4-yl, 0229. Single-dose pharmacokinetics of two ABT-263 pyrrolidin-1-yl, - N(CH), N(CH)(CH(CH)), Solid dispersions were evaluated in non-fasted beagle dogs 7-azabicyclo2.2.1]heptan-7-yl or 2-oxa-5-azabicyclo (n=6), following the same protocol as that of Example 5. Two 2.2.1]hept-5-yl; and R' is ABT-263 solid dispersions (Dispersions I and II) were pre pared. Dispersion I, prepared Substantially according to the process of Example 2, contained 10% ABT-263 free base, 10% 0230 TPGS and 80% copovidone. The powdered disper sion was filled into capsules without any additional ingredi ents to prepare Composition I. Dispersion II, prepared Sub stantially according to the process of Example 1, contained 13.11% ABT-263 bis-HCl (12.18% free base equivalent), 15% TPGS and 71.89% povidone. The powdered dispersion was blended with ProSolviMHD90, sodium starch glycolate and sodium stearyl fumarate in an 82:15:2:1 weight ratio and the blend filled into capsules to prepare Composition II. 0231 PK parameters for Compositions I and II are pre where sented in Table 2. X is —CH2—, —C(CH), or —CH2CH2; X and X’ are both H or both methyl; and TABLE 2 X is fluoro, chloro, bromo or iodo; PK parameters of Solid dispersion compositions in dog (n = 6 Or (2) X is azepan-1-yl, morpholin-4-yl, pyrrolidin-1-yl, CaD AUCD Crna Lig/ml per Tax AUC Ig himl F —N(CH)(CH(CH)) or 7-azabicyclo[2.2.1]heptan-7- Composition Ig/ml mg/kg h Ig himl per mg/kg 96 yl; and R is I 7.5 1...SO 8.5 59.0 11.2 24.6 II 6.4 1.24 7.8 39.2 7.4 16.3

0232. The ABT-263 bis-HCl dispersion (Composition II) prepared with povidone had poorer bioavailability in this dog study than the ABT-263 free base dispersion (Composition I) prepared with copovidone.

What is claimed is: 1. A solid dispersion comprising, in essentially non-crys talline form, a compound of Formula I US 2010/03 11751 A1 Dec. 9, 2010 17

where X, X7 and X are as above; or (3) X is morpholin-4-yl or N(CH4); and R' is CFX SO

O MV O O

r s A-21 X8 where X is as above: O or a pharmaceutically acceptable salt, prodrug, salt of a prodrug or metabolite thereof; dispersed in a solid where matrix that comprises (a) at least one pharmaceutically X is chloro or fluoro; and acceptable water-soluble polymeric carrier and (b) at (1) X is azepan-1-yl, morpholin-4-yl, 1,4-oxazepan-4- least one pharmaceutically acceptable Surfactant. yl, pyrrolidin-1-yl, N(CH), N(CH)(CH(CH) 2. The solid dispersion of claim 1, wherein the compound 2), 7-azabicyclo[2.2.1]heptan-7-yl or 2-oxa-5-azabi of Formula I is ABT-263 or a pharmaceutically acceptable cyclo[2.2.1]hept-5-yl; and R' is salt, prodrug, salt of a prodrug or metabolite thereof. 3. The solid dispersion of claim 1, wherein the compound of Formula I is ABT-263 free base or ABT-263 bis-HC1. 4. The solid dispersion of claim 2, wherein the compound is present in an ABT-263 free base equivalent amount of about 5% to about 40% by weight. 5. The solid dispersion of claim 4, wherein the at least one polymeric carrier is present in an amount of about 40% to about 85% by weight and the at least one surfactant is present in an amount of about 5% to about 20% by weight. 6. The solid dispersion of claim 1, wherein the at least one polymeric carrier is selected from the group consisting of where homopolymers and copolymers of N-vinyl lactams, cellulose X is —CH2—, —C(CH), or —CH2CH2; esters, cellulose ethers, high molecular weight polyalkylene X and X’ are both —H or both methyl; and oxides, polyacrylates, polymethacrylates, polyacrylamides, X is fluoro, chloro, bromo or iodo; vinyl acetate polymers, oligo- and polysaccharides and mix O tures thereof. (2) X is azepan-1-yl, morpholin-4-yl, pyrrolidin-1-yl, —N(CH)(CH(CH)) or 7-azabicyclo[2.2.1]heptan 7. The solid dispersion of claim 1, wherein the at least one 7-yl; and R is polymeric carrier is selected from the group consisting of copovidone, povidone, HPMC-AS and mixtures thereof. 8. The solid dispersion of claim 1, wherein the at least one Surfactant is non-ionic. 9. The solid dispersion of claim 1, wherein the at least one Surfactant is selected from the group consisting of polyoxy ethylene castor oil derivatives, fatty acid monoesters of Sor bitan, polysorbates, poloxamers, C-tocopheryl polyethylene glycol Succinate and mixtures thereof. 10. A process for preparing a solid dispersion, comprising: (a) dissolving an active pharmaceutical ingredient (API) comprising (i) a compound of Formula I US 2010/03 11751 A1 Dec. 9, 2010

where X, X and X’ are as above; or 20. The method of claim 19, wherein the disease is a (3) X is morpholin-4-ylor N(CH3); and R' is neoplastic disease. 21. The method of claim 20, wherein the neoplastic disease is selected from the group consisting of cancer, mesothe lioma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal NY and/or duodenal) cancer, chronic lymphocytic leukemia, acute lymphocytic leukemia, esophageal cancer, cancer of the Small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the where X is as above: adrenal gland, sarcoma of soft tissue, cancer of the urethra, or a pharmaceutically acceptable salt, prodrug, salt of a cancer of the penis, testicular cancer, hepatocellular (hepatic prodrug or metabolite thereof, (ii) at least one phar and/or biliary duct) cancer, primary or secondary central ner maceutically acceptable water-soluble polymeric car Vous system tumor, primary or secondary brain tumor, rier and (iii) at least one pharmaceutically acceptable Hodgkin's disease, chronic or acute leukemia, chronic surfactant in a suitable solvent; and myeloid leukemia, lymphocytic lymphoma, lymphoblastic (b) removing the solvent to provide a solid matrix compris leukemia, follicular lymphoma, lymphoid malignancies of ing the at least one polymeric carrier and the at least one T-cell or B-cell origin, melanoma, multiple myeloma, oral Surfactant and having the compound or a salt, prodrug, cancer, non-small-cell lung cancer, prostate cancer, small salt of a prodrug or metabolite thereof dispersed in an cell lung cancer, cancer of the kidney and/or ureter, renal cell essentially non-crystalline form therein. carcinoma, carcinoma of the renal pelvis, neoplasms of the 11. The process of claim 10, wherein the compound of central nervous system, primary central nervous system lym Formula I is ABT-263 or a pharmaceutically acceptable salt, phoma, non-Hodgkin's lymphoma, spinal axis tumors, brain prodrug, salt of a prodrug or metabolite thereof. stem glioma, pituitary adenoma, adrenocortical cancer, gall 12. The process of claim 10, wherein the API comprises a bladder cancer, cancer of the spleen, cholangiocarcinoma, compound of Formula I in a salt form; and the process further fibrosarcoma, neuroblastoma, retinoblastoma and combina comprises converting said salt form to a free base form, prior tions thereof. to removing the solvent. 22. The method of claim 20, wherein the neoplastic disease 13. The process of claim 12, wherein said converting com is a lymphoid malignancy. prises addition of a base. 23. The method of claim 22, wherein the lymphoid malig 14. The process of claim 12, wherein the salt form is nancy is non-Hodgkin's lymphoma. dissolved in the solvent and is converted therein to the free base form prior to addition of the at least one polymeric 24. The method of claim 20, wherein the neoplastic disease carrier and the at least one surfactant. is chronic lymphocytic leukemia or acute lymphocytic leu 15. The process of claim 12, further comprising extracting kemia. a salt by-product of said conversion, prior to removing the 25. The method of claim 19, wherein the compound of solvent. Formula I in the solid dispersion administered is ABT-263 or 16. The process of claim 10, wherein the solvent is a pharmaceutically acceptable salt, prodrug, salt of a prodrug removed under heat and/or vacuum. or metabolite thereof. 17. The process of claim 10, wherein the solvent comprises 26. The method of claim 24, wherein the solid dispersion is methanol, ethanol or acetone. administered in a dose of about 50 to about 500 mg ABT-263 18. An orally deliverable pharmaceutical dosage form free base equivalent per day at an average treatment interval comprising the solid dispersion of claim 1. of about 3 hours to about 7 days. 19. A method for treating a disease characterized by apo 27. The method of claim 24, wherein the composition is ptotic dysfunction and/or overexpression of an anti-apoptotic administered once daily in a dose of about 200 to about 400 Bcl-2 family protein, comprising orally administering to a mg ABT-263 free base equivalent per day. Subject having the disease a therapeutically effective amount of the solid dispersion of claim 1. ck ck ck ck ck