Pharmaceutical compositions including tolinapant and packaging

Abstract

The present disclosure relates generally pharmaceutical compositions comprising tolinapant or a pharmaceutically acceptable salt thereof, as well as methods of treatment, and packaging of the dosage form.

Description

Attorney Docket No.: 94BB-350572-WO PHARMACEUTICAL COMPOSITIONS INCLUDING TOLINAPANT AND PACKAGING CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 516,799 filed July 31, 2023, which is hereby incorporated by reference herein in its entirety. FIELD

[0002] The present disclosure is directed to pharmaceutical compositions comprising tolinapant, as well as to packaging, methods of storing and kits useful in such methods. The disclosure also relates to the use of such kits in the treatment of diseases, e.g., cancer. BACKGROUND

[0003] Evasion of apoptosis is one of the hallmarks of cancer and apoptosis is a mechanism for programmed cell death that is dysregulated in many tumor types. Inhibitors of apoptosis proteins (IAPs) are key regulators of antiapoptotic and pro-survival signaling pathways; they are often overexpressed in cancer cells and associated with tumor progression and resistance to treatment.

[0004] Tolinapant, also known as ASTX660, is a potent antagonist of IAPs. Tolinapant has a unique IAP antagonist molecular profile and has been shown to exert its activity through both IAP antagonism and via an immune-related mechanism. Tolinapant, has the potential to result in enhanced pro-apoptotic activity and tumor cell death, compared to other IAP antagonists. SUMMARY

[0005] It has now been discovered that tolinapant is oxygen sensitive. When exposed to ambient air, increase of a compound represented by Formula (II), an oxidative degradation product of tolinapant, was observed in drug substance and drug product formulations:

[0006] Inventors of theexcipients and / or the manufacturing / blending process affects the stability of tolinapant, and thus pharmaceutical excipients and blending process are selected for increased stability of tolinapant.

[0007] Further, to keep the oxidative degradation at a low, acceptable level, protective packages are contemplated using components with oxygen barrier properties. As described throughout, this is achieved,Attorney Docket No.: 94BB-350572-WO at least by a blister package or a bottle package capable of stabilizing the oxidative degradation without significant growth.

[0008] In some embodiments, provided herein is a pharmaceutical composition comprising tolinapant or a pharmaceutically acceptable salt thereof, wherein the composition comprises no more than 2% w / w of a compound of Formula (II) compared to tolinapant free base.

[0009] The pharmaceutical composition may comprise about 20-40% w / w of said tolinapant or a pharmaceutically acceptable salt thereof. Said tolinapant or a pharmaceutically acceptable salt thereof may be in an amount equivalent to about 25-35 % w / w of tolinapant free base. The pharmaceutical composition may further comprise one or more excipients selected from microcrystalline cellulose, mannitol, lactose monohydrate, sodium starch glycolate, and magnesium stearate. The pharmaceutical composition may comprise about 20-40 % w / w of mannitol or 20-40 % w / w of lactose monohydrate. The pharmaceutical composition may comprise about 20-40 % w / w of mannitol. The pharmaceutical composition may comprise tolinapant in the amount of about 25-35 % w / w of tolinapant free base, about 25-40% w / w of microcrystalline cellulose, about 20-40 % w / w of mannitol, about 1-10% w / w of sodium starch glycolate, and about 0.1-5% w / w of magnesium stearate. Tolinapant may be provided as tolinapant (+)-L-lactate.

[0010] In some embodiments, provided herein is a pharmaceutical composition comprising: about 20- 45 % w / w of tolinapant or a pharmaceutically acceptable salt thereof; about 25-40 % w / w of microcrystalline cellulose; about 20-40 % w / w of mannitol; about 1-10% w / w of sodium starch glycolate; and about 1-5% w / w of magnesium stearate.

[0011] The pharmaceutical composition may comprise about 30-40 % w / w of tolinapant or a pharmaceutically acceptable salt thereof; about 30-35% w / w of microcrystalline cellulose; about 25-35 % w / w of mannitol; about 1-10% w / w of sodium starch glycolate; and about 1-5% w / w of magnesium stearate. The tolinapant may be provided as a salt, and amount of the salt of tolinapant is equivalent to about 30% w / w of tolinapant free base. The pharmaceutical composition may comprise no more than 2% w / w of a compound of Formula (II) compared to tolinapant free base. Tolinapant may be provided as tolinapant (+)-L-lactate.

[0012] In some embodiments, provided herein is a dosage form comprising the pharmaceutical composition. The dosage form may comprise about 30 mg or 90 mg of tolinapant free base. The dosage form may be a tablet or a capsule. The dosage form may comprise one or more additional anti-cancer agents. The dosage form, upon storage in air for 90 days at 25°C and 60% relative humidity, is configured to include no more than 2% w / w of the compound of Formula (II) compared to tolinapant free base.Attorney Docket No.: 94BB-350572-WO

[0013] In some embodiments, provided herein is a method of treating cancer in a patient in need thereof, comprising administering the pharmaceutical composition or the dosage form. In some embodiments, provided herein is the pharmaceutical composition or the dosage form, for use in the treatment of cancer in a patient in need thereof. In some embodiments, provided herein is a use of the pharmaceutical composition or the dosage form, for manufacturing a medicament for the treatment of cancer in a patient in need thereof.

[0014] The pharmaceutical composition or dosage form may be administered orally. The cancer may be a solid tumor. The cancer may be selected from the group consisting of acute myelogenous leukemia (AML), T-cell lymphomas, peripheral T-cell lymphoma, B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, head and neck cancer, pancreatic cancer, ovarian cancer, breast cancer, colorectal cancer, rectal cancer, and cervical cancer.

[0015] In some embodiments, a packaging for a pharmaceutical composition comprising tolinapant is provided. The packaging comprises a blister pack comprising: a laminate film; a lidding film; and an oxygen absorbent film. The laminate film and the lidding film are sealed to each other and define blisters, and the oxygen absorbent film is positioned within each of the blisters.

[0016] In some embodiments, a packaging for a pharmaceutical composition comprising tolinapant is provided. The packaging comprises a sealed bottle comprising: a bottle container; a bottle cap; and an oxygen absorber.

[0017] The laminate film of the blister pack may comprise one or more material selected from the group consisting of polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), and aluminum foil. The lidding film of the blister pack may comprise one or more material selected from the group consisting of polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), aluminum foil, and paper. The laminate film may be a peel / push film. The interior of each blister may be configured to maintain an atmosphere containing less than 5% by volume of oxygen for at least 60, 90, or 180 days at 25°C and 60% relative humidity. The packaging may include the pharmaceutical composition or the dosage form discussed herein.

[0018] In some embodiments, a kit comprising the pharmaceutical composition and the packaging is provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG.1 is a graph illustrating a ratio of aldehyde degradation product of tolinapant (i.e., the compound of Formula (II)) in 6 different batches of tolinapant (ASTX660) over six months.Attorney Docket No.: 94BB-350572-WO

[0020] FIG.2 is a graph illustrating a ratio of aldehyde degradation product (i.e., the compound of Formula (II)) in six different batches of compositions including tolinapant over six months. DETAILED DESCRIPTION Definitions

[0021] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0022] As used in the present specification, the following words, phrases, and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0023] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0024] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2- hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. -(CH2)3CH3), sec-butyl (i.e. -CH(CH3)CH2CH3), isobutyl (i.e. -CH2CH(CH3)2) and tert-butyl (i.e. -C(CH3)3); and “propyl” includes n-propyl (i.e. -(CH2)2CH3) and isopropyl (i.e. -CH(CH3)2).

[0025] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent heteroaryl group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group (for example, methylenyl, ethylenyl, and propylenyl), an “arylene” group or an “arylenyl” group (for example, phenylenyl or napthylenyl, or quinolinyl for heteroarylene), respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last-mentioned group contains the atom by which the moiety is attached to the rest of the molecule.Attorney Docket No.: 94BB-350572-WO

[0026] “Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20alkenyl), 2 to 8 carbon atoms (i.e., C2-8alkenyl), 2 to 6 carbon atoms (i.e., C2-6alkenyl), or 2 to 4 carbon atoms (i.e., C2-4alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0027] “Alkynyl” refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20alkynyl), 2 to 12 carbon atoms (i.e., C2-12alkynyl), 2 to 8 carbon atoms (i.e., C2-8alkynyl), 2 to 6 carbon atoms (i.e., C2-6alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

[0028] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0029] “Alkoxyalkyl” refers to the group “alkyl-O-alkyl”.

[0030] “Alkylthio” refers to the group “alkyl-S-”. “Alkylsulfinyl” refers to the group “alkyl-S(O)-”. “Alkylsulfonyl” refers to the group “alkyl-S(O)2-”. “Alkylsulfonylalkyl” refers to -alkyl-S(O)2-alkyl.

[0031] “Acyl” refers to a group -C(O)Ry, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0032] “Amido” refers to both a “C-amido” group which refers to the group -C(O)NRyRzand an “N- amido” group which refers to the group -NRyC(O)Rz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or Ryand Rzare taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.

[0033] “Amino” refers to the group -NRyRzwherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0034] “Amidino” refers to -C(NRy)(NRz2), wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0035] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20aryl), 6 to 12 carbon ring atoms (i.e., C6-12aryl), or 6 to 10 carbon ring atoms (i.e., C6-10aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, doesAttorney Docket No.: 94BB-350572-WO not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.

[0036] “Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”.

[0037] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0038] “Carboxyl ester” or “ester” refer to both -OC(O)Rxand -C(O)ORx, wherein Rxis alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0039] “Cyanoalkyl” refers to refers to an alkyl group as defined above, wherein one or more (e.g., 1 or 2) hydrogen atoms are replaced by a cyano (-CN) group.

[0040] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0041] “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”.

[0042] “Imino” refers to a group -C(NRy)Rz, wherein Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0043] “Imido” refers to a group -C(O)NRyC(O)Rz, wherein Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0044] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.

[0045] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples ofAttorney Docket No.: 94BB-350572-WO haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0046] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

[0047] “Haloalkoxyalkyl” refers to an alkoxyalkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

[0048] “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0049] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atom(s), are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include, e.g., ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3,-CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.), and amines (e.g., -CH2NRyCH3, -CH(CH3)NRyCH3, -CH2CH2NRyCH3, -CH2CH2NRyCH2CH2NRyCH3, etc., where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). As used herein, heteroalkyl includes 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0050] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl,Attorney Docket No.: 94BB-350572-WO benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, thiophenyl (i.e., thienyl), tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0051] “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”.

[0052] “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non- aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,Attorney Docket No.: 94BB-350572-WO 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1- azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4- tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0053] “Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-.”

[0054] “Oxime” refers to the group -CRy(=NOH) wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0055] “Sulfonyl” refers to the group -S(O)2Ry, where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0056] “Sulfinyl” refers to the group -S(O)Ry, where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0057] “Sulfonamido” refers to the groups -SO2NRyRzand -NRySO2Rz, where Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0058] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.Attorney Docket No.: 94BB-350572-WO

[0059] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamido, thiol, thioxo, N-oxide, or -Si(Ry)3, wherein each Ryis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0060] In certain embodiments, “substituted” includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NRgRh, -NRgC(O)Rh, -NRgC(O)NRgRh, -NRgC(O)ORh, -NRgS(O)1-2Rh, -C(O)Rg, -C(O)ORg, -OC(O)ORg, -OC(O)Rg, -C(O)NRgRh, ofthe above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced with -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -CH2SO2Rg, or -CH2SO2NRgRh. In the foregoing, Rgand Rhare the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or two of Rgand Rhand Riare taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0061] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.Attorney Docket No.: 94BB-350572-WO

[0062] In many cases, the compounds of this disclosure, i.e., tolinapant, are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0063] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include lactic acid (e.g. (+)-L-lactic acid, (- )-D-lactic acid or (±)-DL-lactic acid), acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0064] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents,Attorney Docket No.: 94BB-350572-WO isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0065] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0066] “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0067] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0068] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of T-cell lymphoma. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art. Tolinapant and Pharmaceutically Acceptable Salts Thereof

[0069] Tolinapant is described in U.S. Patent No.9,783,538 and has a structure represented by Formula (I):Attorney Docket No.: 94BB-350572-WO (I), and is named 1-(6-(4- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethan-1-one (or alternatively 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2- b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1- one).

[0070] Pharmaceutically acceptable salts of tolinapant include acid addition salts. Acid addition salts (mono- or di-salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (-)-D-lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2- sulfonic, naphthalene-1,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.

[0071] In some embodiments, pharmaceutically acceptable salts of tolinapant may be one or more acid addition salts formed from acids selected from the group consisting of acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. In some embodiments, pharmaceutically acceptable salts of tolinapant may be one or more acid addition salts formed from lactic (e.g. (+)-L-lactic, (-)-D-lactic, or (±)-DL-lactic), sulfuric and methanesulfonic (mesylate) acids. In some embodiments, pharmaceutically acceptable salts of tolinapant may be lactate salts (e.g. (+)-L-lactate, (-)-D-lactate, orAttorney Docket No.: 94BB-350572-WO (±)-DL-lactate) or sulfate salts. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) may be a lactate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) may be a (+)-L-lactate salt.

[0072] In some embodiments, the lactate salt may be a (+)-L-lactate salt, such as the 1:1 salt of the compound of Formula (I) and (+)-L-lactic acid, as represented by Formula (Ia):

[0073] As used herein, the of Formula (I) or apharmaceutically acceptable salt thereof, such as the compound of Formula (Ia). As used herein, the term “tolinapant free base” refers specifically to the compound of Formula (I) as an active ingredient. Oxidative Product

[0074] It has been observed that when solid pharmaceutical composition including tolinapant is exposed to ambient air, increase of an oxidative degradation product of tolinapant, such as a compound of Formula (II).

[0075] In sometolinapant or pharmaceutically acceptable salt thereof, including any pharmaceutical compositions described herein, includes no more than 0.1% a / a, 0.2% a / a, 0.3% a / a, 0.4% a / a, 0.5% a / a, 0.6% a / a, 0.7% a / a, 0.8% a / a, 0.9% a / a, 1% a / a, 1.5% a / a, 2% a / a, 2.5% a / a, or 3% a / a of the compound of Formula (II), compared to total tolinapant and derivatives thereof. The content of the compound of Formula (II) within tolinapant may be determined by purity assay, for example using HPLC. In some embodiments, a pharmaceutical composition including tolinapant or its pharmaceutically acceptable salt thereof, including any pharmaceutical compositionsAttorney Docket No.: 94BB-350572-WO described herein, includes no more than 0.05% w / w, 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1% w / w, 1.5% w / w, or 2% w / w of the compound of Formula (II), compared to tolinapant (free base). Pharmaceutical Compositions

[0076] Tolinapant and / or a pharmaceutically acceptable salt thereof as described herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain tolinapant or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0077] In some embodiments, provided herein is a pharmaceutical composition comprising tolinapant or a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition may include about 10-80 % w / w, about 10-75% w / w, about 10-70% w / w, about 10-65% w / w, about 10-60% w / w, about 10-50% w / w, about 10-40% w / w, about 10-39% w / w, about 10-38% w / w, about 10-37% w / w, about 10-36% w / w about 10-35% w / w, about 10-34% w / w, about 10-33% w / w, about 10-32% w / w, about 10-31% w / w about 10-30 % w / w, about 15-80 % w / w, about 15-75% w / w, about 15-70% w / w, about 15- 65% w / w, about 15-60% w / w, about 15-50% w / w, about 15-40% w / w, about 15-39% w / w, about 15-38% w / w, about 15-37% w / w, about 15-36% w / w, about 15-35% w / w, about 15-34% w / w, about 15-33% w / w, about 15-32% w / w, about 15-31% w / w, about 15-30 % w / w, about 20-80 % w / w, about 20-75% w / w, about 20-70% w / w, about 20-65% w / w, about 20-60% w / w, about 20-50% w / w, about 20-40% w / w, about 20-39% w / w, about 20-38% w / w, about 20-37% w / w, about 20-36% w / w, about 20-35% w / w, about 20-34% w / w, about 20-33% w / w, about 20-32% w / w, about 20-31% w / w, about 20-30 % w / w, about 25-80 % w / w, about 25-75% w / w, about 25-70% w / w, about 25-65% w / w, about 25-60% w / w, about 25-50% w / w, about 25-40% w / w, about 25-39% w / w, about 25-38% w / w, about 25-37% w / w, about 25-36% w / w, about 25-35% w / w, about 25-34% w / w, about 25-33% w / w, about 25-32% w / w, about 25-31% w / w, about 25-30 % w / w, about 30-80 % w / w, about 30-75% w / w, about 30-70% w / w, about 30-65% w / w, about 30-60% w / w, about 30-50% w / w, about 30-40% w / w, about 30-39% w / w, about 30-38% w / w, about 30-37% w / w, about 30-36% w / w, about 30-35% w / w, about 30-34% w / w, about 30-33% w / w, about 30-32% w / w, about 30-31% w / w, about 31-50% w / w, about 31-40% w / w, about 31-39% w / w, about 31-38% w / w, about 31-37% w / w, about 31-36% w / w, about 31-35% w / w, about 31-34% w / w, about 31-33% w / w, about 31-32% w / w, about 32-40% w / w, about 32-39% w / w, about 32-38% w / w, about 32-37% w / w, about 32-36% w / w, about 32-35% w / w, about 32-34% w / w, about 32-33% w / w, about 33-40% w / w, about 33-39% w / w, about 33-38% w / w, about 33-37% w / w, about 33-36% w / w, about 33-35% w / w, about 33-34% w / w, about 34-40% w / w, about 34-39% w / w, about 34-38% w / w, about 34-37% w / w, about 34-36% w / w, about 34-35% w / w, about 35-40% w / w, about 35-39% w / w, about 35-38% w / w, about 35-37% w / w, about 35-36% w / w, about 36-40% w / w,Attorney Docket No.: 94BB-350572-WO about 36-39% w / w, about 36-38% w / w, about 36-37% w / w, about 37-40% w / w, about 37-39% w / w, about 37-38% w / w, about 38-40% w / w, about 38-39% w / w, or about 39-40% w / w of tolinapant or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, a pharmaceutical composition may include about 10 % w / w, about 15 % w / w, about 20 % w / w, about 25 % w / w, about 30 % w / w, about 31 % w / w, about 32 % w / w, about 33 % w / w, about 34 % w / w, about 35 % w / w, about 36 % w / w, about 37 % w / w, about 38 % w / w, about 39 % w / w, about 40 % w / w, about 45 % w / w, about 50 % w / w, about 55 % w / w, about 60 % w / w, about 70 % w / w, or about 80 % w / w of tolinapant or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, a pharmaceutical composition may include a salt of tolinapant, and tolinapant content from the salt of tolinapant is equivalent to: about 10-50% w / w, about 10-40% w / w, about 10-35% w / w, about 20-50% w / w, about 20-45% w / w, about 20-40% w / w, about 20-35% w / w, about 25-50% w / w, about 25-45% w / w, about 25-40% w / w, or about 25-35% w / w of tolinapant free base. In some embodiments, a pharmaceutical composition may include a salt of tolinapant, and tolinapant content from the salt of tolinapant is equivalent to about 10 % w / w, about 15 % w / w, about 20 % w / w, about 25 % w / w, about 30 % w / w, about 35 % w / w, about 40 % w / w, or about 50 % w / w of tolinapant free base.

[0080] For preparing solid compositions such as tablets, powders or capsules the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. Some examples of suitable and pharmaceutically acceptable excipients include various organic and inorganic carrier substances conventionally used as formulation materials, as exemplified by excipients, binders, disintegrants, lubricants, antioxidants, coating agents and so on in solid formulations, or which may be incorporated as solvents, solubilizers, suspending agents, isotonizing agents, buffering agents, soothing agents, or the like in liquid formulations. Examples of excipients include starches, sugars, polysaccharides, inorganic compounds and so on. Examples of starches include potato starch, corn starch, rice starch, partially pregelatinized starch, and so on. Examples of sugars include monosaccharides, disaccharides, trisaccharides and sugar alcohols, as exemplified by lactose, sucrose, trehalose, D-mannitol, raffinose, xylitol, erythritol, etc. Examples of polysaccharides include cellulose, dextran and so on, as exemplified by crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. Examples of anti-oxidants include ascorbic acid, ascorbic acid derivatives, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),Attorney Docket No.: 94BB-350572-WO tocopherol, tocopherol derivatives, propyl gallate, sodium ascorbate, sodium metabisulfite, citric acid, lecithin, etc. Some examples of suitable and pharmaceutically acceptable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, sodium starch glycolate, lactose monohydrate, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[0081] In some embodiments, the pharmaceutical composition includes one or more excipients selected from microcrystalline cellulose, mannitol, lactose monohydrate, sodium starch glycolate, and magnesium stearate.

[0082] In some embodiments, a pharmaceutical composition comprising tolinapant or a pharmaceutically acceptable salt thereof, comprises no more than 5% w / w of a compound of Formula (II) compared to tolinapant free base. The pharmaceutical composition may comprise about 20-40 % w / w, or 30%-40% w / w of tolinapant or a pharmaceutically acceptable salt thereof, and one or more excipients. In some embodiments, the pharmaceutically acceptable salt of tolinapant includes tolinapant in an amount equivalent to about 25-35 % w / w of tolinapant free base. The one or more excipients may be selected from microcrystalline cellulose, mannitol, lactose monohydrate, sodium starch glycolate, and magnesium stearate. For example, the pharmaceutical composition may include about 20-40 % w / w of mannitol or 20-40 % w / w of lactose monohydrate. The pharmaceutically acceptable salt of tolinapant may be tolinapant (+)-L-lactate. The pharmaceutical composition may be provided in a capsule.

[0083] In some embodiments, the pharmaceutical composition comprises tolinapant or a pharmaceutically acceptable salt in the amount equivalent to about 20-40 % w / w of tolinapant free base, about 25-40% w / w of microcrystalline cellulose, about 20-40 % w / w of mannitol, about 1-10% w / w of sodium starch glycolate, and about 0.1-5% of magnesium stearate. In some embodiments, the pharmaceutical composition comprises tolinapant or a pharmaceutically acceptable salt thereof in the amount equivalent to about 30 % w / w of tolinapant free base, about 32.75 % w / w of microcrystalline cellulose, about 31 % w / w of mannitol, about 5% w / w of sodium starch glycolate, and about 1.25 % of magnesium stearate. The pharmaceutical composition may be provided in a capsule. In some embodiments, the pharmaceutical composition comprises no more than 5% w / w of a compound of Formula (II) compared to tolinapant free base. The pharmaceutically acceptable salt of tolinapant may be tolinapant (+)-L-lactate. The pharmaceutical composition may be provided in a capsule. The pharmaceutical composition may comprise 30 mg or 90 mg of tolinapant free base.Attorney Docket No.: 94BB-350572-WO

[0084] In some embodiments, the pharmaceutical composition comprises about 20-45 % w / w of tolinapant or a pharmaceutically acceptable salt thereof, about 25-40% w / w of microcrystalline cellulose, about 20-40 % w / w of mannitol, about 1-10% w / w of sodium starch glycolate; and about 1-5% w / w of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 30-40 % w / w of tolinapant or a pharmaceutically acceptable salt thereof, about 30-35% w / w of microcrystalline cellulose, about 25-35 % w / w of mannitol, about 1-10% w / w of sodium starch glycolate; and about 1-5% w / w of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 % w / w of tolinapant or a pharmaceutically acceptable salt thereof, about 32.75 % w / w of microcrystalline cellulose, about 26 % w / w of mannitol, about 5 % w / w of sodium starch glycolate; and about 1.25 % w / w of magnesium stearate. In some embodiments, the tolinapant is provided as a salt, and amount of the salt of tolinapant is equivalent to about 30% w / w of tolinapant free base. In some embodiments, the pharmaceutical composition comprises no more than 5% w / w of a compound of Formula (II) compared to tolinapant free base. The pharmaceutically acceptable salt of tolinapant may be tolinapant (+)-L-lactate. The pharmaceutical composition may be provided in a capsule. The pharmaceutical composition may comprise 30 mg or 90 mg of tolinapant free base.

[0085] The pharmaceutical composition may be manufactured by any appropriate method known in the art. For example, the pharmaceutical composition may be manufactured by dry blend process or the roller compaction process. Dosage Form

[0086] The pharmaceutical compositions or the compounds described herein may be administered in either single or multiple doses. The pharmaceutical composition or the compounds described herein may be administered by various methods including, for example, orally.

[0087] A dosage form for the oral administration may be, for example, capsule or tablets. In making the pharmaceutical compositions that include tolinapant or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, tolinapant is usually mixed with an excipient, and the compositions can be in the form of tablets, pills, powders, granules, or sterile packaged powders. The compositions can be enclosed within a carrier, such as a capsule.

[0088] The tablets, pills, or capsules of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be usedAttorney Docket No.: 94BB-350572-WO for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0089] In some embodiments, the tolinapant is administered as individual tablets or capsules. In some of such embodiments, the tablet or capsule further comprises lactose monohydrate, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the tablet has a film coating comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide red. The tablets or capsules may comprise any of the pharmaceutical composition described herein.

[0090] In some embodiments, the tolinapant may be in a dosage form of capsules, such as a HPMC capsule. The capsule may include any of the pharmaceutical composition described herein elsewhere. In some embodiments, each capsule may include 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, or 160 mg of tolinapant (free base). In some embodiments, a capsule including 30 mg tolinapant (free base), or 90 mg tolinapant (free base).

[0091] In some embodiments, the dosage forms of tolinapant may be formed and / or stored, such that upon storage in air for 30, 60, 90, or 180 days at 25°C and 60% relative humidity, said dosage form includes no more than 5% w / w of the compound of Formula (II) compared to tolinapant free base. Storage of Tolinapant

[0092] To prevent or keep this oxidative degradation at a low level to keep purity of tolinapant above the acceptable level, the pharmaceutical composition including tolinapant or a pharmaceutically acceptable salt thereof may be stored in low oxygen atmosphere. For example, the pharmaceutical composition may be stored under an atmosphere containing less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.

[0093] When the pharmaceutical composition including tolinapant or a pharmaceutically acceptable salt thereof is stored in sufficiently low oxygen level, only very small amount of tolinapant will convert to the oxidated aldehyde product (i.e., the compound of Formula (II)), such that the purity of tolinapant can be maintained within an acceptable level. In some embodiments, upon storage in air for at least 90 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)). In some embodiments, upon storage in air for at least 30 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)). In some embodiments, upon storage in air for at least 60 days at 25°CAttorney Docket No.: 94BB-350572-WO and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)). In some embodiments, upon storage in air for at least 180 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2% w / w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)). In some embodiments, upon storage in air for at least 12 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2% w / w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)). In some embodiments, upon storage in air for at least 18 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)). In some embodiments, upon storage in air for at least 24 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)). In some embodiments, upon storage in air for at least 36 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)). Sealed Packaging

[0094] To achieve this, the pharmaceutical composition including tolinapant may be stored in a sealed packaging which provides a low oxygen atmosphere therein. The sealed packaging may be, for example, blister packs, sealed bottles, sachets, or sealed ampoules. For example, a capsule or tablet containing tolinapant may be individually packaged in blister packs, or capsules or tablets may be packaged in sealed bottles in bulk.

[0095] In some embodiments, the packaging is sealed such that the interior of the packaging provides an atmosphere containing less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.

[0096] Further, the packaging may maintain the low oxygen atmosphere for a prolonged period. In some embodiments, upon storage in air for at least 90 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the packaging may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%,Attorney Docket No.: 94BB-350572-WO 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen. In some embodiments, upon storage in air for at least 30 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the packaging may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen. In some embodiments, upon storage in air for at least 60 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the packaging may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen. In some embodiments, upon storage in air for at least 120 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the packaging may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen. In some embodiments, upon storage in air for at least 180 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the packaging may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.

[0097] To maintain low oxygen level, the packaging may be formed from materials having a low oxygen transmission rate (OTR). For example, the packaging may be formed from materials having an oxygen transmission rate (OTR) of no more than 50 cm3m-2, 100 cm3m-2, 150 cm3m-2200 cm3m-2, 250 cm3m-2, 300 cm3m-2, 350 cm3m-2, 400 cm3m-2, or 500 cm3m-2, as measured at 23°C and 0% relative humidity (RH). In some embodiments, the packaging may be formed from materials including polyethylene terephthalate (PET) or high-density polyethylene (HDPE) .

[0098] In some embodiments, the packaging may include a material to absorb oxygen. For example, the packaging may include Pharmakeep®canisters or packets, StabilOx®oxygen absorbing packets, or Activ-Blister™. The oxygen absorbent material may be provided in a form such as a film, a powder, a powder in a canister, a packet, or a sachet. Blister Pack

[0099] In some embodiments, the packaging may be a blister pack. In the blister pack, each tablet or capsule may be contained within an individually sealed space, such that a patient may take one or more tablets / capsules to consume while maintaining seal for the rest of dosage forms (e.g., tablets or capsules).

[0100] In some embodiments, the blister pack may include a laminate film, a lidding film, and an oxygen absorbent film. In some embodiments, one or more layers of the blister pack may be multi- layered, comprising a laminate film, a lidding film and / or an oxygen absorbent film. In someAttorney Docket No.: 94BB-350572-WO embodiments, the laminate film and / or the lidding film of the blister pack may include the oxygen absorbent film and / or an oxygen scavenger.

[0101] The laminate film and the lidding film may together define blisters for storing tablets or capsules, and the laminate film and the lidding film may be sealed to each other around the blisters, such that each blister may be hermetically sealed. The oxygen absorbent film may be positioned within the cavity of blister, such that it can absorb oxygen and maintain low oxygen atmosphere within the blister. In some embodiments, the oxygen absorbent film can be attached to the lidding film.

[0102] The laminate film may be formed to define cavities for blisters, and the cavities are sized to accommodate dosage forms (e.g., tablets or capsules). The laminate film may be constructed from any suitable material, to have a low oxygen transmission rate. In some embodiments, the laminate film may include multiple layers to provide greater barrier protection. For example, the laminate film may include one or more layers of materials selected from the group consisting of: polyvinyl chloride (PVC), polypropylene (PP), cast polypropylene (CPP), polyvinylidene chloride (PVDC), polyethylene terephthalate (PET), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), aluminum foil, and oxygen scavenger. The laminate film may further include adhesives for attaching its layers together. In some embodiments, the laminate film includes a PVC layer, an oPA layer, an aluminum foil layer, and a PVC layer, which are held together with adhesive disposed therebetween.

[0103] The laminate film may have a barrier property sufficient to maintain low oxygen level within the blisters. In some embodiments, the laminate film may have an oxygen transmission rate (OTR) of no more than 50 cm3m-2, 100 cm3m-2, 150 cm3m-2200 cm3m-2, 250 cm3m-2, 300 cm3m-2, 350 cm3m-2, 400 cm3m-2, or 500 cm3m-2, as measured at 23°C and 0% relative humidity (RH) in 24 hours. In some embodiments, the laminate film may have an oxygen transmission rate (OTR) of less than 0.005 cm3m-2day-1, 0.010 cm3m-2day-1, 0.020 cm3m-2day-1, 0.030 cm3m-2day-1, 0.040 cm3m-2day-1, 0.050 cm3m-2day-1, 0.070 cm3m-2day-1, or 0.1 cm3m-2day-1, as measured at 23°C and 50% relative humidity (RH).

[0104] The lidding film may be any suitable blister lidding film, having a low oxygen transmission rate. The lidding may be push-through, peel, or peel / push type film. In some embodiments, the lidding film may include multiple layers to provide greater barrier protection. For example, the lidding film may include one or more layers of materials selected from the group consisting of: polyvinyl chloride (PVC), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), high density polyethylene (HDPE), polystyrene (PS), aluminum foil, paper, and oxygen scavenger. The lidding film may further include adhesives for attaching its layers together. In some embodiments, the lidding film includes a paper layer, a PET layer, and an aluminum foil layer, which are held together with adhesive disposed therebetween.Attorney Docket No.: 94BB-350572-WO

[0105] The lidding film may have a barrier property sufficient to maintain low oxygen level within the blisters. In some embodiments, the lidding film may have an oxygen transmission rate (OTR) of no more than 50 cm3m-2, 100 cm3m-2, 150 cm3m-2200 cm3m-2, 250 cm3m-2, 300 cm3m-2, 350 cm3m-2, 400 cm3m- 2, or 500 cm3m-2, as measured at 23°C and 0% relative humidity (RH) in 24 hours. In some embodiments, the lidding film may have an oxygen transmission rate (OTR) of less than 0.005 cm3m-2day-1, 0.010 cm3m-2day-1, 0.020 cm3m-2day-1, 0.030 cm3m-2day-1, 0.040 cm3m-2day-1, 0.050 cm3m-2day-1, 0.070 cm3m-2day-1, or 0.1 cm3m-2day-1, as measured at 23°C and 50% relative humidity (RH).

[0106] The oxygen absorbent film may include oxygen scavenging material and / or oxygen absorbing materials and can reduce oxygen within the blister. In some embodiments, the oxygen absorbent film includes oxygen scavenger, such as an oxygen scavenging resin formulation. In some embodiments, the oxygen scavenger may include iron-based, sulfite-based, ascorbate-based, or enzyme-based oxygen scavenging material. In some embodiments, the oxygen absorbent film includes Activ BlistersTM.

[0107] The oxygen absorbent film may have enough oxygen absorbing capacity, such that it can maintain sufficiently low oxygen level within the blisters, without taking up too much space. For example, the oxygen absorbent film may have oxygen absorbing capacity greater than 0.1 cm3m-2, 0.2 cm3m-2, 0.3 cm3m-2, 0.4 cm3m-2, 0.5 cm3m-2, 0.6 cm3m-2, 0.7 cm3m-2, 0.8 cm3m-2, 0.9 cm3m-2, 1.0 cm3m-2, 2.0 cm3m-2, 3.0 cm3m-2, or 5.0 cm3m-2.

[0108] The oxygen absorbent film may be sized according to the size of blister and dosage form (e.g., capsule or tablet), such that the oxygen absorbent film fits within the blister. For example, the oxygen absorbent film may have a length of 30 mm, 29 mm, 28 mm, 27 mm, 26 mm, 25 mm, 24 mm, 23 mm, 22 mm, 21 mm, or 20 mm.

[0109] The laminate film, the lidding film, and the oxygen absorbent film may be tightly sealed, such that the interior of the blisters provides an atmosphere containing less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.

[0110] Further, the blister pack may maintain the low oxygen atmosphere for a prolonged period. In some embodiments, upon storage in air for at least 90 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the blister may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen. In some embodiments, upon storage in air for at least 30 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the blister may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen. In some embodiments, upon storage in air for at least 60 days at 25°C and 60 % relative humidity (RH), the atmosphere insideAttorney Docket No.: 94BB-350572-WO the blister may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen. In some embodiments, upon storage in air for at least 120 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the blister may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen. In some embodiments, upon storage in air for at least 180 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the blister may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.

[0111] A pharmaceutical composition including tolinapant may be stored within the blister of the blister pack. Within the blister, only very small amount of tolinapant may convert to the oxidated aldehyde degradation product (i.e., the compound of Formula (II)), such that the purity of tolinapant can be maintained within an acceptable level. In some embodiments, upon storage within the blister pack in air for at least 90 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)). In some embodiments, upon storage within the blister pack in air for at least 30 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)). In some embodiments, upon storage within the blister pack in air for at least 60 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w w / w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)). In some embodiments, upon storage within the blister pack in air for at least 180 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)). In some embodiments, upon storage within the blister pack in air for at least 12 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)). In some embodiments, upon storage within the blister pack in air for at least 18 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%,Attorney Docket No.: 94BB-350572-WO 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)). In some embodiments, upon storage within the blister pack in air for at least 24 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)). In some embodiments, upon storage within the blister pack in air for at least 36 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the oxidated aldehyde degradation product (i.e. the compound of Formula (II)).

[0112] The blister pack may be sealed with sufficient durability, such that the blister pack can maintain the seal even after exposed to stressed conditions for a prolonged time. For example, the blister pack can maintain the seal after being exposed to the temperature of greater than 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C or 80°C, for a prolonged time, such as greater than 2 weeks, 1 month, 2 month, 3 month, 4 month, 5 month or 6 month, such that oxygen concentration in blister stays less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume.

[0113] In some embodiments, a blister pack includes a laminate film, a lidding film, and an oxygen absorbent film, the laminate film and the lidding film are sealed to each other and define blisters. The oxygen absorbent film may be positioned within each of the blisters. The blister pack may include, within the blisters, a pharmaceutical composition comprising tolinapant or a pharmaceutically acceptable salt thereof, such as the pharmaceutical compositions described herein. For example, the pharmaceutical composition comprises tolinapant or a pharmaceutically acceptable salt in the amount equivalent to about 20-40 % w / w of tolinapant free base, about 25-40% w / w of microcrystalline cellulose, about 20-40 % w / w of mannitol, about 1-10% w / w of sodium starch glycolate, and about 0.1-5% of magnesium stearate. In some embodiments, the pharmaceutical composition comprises tolinapant or a pharmaceutically acceptable salt thereof in the amount equivalent to about 30 % w / w of tolinapant free base, about 32.75 % w / w of microcrystalline cellulose, about 31 % w / w of mannitol, about 5% w / w of sodium starch glycolate, and about 1.25 % of magnesium stearate. The pharmaceutical composition may be provided in a capsule. In some embodiments, the pharmaceutical composition comprises about 20-45 % w / w of tolinapant or a pharmaceutically acceptable salt thereof, about 25-40% w / w of microcrystalline cellulose, about 20-40 % w / w of mannitol, about 1-10% w / w of sodium starch glycolate; and about 1-5% w / w of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 30-40 % w / w of tolinapant or a pharmaceutically acceptable salt thereof, about 30-35% w / w of microcrystallineAttorney Docket No.: 94BB-350572-WO cellulose, about 25-35 % w / w of mannitol, about 1-10% w / w of sodium starch glycolate; and about 1-5% w / w of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 % w / w of tolinapant or a pharmaceutically acceptable salt thereof, about 32.75 % w / w of microcrystalline cellulose, about 26 % w / w of mannitol, about 5 % w / w of sodium starch glycolate; and about 1.25 % w / w of magnesium stearate. The pharmaceutical composition contained within the blister pack, may include no more than 1, 2, 3%, 4%, or 5% w / w of an aldehyde degradation product of tolinapant (i.e., the compound of Formula (II)) compared to tolinapant free base. In some embodiments, the pharmaceutical composition is provided in a capsule. Sealed Bottle

[0114] In some embodiments, the packaging for storing capsules or tablets including a pharmaceutical composition including tolinapant, may be a sealed bottle. In some embodiments, the sealed bottle may include a bottle container, a bottle cap, and an oxygen scavenger.

[0115] The bottle container and the bottle cap together define a space for storing tablets or capsules. In some embodiments, the mouth of the bottle container may be sealed, such that the space inside the bottle container is fully sealed. The oxygen absorber may be positioned within the space inside the bottle container, such that it can absorb oxygen and maintain low oxygen atmosphere within the space inside the bottle container. In some embodiments, the oxygen absorber may be attached or otherwise fixed onto an inner surface of the bottle container.

[0116] The bottle container may be formed to define cavities for containing dosage forms (e.g., tablets or capsules), and may be sized to accommodate certain amount of dosage forms (e.g., tablets or capsules). For example, the bottle container may accommodate up to 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 dosage forms (e.g., tablets or capsules) of the pharmaceutical composition including tolinapant. The bottle container may be constructed from any suitable material, to have a low oxygen transmission rate. In some embodiments, the bottle container may include multiple layers to provide greater barrier protection. The bottle container may be include one or more materials selected from the group consisting of: polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), and aluminum foil.

[0117] The bottle container may have a barrier property sufficient to maintain low oxygen level within the bottle. In some embodiments, the bottle container may have an oxygen transmission rate (OTR) of no more than 50 cm3m-2, 100 cm3m-2, 150 cm3m-2200 cm3m-2, 250 cm3m-2, 300 cm3m-2, 350 cm3m-2, 400 cm3m-2, or 500 cm3m-2, as measured at 23°C and 0% relative humidity (RH) in 24 hours. In some embodiments, the bottle container may have an oxygen transmission rate (OTR) of less than 0.005 cm3m-2day-1, 0.010 cm3m-2day-1, 0.020 cm3m-2day-1, 0.030 cm3m-2day-1, 0.040 cm3m-2day-1, 0.050 cm3m-2day-1, 0.070 cm3m-2day-1, or 0.1 cm3m-2day-1, as measured at 23°C and 50% relative humidity (RH).Attorney Docket No.: 94BB-350572-WO

[0118] The bottle container may be sealed at its mouth, such that the pharmaceutical composition is better protected from oxygen before the bottle is opened. In some embodiments, the mouth of the bottle container may be sealed with a sealing film having an oxygen barrier property. For example, the sealing film may have an oxygen transmission rate (OTR) of no more than 50 cm3m-2, 100 cm3m-2, 150 cm3m-2200 cm3m-2, 250 cm3m-2, 300 cm3m-2, 350 cm3m-2, 400 cm3m-2, or 500 cm3m-2, as measured at 23°C and 0% relative humidity (RH). In some embodiments, the sealing film may have an oxygen transmission rate (OTR) of less than 0.005 cm3m-2day-1, 0.010 cm3m-2day-1, 0.020 cm3m-2day-1, 0.030 cm3m-2day-1, 0.040 cm3m-2day-1, 0.050 cm3m-2day-1, 0.070 cm3m-2day-1, or 0.1 cm3m-2day-1, as measured at 23°C and 50% relative humidity (RH). In some embodiments, the sealing film may be induction sealed to the storage bottle.

[0119] In some embodiments, the sealing film may include multiple layers to provide greater barrier protection. For example, the sealing film may include one or more layers of materials selected from the group consisting of: polyvinyl chloride (PVC), polypropylene (PP), polyethylene terephthalate (PET), polyethylene terephthalate (PEN), cyclic polyolefin (COP), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), high density polyethylene (HDPE), aluminum foil, and paper.

[0120] The bottle cap may also have a low oxygen transmission rate. For example, the bottle cap may include one or more materials selected from the group consisting of: polyvinyl chloride (PVC), polypropylene (PP), polyethylene terephthalate (PET), polyethylene terephthalate (PEN), cyclic polyolefin (COP), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), high density polyethylene (HDPE), and aluminum foil.

[0121] The bottle cap may have a barrier property sufficient to maintain low oxygen level within the bottle. In some embodiments, the bottle cap may have an oxygen transmission rate (OTR) of no more than 50 cm3m-2, 100 cm3m-2, 150 cm3m-2, 200 cm3m-2, 250 cm3m-2, 300 cm3m-2, 350 cm3m-2, 400 cm3m-2, or 500 cm3m-2, as measured at 23°C and 0% relative humidity (RH) in 24 hours. In some embodiments, the bottle cap may have an oxygen transmission rate (OTR) of less than 0.005 cm3m-2day-1, 0.010 cm3m-2day-1, 0.020 cm3m-2day-1, 0.030 cm3m-2day-1, 0.040 cm3m-2day-1, 0.050 cm3m-2day-1, 0.070 cm3m-2day-1, or 0.1 cm3m-2day-1, as measured at 23°C and 50% relative humidity (RH).

[0122] The oxygen absorber may include oxygen absorbing material and may be provided in any suitable forms, such as a sachet, a packet, a canister, or a polymer film. In some embodiments, the oxygen absorber may be a canister including oxygen absorbing material. In some embodiments, the oxygen absorber may be Pharmakeep®canisters or packets, StabilOx®oxygen absorbing packets, or Activ Blister™.

[0123] The oxygen absorber may have enough oxygen absorbing capacity, such that it can maintain sufficiently low oxygen level within the bottle container, without taking up too much space. For example,Attorney Docket No.: 94BB-350572-WO the oxygen absorber may have oxygen absorbing capacity greater than 0.1 cm3m-2, 0.2 cm3m-2, 0.3 cm3m- 2, 0.4 cm3m-2, 0.5 cm3m-2, 0.6 cm3m-2, 0.7 cm3m-2, 0.8 cm3m-2, 0.9 cm3m-2, 1.0 cm3m-2, 2.0 cm3m-2, 3.0 cm3m-2, or 5.0 cm3m-2.

[0124] When the bottle is assembled and sealed, the interior space of the bottle may maintain an atmosphere containing less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.

[0125] Further, the bottle may maintain the low oxygen atmosphere for a prolonged period. In some embodiments, upon storage in air for at least 90 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the bottle may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% by volume of oxygen. In some embodiments, upon storage in air for at least 30 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the bottle may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% by volume of oxygen. In some embodiments, upon storage in air for at least 60 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the bottle may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% by volume of oxygen. In some embodiments, upon storage in air for at least 120 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the bottle may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% by volume of oxygen. In some embodiments, upon storage in air for at least 180 days at 25°C and 60 % relative humidity (RH), the atmosphere inside the bottle may maintain less than 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume of oxygen.

[0126] A pharmaceutical composition including tolinapant may be stored within the bottle. Within the bottle, only very small amount of tolinapant may convert to the oxidated aldehyde form (i.e., Formula (II)), such that the purity of tolinapant can be maintained within an acceptable level. In some embodiments, upon storage within the bottle in air for at least 90 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II). In some embodiments, upon storage within the bottle in air for at least 30 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be convertedAttorney Docket No.: 94BB-350572-WO to the compound of Formula (II). In some embodiments, upon storage within the bottle in air for at least 60 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II). In some embodiments, upon storage within the bottle in air for at least 180 days at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II). In some embodiments, upon storage within the bottle in air for at least 12 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II). In some embodiments, upon storage within the bottle in air for 18 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II). In some embodiments, upon storage within the bottle in air for 24 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II). In some embodiments, upon storage within the bottle in air for 36 months at 25°C and 60 % relative humidity (RH), no more than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% w / w of tolinapant free base in the pharmaceutical composition may be converted to the compound of Formula (II).

[0127] The bottle may be sealed with sufficient durability, such that the bottle can maintain the seal even after exposed to stressed conditions for a prolonged time. For example, the bottle can maintain the seal after being exposed to the temperature of greater than 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C or 80°C, for a prolonged time, such as greater than 2 weeks, 1 month, 2 month, 3 month, 4 month, 5 month or 6 month, such that oxygen concentration in blister stays less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by volume.

[0128] In some embodiments, a sealed bottle includes: a bottle container; a bottle cap; and an oxygen absorber within the bottle. The sealed bottle may include, a pharmaceutical composition comprising tolinapant or a pharmaceutically acceptable salt thereof, such as the pharmaceutical compositions described herein. For example, the pharmaceutical composition comprises tolinapant or a pharmaceutically acceptable salt in the amount equivalent to about 20-40 % w / w of tolinapant free base, about 25-40% w / w of microcrystalline cellulose, about 20-40 % w / w of mannitol, about 1-10% w / w of sodium starch glycolate, and about 0.1-5% w / w of magnesium stearate. In some embodiments, theAttorney Docket No.: 94BB-350572-WO pharmaceutical composition comprises tolinapant or a pharmaceutically acceptable salt thereof in the amount equivalent to about 30 % w / w of tolinapant free base, about 32.75 % w / w of microcrystalline cellulose, about 31 % w / w of mannitol, about 5% w / w of sodium starch glycolate, and about 1.25 % of magnesium stearate. The pharmaceutical composition may be provided in a capsule. In some embodiments, the pharmaceutical composition comprises about 20-45 % w / w of tolinapant or a pharmaceutically acceptable salt thereof, about 25-40% w / w of microcrystalline cellulose, about 20-40 % w / w of mannitol, about 1-10 % w / w of sodium starch glycolate; and about 1-5% w / w of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 30-40 % w / w of tolinapant or a pharmaceutically acceptable salt thereof, about 30-35 % w / w of microcrystalline cellulose, about 25-35 % w / w of mannitol, about 1-10 % w / w of sodium starch glycolate; and about 1-5 % w / w of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 % w / w of tolinapant or a pharmaceutically acceptable salt thereof, about 32.75 % w / w of microcrystalline cellulose, about 26 % w / w of mannitol, about 5 % w / w of sodium starch glycolate; and about 1.25 % w / w of magnesium stearate. The pharmaceutical composition contained within the sealed bottle, may include no more than 1, 2, or 3% w / w of an aldehyde derivative of tolinapant (i.e., compound of Formula (II)) compared to tolinapant free base. In some embodiments, the pharmaceutical composition is provided in a capsule. Kits

[0129] Provided herein are also kits that include a pharmaceutical composition including tolinapant or a pharmaceutically acceptable salt, and a sealed packaging, such as any packaging described in this specification. In one embodiment, a kit further includes instructions for use, a label and / or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein. The kit may be used for the treatment of cancer for patients in need thereof. For example, a kit including the pharmaceutical composition including tolinapant or a pharmaceutically acceptable salt thereof, and a blister pack or a bottle, such as the blister packs or bottles described herein, may be provided. The pharmaceutical composition or its dosage form may be contained within the packaging, such as the blister packs or the sealed bottles. Uses and Method of Treatment

[0130] A pharmaceutical composition including tolinapant or pharmaceutically acceptable salt thereof, or a kit including the pharmaceutical composition described herein, may be used for the treatment of, or manufacture a medicament for the treatment of one or more diseases or conditions mediated by IAP, including cancers mediated by IAP. Also provided herein are also methods of treating one or more one or more diseases or conditions mediated by IAP, including cancers mediated by IAP.Attorney Docket No.: 94BB-350572-WO

[0131] Cancers that can be treated may be a solid tumor or leukemia. Cancers that can be treated include, but are not limited to, acute myelogenous leukemia (AML), T-cell lymphomas, peripheral T-cell lymphoma, B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, head and neck cancer, pancreatic cancer, ovarian cancer, breast cancer, colorectal cancer, rectal cancer, and cervical cancer. The cancer can be an advanced cancer, such as an advanced head and neck cancer, pancreatic cancer, ovarian cancer, colorectal cancer, rectal cancer, or cervical cancer. The head and neck cancer may be recurrent / metastatic head and neck squamous cell carcinoma (HNSCC). The breast cancer may be triple-negative breast cancer. The T-cell lymphoma may be progressive, or refractory and relapsed peripheral T-cell lymphoma (PTCL), or relapsed or refractory cutaneous T-cell lymphoma (CTCL). Combination Therapies

[0132] In one embodiment, tolinapant or a pharmaceutically acceptable salt, compositions, or dosage forms disclosed herein may be used / administered in combination with one or more additional therapeutic agents that are being used and / or developed to treat cancers or T-cell lymphomas. In one embodiment, a dosage form comprising tolinapant or a pharmaceutically acceptable salt or the pharmaceutical compositions disclosed herein, may further include said additional therapeutic agents that are being used and / or developed to treat cancers or T-cell lymphomas. For example, the one or more additional therapeutic agents may be selected from cedazuridine, azacitidine, venetoclax, navitoclax, entinostat, cisplatin, dexamethasone, paclitaxel, bevacizumab, pembrolizumab, or capecitabine. In one embodiment, a dosage form comprising tolinapant or a pharmaceutically acceptable salt or the pharmaceutical compositions disclosed herein, may further include said additional therapeutic agents that are being used and / or developed to treat cancers or T-cell lymphomas. In some embodiments, the one or more additional therapeutic agents may be an additional IAP inhibitor.

[0133] In one embodiment, tolinapant or a pharmaceutically acceptable salt, compositions, or dosage forms disclosed herein, are administered in combination with therapeutical procedure, such as bone marrow / stem cell transplant, CAR-T cell therapies, or radiation therapy. In some embodiments, the pharmaceutical composition or a dosage form described herein may include one or more anti-cancer agents in addition to tolinapant or pharmaceutically acceptable salt thereof. Dosing

[0134] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of tolinapant or a pharmaceuticallyAttorney Docket No.: 94BB-350572-WO acceptable salt thereof described herein per kilogram of the subject’s body weight (mg / kg). Dosages of between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, a dosage of between 0.5 and 60 mg / kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.

[0135] The daily dosage may also be described as a total amount of tolinapant or a pharmaceutically acceptable salt thereof described herein administered per dose or per day. For example, daily dosage of tolinapant (free base) may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg / day, between about 1 to 2,000 mg / day, between about 1 to 1,000 mg / day, between about 10 to 500 mg / day, between about 20 to 500 mg / day, between about 50 to 300 mg / day, between about 75 to 200 mg / day, or between about 15 to 150 mg / day.

[0136] When administered orally, the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 1,000-2,000 mg / day, between about 10-500 mg / day, between about 50-300 mg / day, between about 100-200 mg / day, between about 75-200 mg / day, or between about 100-150 mg / day. For example, the total daily dosage for a human subject may be about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg / day. In some embodiments, the total daily dose for a human subject may be about 30, 60, 90, 120, 150, or 180 mg per day.

[0137] Tolinapant or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with tolinapant may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.

[0138] In a particular embodiment, the method comprises administering to the subject an initial daily dose of about 30 to 200 mg of tolinapant or a pharmaceutical salt thereof and increasing the dose by increments until clinical efficacy is achieved. In some embodiments, increments of about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, or 180 mg can be used to increase the dose. In some embodiments, increments of about 30, 60, or 90 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.Attorney Docket No.: 94BB-350572-WO EXAMPLES

[0139] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. Example 1

[0140] A capsule including a pharmaceutical composition including tolinapant (as (+)-L-lactate salt) was formed. The formulation was formed by the dry blend process. Specifically, the ingredients including microcrystalline cellulose, mannitol, and sodium starch glycolate were sieved and charged to the blender, and were blended at 6 rpm blender speed at 10 kg batch scale. The blend was passed through a sieving equipment to de-agglomerate. The sieved blend was returned to the blender and blended at 6 rpm blender speed. Magnesium stearate was screened, and charge the requisite amount to the blender. The blend with magnesium stearate were blended to achieve the final blend. The final blend was encapsulated into an appropriate size capsule for either 30 mg, 90 mg, or 180 mg strength, and the filled capsules were polished. Example 2

[0141] A pharmaceutical formulation containing tolinapant of Table 1 was formed using the method similar to the process described in Example 1. Table 1 30mg C%180 mg Capsule t llAttorney Docket No.: 94BB-350572-WO Example 3

[0142] Two formulations of tolinapant as (+)-L-lactate salt, including lactose monohydrate as a filler, were manufactured. One formulation, shown in Table 2, was manufactured by roller compaction. Specifically, tolinapant and excipients were each sieved and blended to form a uniform blend. The blend was roller compacted, and granulated by passing through granulator or mill. Extra-granular excipients and lubricant was added, and blended to achieve a uniform final blend. The final blend was encapsulated.

[0143] The other formulation, shown in Table 3, was manufactured by dry blend, using the method similar to the process described in Example 1. Each formulation was packaged in PET bottles with oxygen absorbing canisters for stability study at 40°C / 75% RH, 25°C / 60% RH, and 5°C. The stability study was conducted by determination of content of the aldehyde derivative of tolinapant (i.e., a compound of Formula (II)). Table 2 Formulation with Lactose Monohydrate Manufactured by Components Roller Compaction ProcessFormulation with Lactose Manufactured by Dry Blend C m n nt Prcompound of Formula (II)) was HPLC on a reversed-phase column with UV detection at 321 nm. The HPLC method used a Zorbax Bonus-RP amide-linked sterically-protected diisopropyl-C14 highly endcapped column, 150 x 4.6 mm, 3.5 μm. The mobile phases A and B consisted of 0.1% trifluoroaceticAttorney Docket No.: 94BB-350572-WO acid in water:acetonitrile (90:10) (A) and 0.1% trifluoroacetic acid in water:acetonitrile (10:90) (B), delivered at a flow rate of 1 mL / min in a multi-step gradient profile described in Table 4 below. Table 4 Time (minutes) A (%) B (%) 0 100 0

[0145] The column tempe µL. Samples and standards were prepared as 1.0 mg / mL solutions in water / acetonitrile (50:50). Identification was accomplished by comparing the retention time of the aldehyde peak in the sample to that of the reference standard. The % w / w aldehyde (i.e., the compound of Formula (II)) content was calculated versus tolinapant label claim by external standard analysis.

[0146] The results shown in Table 5 show that, after 6-month storage at 40°C / 75% RH, the aldehyde degradation product increased from 0.14% a / a to 0.75% a / a for the formulation of Table 2 (manufactured by roller compaction), whereas the content of aldehyde degradation product (the compound of Formula (II)) increased from 0.10% a / a to 0.35% a / a for the formulation of Table 3 (manufactured by dry blend). It was also observed that the aldehyde derivative content increased for both formulations at all 3 storage conditions. Table 5 Tolinapant Related Substances (% a / a) Formulation Stora e Condition The com ound of Formula (II) m 7 1

[0147] Based on the above results, it was concluded that the aldehyde derivative (i.e., compound of Formula (II)) content increases over time for the formulations including lactose monohydrate as a filler. Additionally, tolinapant degradation to the aldehyde derivative (i.e., compound of Formula (II)) was less significant for the formulation manufactured by dry blend than formulation manufactured by the roller compaction.Attorney Docket No.: 94BB-350572-WO Example 4

[0148] Two formulations of tolinapant 30 mg capsule, including mannitol as a filler, were manufactured. One formulation, shown in Table 6, was manufactured by roller compaction, and the other formulation, shown in Table 7, was manufactured by dry blend, using the methods similar to the process described in Example 2. Each formulation was packaged in PET bottles with Pharmakeep® oxygen absorbing canisters (2 canisters of 1 g each). A stability study was conducted at the storage conditions of 60°C (2 weeks), 40°C / 75% RH (6 months), 25°C / 60% RH (24 months), and 5°C (24 months). The stability study was conducted using the similar method described in Example 3. Table 6 Formulation with Mannitol Manufactured by Roller Components Compaction Processl. Table 7 Formulation with Mannitol Manufactured by Dry Blend C m n nt Prree base equ va ent and t e d erence n adjustment s compensated w t adjusted to t e er mann tol.

[0149] The stability results, shown in Table 8, shows that the degradation of tolinapant to the compound of Formula (II) was more significant for the roller compaction formulation of tolinapant 30 mg capsule than the dry blend formulation.Attorney Docket No.: 94BB-350572-WO Table 8 Tolinapant Related Substances (% a / a) Formulation Storage Condition The compound of Formula (II) m 5 5Example 5

[0150] Tolinapant formulations for 30 mg and 90 mg capsule were developed using the method described in Example 1. The composition of the formulation is provided in Table 9. Compared to the formulations of Examples 3-4, the magnesium stearate level in the formulation was increased from 1.0% to 1.25% to enhance the lubricity during the encapsulation process. Table 9 Component%30mg Capsule 90 mg Capsule w / w (mg / Capsule) (mg / Capsule) 0)q p .

[0151] A total of 3 blend batches and 6 capsule batches (3 batches of 30 mg capsules and 3 batches of the 90 mg capsule) were manufactured. The 6 bulk capsule batches were packaged in bottle and blister packages for 36-month primary stability study. Up to 12-month data are available. Example 6

[0152] A blister package was formed with a foil laminate (Formpack 4 Ply 92555 supplied by Amcor Flexibles, 60µ foil layer) and a foil lidding (Foil 1935-PE supplied by Constantia Flexibles). For one batch of the blister package, an oxygen absorbing film (Activ-BlisterTMCSP film supplied by Aptar CSPAttorney Docket No.: 94BB-350572-WO technologies) was added inside the blister cavity, adhered to the lidding, while the other batch was without the oxygen absorbing film. Tolinapant 180 mg (180 mg as free base) capsules of Example 2 were stored in the blister cavity of these blister packages under stressed conditions (50 °C / ambient humidity, 25 °C / 60%RH, 25 °C / 75%RH) for up to 6 months. The stressed samples were tested for assay and aldehyde degradation product (i.e., compound of Formula (II)) using the HPLC as described with regards to Example 3. The result is shown in Table 10. Table 10 Attributes Initial50oC 25oC / 60% RH 40oC / 75% RH 2 months 3 months 6 months 3 months 6 monthsabsorbent film was significantly smaller than tolinapant stored in the blister package without an oxygen absorbent film. Example 7

[0154] A blister package was formed with a foil laminate (Formpack 4 Ply 92555 supplied by Amcor Flexibles, 60µm foil layer) and a foil lidding (Foil 1935-PE supplied by Constantia Flexibles). An oxygen absorbing film (Activ-BlisterTM CSP film supplied by Aptar CSP technologies) was added inside the blister cavity, adhered to the lidding, while the other batch was without the oxygen absorbing film.

[0155] Tolinapant 30 mg (as the free base) capsule of Example 5 was packaged with the blister package for stressed stability study. The blister packages including the tolinapant capsules were stored under stressed conditions of 60°C, 40°C, and 25°C for up to 1 month. The stressed samples were tested for assay and degradation products. The blister seal integrity was confirmed by measuring the oxygen level in the sealed blister cavities and the oxygen absorbing capacity of the CSP film recovered from the blister cavity. The results are shown in Table 11.Attorney Docket No.: 94BB-350572-WO Table 11 Tolinapant 30 mg Capsule Degradation Products 9)

[0156] As shown in Table 11, the drug product was stable through the stressed storage period. There was no adverse trending in the degradation product profile. Aldehyde degradation product (i.e., the compound of Formula (II)) peak remained stable with no significant increase after 1 month stressing at all temperatures.

[0157] The oxygen concentration in the blister cavity remained low, i.e., 4.9 – 7.3% at T0 and 1.3-4.9% under all stress conditions for 1 month. The oxygen level in the cavities remained low, relative to the atmospheric concentration in ambient air of 21%. The stressing did not cause the oxygen concentration to increase, supporting that the seal integrity was maintained.

[0158] The oxygen absorbing capacity of the oxygen absorbent films recovered from the blister cavities of the stressed samples showed that the oxygen absorbent film was retaining full capacity, supporting that the seal integrity was maintained. Example 8

[0159] A blister package was formed with a foil laminate (Formpack 4 Ply 92555 supplied by Amcor Flexibles, 60µ foil layer) and a foil lidding (Peel / Push 1935-PE supplied by Constantia Flexibles). An oxygen absorbing film (Activ-BlisterTMCSP film supplied by Aptar CSP technologies) was added inside the blister cavity, adhered to the lidding.

[0160] Blister stability samples of tolinapant capsules, including 3 batches of 30 mg capsule and 3 batches of 90 mg capsule from Example 5 were packaged in the selected blister package.

[0161] A stressed stability test, at 60°C for 2 weeks, was performed to assess the blister seal integrity of the packaged blisters. The results of the stressed stability test are provided in Table 12.Attorney Docket No.: 94BB-350572-WO Table 12 Tolinapant 30 mg Tolinapant 90 mg Tolinapant 90 mg Caps1Caps1Caps1r s )2Blister samples stored at 5°C for 2 weeks.

[0162] As shown in Table 12, assay and degradation profile were consistent with no adverse trending. Further, aldehyde product (i.e., compound of Formula (II)) in stressed samples did not increase after two weeks. Also, oxygen concentration in blister cavity remained low, essentially zero, for two weeks. Oxygen absorbing capacity of the CSP film remained unchanged, meeting the supplier specification limit. These results therefore support that the blister packages were properly sealed, and the seal was maintained through stressed conditions.

[0163] The blister packages were also tested under The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) conditions for primary stability study. The aldehyde degradation product (i.e., compound of Formula (II)) levels of samples stored at 40°C and 75% RH for up to 6 months are provided in FIG.1, showing that the aldehyde degradation product (i.e., compound of Formula (II)) level was stable in the blister packs with no adverse growing trend observed. Up to 18 months of primary stability data (data not shown here) of these batches stored at 25°C and 60% RH and 2-8 °C also show that the aldehyde degradation product (i.e., compound of Formula (II)) level was stable without any increase trending.

[0164] Therefore, the results support that the blister package is adequate in protecting tolinapant from exposing to oxygen and minimizing the oxidative degradation.Attorney Docket No.: 94BB-350572-WO Example 9

[0165] A bottle package for tolinapant capsules were prepared. The bottle package included polyethylene terephthalate (PET) bottle (Amber color supplied by Drug Plastics) containing tolinapant 30 mg capsules and Pharmakeep CD-2.15 oxygen absorber canister (supplied by Airnov Healthcare Packaging).

[0166] Another bottle package for tolinapant capsules were prepared. The bottle package included high density polyethylene (HDPE) bottle containing tolinapant 30 mg capsules of Example 2 and Pharmakeep CD-2.15 oxygen absorber canister (supplied by Airnov Healthcare Packaging).

[0167] The bottle packages containing tolinapant capsules were tested for degradation product profiles (aldehyde degradation product (i.e., compound of Formula (II)) and total tolinapant related substance at storage conditions of 2-8°C and 25°C / 60%RH for 48 months and 40°C / 75%RH for 6 months. The results are shown in Table 13. Table 13 Impurities (% area / area) Th d f F l II T l T li R l d S b 8 8 7 7 0 ss s ow , e s a y o e o apa capsu es pac age o es w Pharmakeep oxygen scavenger was acceptable, and did not show adverse trending of total tolinapant related substances. Specifically, there was no significant change in the aldehyde degradation (i.e., compound of Formula (II)) over 48 months at storage conditions of 25°C / 60% RH and 6 months at 40°C / 75% RH. On the other hand, the stability of tolinapant 30 mg capsule packaged in HDPE bottles with Pharmakeep oxygen scavenger showed significant increase in the aldehyde degradation product (i.e., compound of Formula (II)) and total tolinapant related substances at storage conditions of 25°C / 60% RHAttorney Docket No.: 94BB-350572-WO and 40°C / 75% RH. The increasing trends suggests that the oxygen barrier property of HDPE bottles was inadequate in protecting tolinapant drug products.

[0169] At 2-8°C storage condition, the level of aldehyde degradation product (i.e., compound of Formula (II)) to total tolinapant related substances remain unchanged in PET bottles. However, in HDPE bottles, the level of aldehyde degradation product (i.e., compound of Formula (II)) and total tolinapant related substances is stable for up to 24 months at 2-8°C, after which increasing trends are observed.

[0170] The above results indicate that the PET bottle is suitable in keeping the aldehyde degradation product (i.e., compound of Formula (II)) stable without any significant change for storage at room temperature. Therefore, PET is a superior oxygen barrier which slow down the oxygen ingress maintaining a low oxygen level in the bottle interior. Example 10

[0171] A bottling study was conducted to confirm the packaging process parameters. The package was 50 mL PET White Bottle with 33mm cap HS035 w / .035 WLP and a Pharmakeep canister per bottle. The induction sealer used was AP7114. The fixed process parameters include ionized air pressure: 40 psi (±5 psi), conveyor speed: 21 fpm, and induction seal coil height above cap: 1 / 8’’ (± 1 / 16’’)

[0172] The process parameters studied in DOE design included capping torque force pre- and post- induction sealing as well as the induction sealer power. The study design including parameter ranges is shown in Table 14. To confirm the bottle seal integrity, the in-process seal integrity tests, including visual inspection and dye ingress leak test were performed. In addition, the packaged bottles were subjected to additional stressed test of seal integrity as follows. The packaged bottle samples were stored at 60°C stressed condition for 2 weeks and tested of oxygen concentration inside the bottles and the oxygen absorbing capacity of the Pharmakeep canister recovered. The results are shown in Table 15.Attorney Docket No.: 94BB-350572-WO Table 14 Pre-Seal Application Post-Seal Application GroupTorque ForcSealing BottleNoSettinge (in / lb)Power (%)Torque Force (in / lb)NoResults of Stability Tests Packaging parametersRemaining oxygen) sAttorney Docket No.: 94BB-350572-WO

[0173] As shown in Table 15, the in-process control test confirmed that all samples passed the leak test and thus acceptable. The results of the stressed tests provided in Table 15 show that the oxygen concentration in the head space (void space above the dosage units in the bottle) was ≤ 9.26% initially and ≤ 4.2 % after storage of 2 weeks at 60°C. The oxygen absorbing capacity of Pharmakeep canister was maintained at 24.0 - 31.8 mL (except for 1 sample at 11.4 mL which is attributed to variability of measurement). The data indicate a fully capacity, if greater than or equal with 20 mL, according to the supplier specification. Further, statistical analysis (data not shown here) indicated that none of the process parameters studied has significant impacts on the oxygen level inside the sealed bottles nor on Pharmakeep capacity. Therefore, it was concluded that the process parameters studied, i.e., torque (pre- and post- induction sealing) range of 15 - 25 lb / in2and induction seal power range of 75 - 85%, were acceptable for bottle packaging for tolinapant. Example 11

[0174] A simulation study was performed on a bottle container closure system to assess oxygen ingress into sealed bottles. Relevant assumptions included, - tolinapant 30 mg and 90 mg capsules are encapsulated in Size 3 and Size 1 capsules, respectively, - Each bottle contains 14 capsules, - Oxygen transmission through the bottle system is through the bottle surface and the foil seal is considered impermeable to oxygen.

[0175] The simulation compared, - 2 containers of different oxygen barrier property: 62 cc PET bottle and 65 cc Oxy-guard bottle; - 3 storage temperatures / humidity conditions, 40°C / 75% RH, 25°C / 60% RH, and 5°C; - 2 different quantities of oxygen absorber, 1 g oxygen absorber (Pharmakeep®CD-1G) and 2 g oxygen absorber (Pharmakeep CD-2.15G); and - 2 different tolinapant capsule sizes: Size 1 and Size 3

[0176] For bottles containing size 1 capsules stored at 25 °C / 60% RH, with 1 g oxygen absorber (Pharmakeep®CD-2.15G), the interior head space was maintained oxygen free for 3 years in Oxy- Guard™ bottle and approximately 1 year in PET bottle. After 1 year, the oxygen level slowly increased in PET bottle.

[0177] For bottles containing size 3 capsules stored at 25 °C / 60% RH, with 1 g oxygen absorber (Pharmakeep®CD-2.15G), the interior head space was maintained oxygen free for 3 years in Oxy- Guard™ bottle and less than 1 year in PET bottle.Attorney Docket No.: 94BB-350572-WO

[0178] For bottles containing size 1 capsules stored at 25°C / 60% RH, with 2 g oxygen absorber (Pharmakeep®CD-2.15G), the interior head space was maintained oxygen free for 3 years in both Oxy- Guard™ and PET bottles.

[0179] For bottles containing size 3 capsules stored at 25°C / 60% RH, with 2 g oxygen absorber (Pharmakeep®CD-2.15G), the interior head space was maintained oxygen free for 3 years in both Oxy- Guard™ and PET bottles.

[0180] For bottles containing size 1 capsules stored at 40°C / 75% RH, with 2 g oxygen absorber (Pharmakeep®CD-2.15G), the interior head space was maintained oxygen free for 3 years in both Oxy- Guard™ and PET bottles.

[0181] For bottles containing size 3 capsules stored at 40°C / 75% RH, with 2 g oxygen absorber (Pharmakeep®CD-2.15G), the interior head space was maintained oxygen free for 3 years in both Oxy- Guard™ and PET bottles.

[0182] For bottles containing size 1 capsules stored at 5°C, with 2 g oxygen absorber (Pharmakeep®CD-2.15G), the interior head space was maintained oxygen free for 3 years in both Oxy-Guard™ and PET bottles.

[0183] For bottles containing size 3 capsules stored at 5°C, with 2 g oxygen absorber (Pharmakeep®CD-2.15G), the interior head space was maintained oxygen free for 3 years in both Oxy-Guard™ and PET bottles.

[0184] Based on the simulation results, both PET and Oxy-Guard™ bottles with 2 g Pharmakeep®oxygen absorbers are suitable for storing tolinapant as they were able to maintain oxygen-free interior inside the sealed bottles for up to 3 years regardless of the storage condition. Example 12

[0185] The performance of the selected bottle package was further confirmed in the primary stability study of the registration batches.

[0186] A bottle package for tolinapant capsules were prepared. The bottle package included polyethylene terephthalate (PET) bottle container (50cc wide mouth pharmaceutical round, white polyethylene terephthalate bottle supplied by Drug Plastics), 33 mm child resistant ribbed side white cap with a seal liner (33mm SecurRx Ribbed Side Test Top white cap supplied by Drug Plastics), and Pharmakeep®CD-2.15 oxygen absorber canister (supplied by Airnov Healthcare Packaging).

[0187] Six batches of tolinapant capsules, 3 batches of 30 mg capsule and 3 batches of 90 mg capsule, were manufactured and packaged in the PET bottle. The bottled batches were tested for the primary stability study. The stability data generated up to date showed that the level of the aldehyde degradation product (i.e., compound of Formula (II)) is within acceptable range. The performance of the bottleAttorney Docket No.: 94BB-350572-WO package stored under the stressed condition of 40°C / 75% RH is illustrated in FIG.2. The aldehyde degradation (i.e., compound of Formula (II)) was shown to remain stable without a growing trend. * * *

[0188] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0189] The disclosures illustratively described herein may suitably be practiced in the absence of any element or elements, limitation, or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claims.

[0190] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.

[0191] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

Attorney Docket No.: 94BB-350572-WO CLAIMS 1. A pharmaceutical composition comprising tolinapant or a pharmaceutically acceptable salt thereof, wherein the composition comprises no more than 2% w / w of a compound of Formula (II) compared to tolinapant free base: .

2. The pharmaceutical composition of claim 1, comprising about 20%-40% w / w of said tolinapant or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 1, wherein said tolinapant or a pharmaceutically acceptable salt thereof is in an amount equivalent to about 25-35 % w / w of tolinapant free base.

4. The pharmaceutical composition of any of the preceding claims, further comprising one or more excipients selected from microcrystalline cellulose, mannitol, lactose monohydrate, sodium starch glycolate, and magnesium stearate.

5. The pharmaceutical composition of any of the preceding claims, wherein the pharmaceutical composition comprises about 20-40 % w / w of mannitol or 20-40 % w / w of lactose monohydrate.

6. The pharmaceutical composition of any of the preceding claims, wherein the pharmaceutical composition comprises about 20-40 % w / w of mannitol.

7. The pharmaceutical composition of any one of claims 1, 3, 4, 5, and 6, wherein the pharmaceutical composition comprises tolinapant in the amount of about 25-35 % w / w of tolinapant free base, about 25-40% w / w of microcrystalline cellulose, about 20-40 % w / w of mannitol, about 1-10% w / w of sodium starch glycolate, and about 0.1-5% w / w of magnesium stearate.Attorney Docket No.: 94BB-350572-WO 8. The pharmaceutical composition of any of the preceding claims, wherein tolinapant is provided as tolinapant (+)-L-lactate.

9. A pharmaceutical composition comprising: about 20-45 % w / w of tolinapant or a pharmaceutically acceptable salt thereof; about 25-40 % w / w of microcrystalline cellulose; about 20-40 % w / w of mannitol; about 1-10% w / w of sodium starch glycolate; and about 1-5% w / w of magnesium stearate.

10. The pharmaceutical composition of claim 9, comprising: about 30-40 % w / w of tolinapant or a pharmaceutically acceptable salt thereof; about 30-35% w / w of microcrystalline cellulose; about 25-35 % w / w of mannitol; about 1-10% w / w of sodium starch glycolate; and about 1-5% w / w of magnesium stearate.

11. The pharmaceutical composition of claim 9 or 10, wherein the tolinapant is provided as a salt, and amount of the salt of tolinapant is equivalent to about 30% w / w of tolinapant free base.

12. The pharmaceutical composition of any one of claims 9 to 11, wherein the pharmaceutical composition comprises no more than 2% w / w of a compound of Formula (II) compared to tolinapant free base: .

13. The pharmaceutical composition of any one of claims 9 to 12, wherein tolinapant is provided as tolinapant (+)-L-lactate.Attorney Docket No.: 94BB-350572-WO 14. The pharmaceutical composition of any one of claims 9 to 13, wherein the composition is provided within a capsule.

15. A dosage form comprising a pharmaceutical composition of any one of claims 1 to 14.

16. The dosage form of claim 15, comprising about 30 mg of tolinapant free base.

17. The dosage form of claim 15, comprising about 90 mg of tolinapant free base.

18. The dosage form of any one of claims 15 to 17, wherein the dosage form is a tablet.

19. The dosage form of any one of claims 15 to 17, wherein the dosage form is a capsule.

20. The dosage form of any one of claims 15 to 19, wherein the dosage form comprises one or more additional anti-cancer agents.

21. The dosage form of any one of claims 15 to 20, wherein upon storage in air for 90 days at 25°C and 60% relative humidity, said dosage form is configured to include no more than 2% w / w of the compound of Formula (II) compared to tolinapant free base.

22. A method of treating cancer in a patient in need thereof, comprising administering a pharmaceutical composition of any of claims 1 to 14 or a dosage form of any one of claims 15 to 21.

23. The method of claim 22, wherein the pharmaceutical composition or dosage form is administered orally.

24. The method of claim 22 or 23, wherein the cancer is a solid tumor.

25. The method of claim 22 or 23, wherein the cancer is selected from the group consisting of: acute myelogenous leukemia (AML), T-cell lymphomas, peripheral T-cell lymphoma, B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, head and neck cancer, breast cancer, pancreatic cancer, ovarian cancer, colorectal cancer, rectal cancer, and cervical cancer.Attorney Docket No.: 94BB-350572-WO 26. A pharmaceutical composition of any of claims 1 to 16 or a dosage form of any one of claims 17 to 21, for use in the treatment of cancer in a patient in need thereof.

27. The pharmaceutical composition or dosage form of claim 26, wherein the cancer is selected from the group consisting of: acute myelogenous leukemia (AML), T-cell lymphomas, peripheral T-cell lymphoma, B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, head and neck cancer, pancreatic cancer, ovarian cancer, breast cancer, colorectal cancer, rectal cancer, and cervical cancer.

27. Use of a pharmaceutical composition of any of claims 1 to 15 or a dosage form of any one of claims 16 to 20, for manufacturing a medicament for the treatment of cancer in a patient in need thereof.

28. The use of claim 27, wherein the cancer is selected from the group consisting of acute myelogenous leukemia (AML), T-cell lymphomas, peripheral T-cell lymphoma, B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, head and neck cancer, pancreatic cancer, ovarian cancer, breast cancer, colorectal cancer, rectal cancer, and cervical cancer.

29. A packaging for a pharmaceutical composition comprising tolinapant, the packaging comprises: a blister pack comprising a laminate film, a lidding film, and an oxygen absorbent film, wherein the laminate film and the lidding film are sealed to each other and define blisters, and wherein the oxygen absorbent film is positioned within each of the blisters; or a sealed bottle comprising a bottle container, a bottle cap, and an oxygen absorber.

30. The packaging of claim 29, wherein the laminate film of the blister pack comprises one or more materials selected from the group consisting of polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), and aluminum foil.

31. The packaging of claim 29 or 30, wherein the lidding film of the blister pack comprises one or more materials selected from the group consisting of polyvinyl chloride (PVC) , polyvinylidene chloride (PVDC), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate (PC), polyamide nylon (OPA), polyethylene (PE), aluminum foil, and paper.

32. The packaging of any one of claims 29 to 31, wherein the laminate film is a peel / push film.Attorney Docket No.: 94BB-350572-WO 33. The packaging of any one of claims 29 to 32, wherein the interior of each blister is configured to maintain an atmosphere containing less than 5% by volume of oxygen for at least 60 days at 25°C and 60% relative humidity.

34. The packaging of any one of claims 29 to 32, wherein the interior of each blister is configured to maintain an atmosphere containing less than 5% by volume of oxygen for at least 90 days at 25°C and 60% relative humidity.

35. The packaging of any one of claims 29 to 32, wherein the interior of each blister is configured to maintain an atmosphere containing less than 5% by volume of oxygen for at least 180 days at 25°C and 60% relative humidity.

36. The packaging of any one of claims 29 to 35, comprising a pharmaceutical composition of any of claims 1 to 15 or a dosage form of any one of claims 16 to 21.

37. A kit comprising: a pharmaceutical composition of any one of claims 1 to 15 or a dosage form of any one of claims 16 to 21; and a packaging of any one of claims 29 to 35.

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