Combination therapy with trinapant, cedazuridine, and decitabine for the treatment of T-cell lymphoma

Abstract

The present disclosure relates generally to methods of treating T-cell lymphoma with combination therapy.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 374,137, filed August 31, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to the treatment of T-cell lymphoma with certain combination therapies. [Background technology]

[0003] Evasion of apoptosis is one of the hallmarks of cancer; apoptosis is a mechanism of programmed cell death that is dysregulated in many tumor types. Inhibitors of apoptosis proteins (IAPs) are key regulators of anti-apoptotic and pro-survival signaling pathways, which are often overexpressed in cancer cells and associated with tumor progression and resistance to therapy. In some cases, T-cell lymphomas acquire resistance to IAP inhibitor therapy. Improved treatments for T-cell lymphomas are needed, including therapies that can resensitize tumor cells resistant to the effects of IAPs to IAP inhibitors. Summary of the Invention

[0004] It is believed that combining trinapant with decitabine enhances immunogenic cell death in T-cell lymphoma. It is further contemplated that decitabine, when combined with cedazuridine, may be administered orally. In one embodiment, the present disclosure provides a method for treating T-cell lymphoma in a subject in need thereof, comprising administering to the subject: trinapant or a pharmaceutically acceptable salt thereof, Cedazuridine or a pharmaceutically acceptable salt thereof, and The method includes administering decitabine or a pharmaceutically acceptable salt thereof.

[0005] In one embodiment, the administration of each agent is oral.

[0006] Also provided is a pharmaceutical composition comprising trinapant or a pharmaceutically acceptable salt thereof, cedazuridine or a pharmaceutically acceptable salt thereof, and decitabine or a pharmaceutically acceptable salt thereof.

[0007] An advantage of the combination therapy described herein is that trinapant, cedazuridine, and decitabine can be administered orally, which can potentially improve patient compliance. [Brief explanation of the drawings]

[0008] [Figure 1] 1A is a photograph of a Western blot result showing RIPK3 expression in parental cells or CT26 cells (a murine colon adenocarcinoma cell line) genetically engineered to express RIPK3, according to one embodiment (A), and a graph showing lytic cell death upon trinapant treatment over time (B).

[0009] [Figure 2] 1 is a photograph of Western blot results of RIPK3 expression in human and mouse cell lines, including T-cell lymphoma cell lines, according to one embodiment.

[0010] [Figure 3] 1A shows a graph depicting the average baseline methylation levels of the RIPK3 gene in different cell lines, according to one embodiment; FIG. 1B shows a graph depicting the relative changes in methylation levels of the RIPK3 gene in different cell lines after decitabine treatment, FIG. 1C shows a graph depicting the dose response and time course of RIPK3 demethylation in Karpas-299 cells with decitabine treatment, and FIG. 1D shows a graph depicting the relative changes in LINE-1 methylation levels after decitabine treatment. [Figure 4]

[0011] [Figure 5]1 shows a graph illustrating the reduction in cell viability and level of synergy with the combination of decitabine and trinapant, according to one embodiment.

[0012] [Figure 6] 1 shows a graph depicting lytic cell death of human H9 cells over time upon treatment with trinapant and / or decitabine, according to one embodiment.

[0013] [Figure 7] 1 shows a graph depicting HMGB1 (a biomarker of lytic cell death) concentrations upon treatment with trinapant and / or decitabine, according to one embodiment.

[0014] [Figure 8] 1 is a photograph of a Western blot result of BW5147.G.1.4 cell line lysate after 48 hours of treatment with decitabine and trinapant, according to one embodiment.

[0015] [Figure 9-1] Graphs A and B show the concentrations of cytokines and chemokines secreted in vitro after treating BW5147 cells with trinapant and / or decitabine for 48 hours, according to one embodiment. [Figure 9-2] Graphs A and B show the concentrations of cytokines and chemokines secreted in vitro after treating BW5147 cells with trinapant and / or decitabine for 48 hours, according to one embodiment.

[0016] [Figure 10-1] 1 shows a photograph (A) of a Western blot result of BW5147.G.1.4 cell line lysate after 5 days of in vivo treatment with decitabine and / or trinapant, and a graph (B) showing plasma HMGB1 concentrations after 5 days of in vivo treatment with decitabine and / or trinapant, according to one embodiment. [Figure 10-2]1 shows a photograph (A) of a Western blot result of BW5147.G.1.4 cell line lysate after 5 days of in vivo treatment with decitabine and / or trinapant, and a graph (B) showing plasma HMGB1 concentrations after 5 days of in vivo treatment with decitabine and / or trinapant, according to one embodiment.

[0017] [Figure 11-1] 1 shows a graph depicting plasma concentrations of cytokines and chemokines after 5 days of in vivo treatment of BW5147.G.1.4 cells with trinapant and / or decitabine, according to one embodiment. [Figure 11-2] 1 shows a graph depicting plasma concentrations of cytokines and chemokines after 5 days of in vivo treatment of BW5147.G.1.4 cells with trinapant and / or decitabine, according to one embodiment.

[0018] [Figure 12] 1 shows the relative expression levels of several genes in KARPAS-299 xenografts after treatment with trinapant and / or decitabine, according to one embodiment.

[0019] [Figure 13] 1 is a photograph of Western blot results of KARPAS-299 xenograft cell lysates after treatment with decitabine or trinapant and decitabine, according to one embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0020] definition In the following description, exemplary embodiments of the present technology are described, however, it should be recognized 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.

[0021] As used herein, the following words, phrases and symbols are generally intended to have the meanings indicated below, unless otherwise indicated by the context in which they are used.

[0022] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes at the beginning or end of a chemical group are for convenience. Chemical groups may be shown with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of the group. No directionality is shown or implied by the order in which chemical groups are written or named unless chemically or structurally required.

[0023] Prefix “C” u~v " indicates that the following group has u to v carbon atoms. For example, "C 1~6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0024] Reference herein to a value or parameter "about" includes (and describes) embodiments that refer to the value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated amount ±5%. In certain other embodiments, the term "about" includes the stated amount ±1%. Also, the term "about X" includes the reference to "X." Additionally, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, 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 of skill in the art.

[0025] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a group having 1 to 20 carbon atoms (i.e., C 1~20alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), or 1 to 4 carbon atoms (i.e., C 1~4 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 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 a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can 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).

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

[0027] "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 refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 12 carbon ring atoms (i.e., C 6~12aryl), or 6 to 10 carbon ring atoms (i.e., C 6~10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or in any way overlap with heteroaryl, as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl.

[0028] "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., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to a group having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0029] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group that may or may not be replaced by a non-hydrogen moiety.

[0030] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compound includes both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0031] All formulas or structures shown herein are also intended to represent unlabeled forms of compounds as well as isotopically labeled forms. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom having the mass or mass number of a selected atom. Examples of isotopes that can be incorporated into compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine. 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure include, for example, 3 H, 13 C and 14 Radioactive isotopes such as C may be incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including metabolism studies, reaction kinetic studies, drug or substrate tissue distribution assays, or radiotherapy of patients.

[0032] The present disclosure also includes "deuterated analogs" of trinapant, cedazuridine, and / or decitabine in which one to n hydrogens bonded to a carbon atom have been replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit enhanced resistance to metabolism and are therefore useful for extending the half-life of any compound when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0033] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, can increase metabolic stability and confer certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful for PET or SPECT studies. The isotopically labeled compounds and prodrugs thereof of the present disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparations described below, replacing non-isotopically labeled reagents with readily available isotopically labeled reagents. It is understood that deuterium in this context is considered a substituent in the compound.

[0034] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, all atoms specifically designated as deuterium (D) are meant to represent deuterium.

[0035] In many cases, the compounds of the present disclosure, i.e., trinapant, cedazuridine, and / or decitabine, are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0036] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0037] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, when a compound described herein is 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, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can 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 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-toluenesulfonic acid, salicylic acid, and the like. Similarly, 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 salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (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), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)). tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (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 salts of mixed amines. Specific examples of suitable amines include, but are not limited to, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0038] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, 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.

[0039] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0040] Trinapant is described in U.S. Pat. No. 9,783,538 and has the following structure: [ka] and It is called 1-(6-(4-fluorobenzyl)-5-(hydroxymethyl)-3,3-dimethyl-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 (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).

[0041] Cedazuridine is described in U.S. Pat. No. 8,268,800 and has the following structure: [ka] and It is called (R)-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-hydroxytetrahydropyrimidin-2(1H)-one.

[0042] Decitabine has the following structure: [ka] and It is called 5-aza-2'-deoxycytidine or 4-amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1,3,5-triazin-2(1H)-one.

[0043] Treatment Methods and Uses "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., alleviating one or more symptoms caused by the disease or condition and / or reducing the severity of the disease or condition), b) slowing or halting the progression of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition), and / or c) relieving the disease, i.e., causing a reduction in clinical symptoms (e.g., improving the disease state, causing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0044] "Prevention" or "preventing" means any treatment of a disease or condition so that the clinical symptoms of the disease or condition do not occur. In some embodiments, the compounds can be administered to subjects (including humans) at risk for or who have a family history of the disease or condition.

[0045] "Subject" refers to an animal, such as a mammal (including a human), that has been the object of or is the subject of treatment, observation, or experiment. The methods described herein may be useful in human treatment and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0046] 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, refers to an amount sufficient to provide a therapeutic effect when administered to a subject, such that a therapeutic benefit is achieved, such as amelioration of symptoms or delay in progression of a disease. For example, a therapeutically effective amount may be an amount sufficient to alleviate the symptoms of T-cell lymphoma. A therapeutically effective amount may vary depending on the subject and disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the method of administration, and can be readily determined by one of ordinary skill in the art.

[0047] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as an animal or human. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine optimal schedules and / or doses of administration of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gathered from such use can be used for experimental purposes or in the clinic to design protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will become apparent to those skilled in the art. Selected compounds may be further characterized to test for safety or tolerable doses in human or non-human subjects. Such properties can be tested using methods commonly known to those skilled in the art.

[0048] In some embodiments, a method for treating T-cell lymphoma in a subject in need thereof comprises administering to the subject: trinapant or a pharmaceutically acceptable salt thereof, Cedazuridine or a pharmaceutically acceptable salt thereof, and Provided herein are methods comprising administering decitabine or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the T-cell lymphoma is relapsed or refractory T-cell lymphoma. In some embodiments, the T-cell lymphoma has been previously treated with a hypomethylating agent. In some embodiments, the hypomethylating agent is decitabine. In some embodiments, the T-cell lymphoma has not been previously treated with an agent for treating T-cell lymphoma.

[0050] In some embodiments, the T-cell lymphoma is selected from peripheral T-cell lymphoma, non-specified peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, follicular T-cell lymphoma, nodal peripheral T-cell lymphoma with T-follicular helper (TFH) cell phenotype, adult T-cell lymphoma / leukemia, anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, nasal NK / T-cell lymphoma, hepatosplenic T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and cutaneous (skin) T-cell lymphoma.

[0051] In some embodiments, the T-cell lymphoma is relapsed or refractory peripheral T-cell lymphoma (R / R PTCL).

[0052] In some embodiments, the T cell lymphoma is peripheral T cell lymphoma not otherwise specified. In some embodiments, the T cell lymphoma is angioimmunoblastic lymphoma.

[0053] In some embodiments, the T cell lymphoma is nodal peripheral T cell lymphoma with follicular helper (TFH) cell phenotype. In some embodiments, the T cell lymphoma is adult T cell lymphoma / leukemia.

[0054] In some embodiments, the T-cell lymphoma is anaplastic large cell lymphoma (ALCL).

[0055] In some embodiments, the T cell lymphoma is hepatosplenic T cell lymphoma. In some embodiments, the T cell lymphoma is monotypic epitheliotropic intestinal T cell lymphoma. In some embodiments, the T cell lymphoma is subcutaneous panniculitis-like T cell lymphoma. In some embodiments, the T cell lymphoma is cutaneous (skin) T cell lymphoma.

[0056] In some embodiments, the T-cell lymphoma is enteropathy-associated T-cell lymphoma.

[0057] In some embodiments, the T-cell lymphoma is cutaneous T-cell lymphoma. In some embodiments, the cutaneous T-cell lymphoma is mycosis fungoides or Sézary syndrome.

[0058] In some embodiments, the T-cell lymphoma is T-lymphoblastic lymphoma / leukemia or adult T-cell lymphoma / leukemia.

[0059] In some embodiments, trinapant is administered once daily for seven consecutive days every other week of each 28-day cycle. In some embodiments, the dose of trinapant is 30 mg or 90 mg per day.

[0060] In some embodiments, cedazuridine and decitabine are administered once daily on days 1-5 of each 28-day cycle. In some embodiments, the dose of cedazuridine is 100 mg daily and the dose of decitabine is 35 mg daily.

[0061] In some embodiments, the subject has not been treated with any compound that is metabolized by cytidine deaminase.

[0062] In some embodiments, trinapant, cedazuridine, and decitabine are administered orally.

[0063] Additional combination therapy In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents being used and / or developed to treat T-cell lymphoma, such as bone marrow / stem cell transplantation and / or CAR T-cell therapy.

[0064] In some embodiments, the one or more additional therapeutic agents may be an additional IAP inhibitor.

[0065] kit The present disclosure also provides kits comprising trinapant, cedazuridine, and / or decitabine, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog of each, in suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises trinapant, cedazuridine, and / or decitabine, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog of each, in combination with a label and / or instructions for use of the compound in the treatment of an indication, including a disease or condition described herein.

[0066] Also provided herein is an article of manufacture comprising any compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, in a suitable container, which may be a vial, jar, ampoule, pre-filled syringe, and intravenous bag.

[0067] Pharmaceutical Compositions and Modes of Administration The compounds provided herein are typically administered in the form of pharmaceutical compositions. Accordingly, the present disclosure also provides pharmaceutical compositions containing one or more compounds described herein, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and additives. Suitable pharmaceutically acceptable vehicles include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared by methods known in the pharmaceutical arts. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0068] In some embodiments, the pharmaceutical composition comprises: trinapant or a pharmaceutically acceptable salt thereof, Cedazuridine or a pharmaceutically acceptable salt thereof, and Provided herein are pharmaceutical compositions comprising decitabine or a pharmaceutically acceptable salt thereof.

[0069] The pharmaceutical compositions can be administered in either a single dose or multiple doses. The pharmaceutical compositions can be administered by a variety of methods, including, for example, intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, or oral.

[0070] One mode of administration is parenteral, for example, by injection or intravenous infusion. Forms into which the pharmaceutical compositions described herein can be incorporated for administration by injection include, for example, aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0071] Oral administration may be another route of administration for the compounds described herein. Administration may be, for example, via capsules or enteric-coated tablets. In preparing pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the active ingredient is typically diluted with an additive and / or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the additive serves as a diluent, it may be in the form of a solid, semi-solid, or liquid material that functions as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), e.g., ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solution, and sterile packaged powder.

[0072] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propyl hydroxybenzoates, sweeteners, and flavoring agents.

[0073] Compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are described in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods disclosed herein employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0074] To prepare solid compositions such as tablets, 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 these preformulation compositions are referred to as homogeneous, the active ingredient is dispersed evenly throughout the composition, so that the composition can be readily subdivided into equally effective unit dosage forms such as, for example, tablets, pills, and capsules.

[0075] Tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of an outer membrane covering the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0076] In some embodiments, cedazuridine, decitabine, and trinapant are administered as individual tablets or capsules. In some embodiments, cedazuridine and decitabine are administered as a tablet containing a fixed-dose combination of cedazuridine and decitabine. In some such embodiments, the tablet contains a fixed-dose combination of 100 mg of cedazuridine and 35 mg of decitabine. In some such embodiments, the tablet further contains lactose monohydrate, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the tablet has a film coating containing polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and red iron oxide. In some embodiments, trinapant is administered as a capsule or tablet combined with a fixed-dose combination tablet containing cedazuridine and decitabine.

[0077] dosage The specific dose level of the compounds of the present application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, concomitant drug use, and the severity of the particular disease in the subject being treated. For example, doses can be expressed as milligrams of a compound described herein per kilogram of subject body weight (mg / kg). Doses of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, doses of about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalizing according to subject body weight is particularly useful when using drugs in both children and adults, or when adjusting doses between subjects of widely differing size, such as occurs when converting an effective dose in a non-human subject, such as a dog, to a dose appropriate for a human subject.

[0078] Daily doses may also be described as the total amount of a compound described herein administered per administration or per day. The daily dose of trinapant, cedazuridine, and / or decitabine may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0079] When administered orally, the total daily dose for a human subject can be 1 mg to 1,000 mg, about 1,000 to 2,000 mg / day, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day.

[0080] The compounds or compositions of the present application may be administered once, twice, three times, or four times daily using any suitable regimen described above. Administration or treatment with the compounds may also continue for several days; for example, treatment typically continues for at least 7, 14, or 28 days during one treatment cycle. Treatment cycles are well known in cancer chemotherapy and frequently alternate with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. In other embodiments, treatment cycles may also be continuous.

[0081] In certain embodiments, the method includes administering to a subject an initial daily dose of about 1 to 800 mg of a compound described herein and gradually increasing the dose until clinical efficacy is achieved. The dose may be increased using increments of about 5, 10, 25, 50, or 100 mg. The dosage may be increased daily, every other day, twice weekly, or once weekly.

[0082] In some embodiments, patients are administered trinapant at three consecutive dose levels (120, 150, and 180 mg / day on days 1-7 and 15-21 of a 28-day cycle) in combination with fixed-dose oral decitabine / cedazuridine, or as a single agent in combination with fixed-dose oral decitabine / cedazuridine. The starting dosage of oral decitabine / cedazuridine in both arms is the standard FDC tablet (35 mg decitabine / 100 mg cedazuridine). [Example]

[0083] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in these examples represent well-functioning techniques in the practice of the present disclosure and, therefore, can be considered to constitute specific modes for its practice. However, those skilled in the art should, in light of the present disclosure, understand that many changes can be made to the specific embodiments disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.

[0084] Example 1 Example 1-1 CT26 is a mouse colon adenocarcinoma cell line that does not express receptor-interacting serine / threonine protein kinase 3 (RIPK3). RIPK3 was re-expressed in the CT26 line (derived from ATCC) using CRISPR activation (CRISPRa) (Figure 1A). Control CT26 cells that do not express RIPK3 and RIPK3-reexpressing CT26 cells were treated with 1 μM trinapant. Lytic cell death upon trinapant treatment was measured for CT26 control cells and RIPK3-reexpressing CT26 cells by real-time microscopy (IncuCyte) assay (Figure 1B). As shown in Figure 1B, RIPK3-reexpressing CT26 cells exhibited higher lytic cell death than control CT26 cells upon treatment with trinapant, demonstrating that RIPK3 expression increased trinapant-induced cell death.

[0085] Example 1-2 Two types of human T-cell lymphoma cell lines (H9 and Karpas-299, ECACC, Porton Down, Salisbury, UK) were treated with 0.01, 0.1, or 1 μM decitabine (DAC) for 4 days, or without decitabine (DAC). Two types of mouse cell lines (BW5147.G.1.4, T-cell lymphoma, DSMZ, Braunschweig, Germany, and CT26) were treated with 0.01, 0.1, or 1 μM decitabine (DAC) for 2 days, or without decitabine (DAC). As shown in Figure 2, RIPK3 expression was detected after treatment of Karpas-299 or CT26 cells with decitabine (DAC), indicating that RIPK3 was re-expressed after the addition of decitabine in both mouse and human cells, even though RIPK3 was normally silenced in Karpas-299 or CT26 cells. On the other hand, as shown in Figure 2, H9 cells and BW5147.G.1.4 cells showed high basal RIPK3 expression before treatment with decitabine (DAC).

[0086] Examples 1-3 DNA from human H9, Karpas-299, Sup-M2 (DSMZ), and Sup-T1 (ECACC) cell lines was sequenced to determine the methylation status of the RIPK3 gene by pyrosequencing (EpigenDX). As shown in panel A of Figure 3, human H9 cells had low basal methylation of the RIPK3 gene promoter, while Karpas-299, Sup-M2, and Sup-T1 cells showed relatively high basal methylation of the RIPK3 gene promoter. These cell lines were treated with 0.01, 0.1, and 1 μM decitabine (DAC) for 4 days, and the DNA of the cells was sequenced to determine the methylation status of the RIPK3 gene by pyrosequencing (EpigenDX). As shown in panels B and C of Figure 3, decitabine (DAC) treatment resulted in demethylation of the RIPK3 gene promoter over time. Also, as shown in Figure 3, panel D, decitabine (DAC) treatment resulted in the demethylation of LINE-1.

[0087] Examples 1-4 Human T-cell lymphoma (H9) cell lines were treated with decitabine (DAC) (0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, and 10 μM) for 48 hours, and IFNγ release was measured using an electrochemiluminescence immunoassay (Meso Scale Discovery). As shown in Figure 4, IFNγ release from H9 cells increased similarly to cells treated with decitabine alone for 48 hours. The results in Examples 1-1 to 1-4 demonstrate that certain sensitive cells from T-cell lymphoma patients can re-express silenced promoters of members of the lipopoposome complex (e.g., RIPK3) during treatment, and that the re-expressed lipopoposome complex containing RIPK3 can increase trinapant-induced cell death. Therefore, treatment with decitabine results in improved response rates to trinapant treatment.

[0088] Examples 1-5 Human T-cell lymphoma cell lines (H9) and murine T-cell lymphoma cell lines (BW5147.G.1.4) were treated with decitabine (DAC) alone, trinapant alone, or the combination of decitabine (DAC) and trinapant for 72 hours, and cell viability was measured using a proliferation assay (CellTiterGlo). The combination of decitabine (DAC) and trinapant decreased cell viability, and the synergistic effect of decitabine (DAC) and trinapant was evaluated using the HSA model with Combenfit. The plots are shown in Figure 5 (Panel A: H9 cell line, Panel B: BW5147.G.1.4 cell line). As shown in Figure 5, the combination of decitabine and trinapant demonstrated synergistic effects, particularly for the human H9 cell line.

[0089] Examples 1-6 Human T-cell lymphoma (H9) cell lines were treated with decitabine (DAC) alone, trinapant alone, and the combination of decitabine (DAC) and trinapant for 72 hours, and lytic cell death over time was measured by Cytotox staining of H9 cells and a stereomicroscope (IncuCyte) assay. The results are shown in Figure 6. As shown in Figure 6, the combination of decitabine (DAC) and trinapant showed a synergistic increase in lytic cell death.

[0090] Examples 1-7 Murine T-cell lymphoma (BW5147.G.1.4) cell lines were treated with decitabine (DAC) alone, (decitabine (DAC) + 0.1 μM trinapant), and (decitabine (DAC) + 1 μM trinapant) for 24 hours. The concentration of decitabine (DAC) was varied between 0, 0.001, 0.01, 0.1, 1, and 10 μM. HMGB1 released from the cells was measured by ELISA after 24 hours. The concentration of HMGB1 at different concentrations of decitabine (DAC) and trinapant is shown in Figure 7. As shown in Figure 7, the combination of decitabine (DAC) and trinapant showed increased HMGB1 levels compared to decitabine alone, indicating increased lytic cell death.

[0091] Examples 1-8 Murine T-cell lymphoma (BW5147.G.1.4) cell line was treated with decitabine (DAC) alone or in combination with trinapant for 48 hours. After 48 hours, cells were lysed and interferon signaling and PD markers were analyzed by Western blotting, as shown in Figure 8. Western blot analysis confirmed that DNMT1 expression decreased with increasing concentrations of decitabine, and that the addition of trinapant suppressed cIAP1 expression.

[0092] Examples 1-9 Murine T-cell lymphoma (BW5147.G.1.4) cell lines were treated with decitabine (DAC) alone, trinapant alone, or the combination of decitabine (DAC) and trinapant for 48 hours. After 48 hours, key inflammatory mediators were measured by Luminex assay (Ampersand), as shown in panel A of Figure 9. As shown in panel B of Figure 9, when BW5147.G.1.4 cells were treated with the combination of decitabine and trinapant, the concentration of IP-10 was significantly higher than that of decitabine or trinapant alone.

[0093] Examples 1-10 BW5147.G.1.4 tumor-bearing AKR / J mice were treated daily with decitabine (DAC) (0.3 mg / kg i.p.), trinapant (25 mg / kg po), or their combination. BW5147 cells were harvested on day 5, and Western blotting of BW5147 cell lysates is shown in Figure 10, panel A.

[0094] Plasma HMGB1 levels after 5 days of treatment with decitabine (DAC), trinapant, and the combination were measured using ELISA, and the combination showed increased HMGB1 concentrations, as shown in Figure 10, panel B. Plasma cytokine and chemokine levels were measured after 5 days of treatment, and the results are shown in Figure 11.

[0095] Examples 1-11 A KARPAS-299 xenograft mouse model was prepared by injecting KARPAS-299 cells. Mice bearing KARPAS-299 xenografts were treated with decitabine (DAC) and / or trinapant for 5 days. Tumor cells were harvested and analyzed for gene expression changes (Figure 12). As shown in Figure 12, the xenografts showed upregulation of interferon, other cytokines / chemokines, and cancer-testis antigens by decitabine (DAC). Some biomarkers were further enhanced by the combination of decitabine (DAC) and trinapant. As shown in Figure 13, harvested KARPAS-299 cells were lysed, and re-expression of RIPK3 was also confirmed by Western blot.

[0096] Example 2 This study is an open-label study of the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of trinapant in combination with oral decitabine / cedazuridine in subjects with relapsed or refractory peripheral T-cell lymphoma (R / R PTCL).

[0097] Phase 1 is an open-label, randomized, multicenter, two-arm study to evaluate the safety of trinapant in combination with oral decitabine / cedazuridine and to determine the recommended phase 2 dose (RP2D) for combination treatment (trinapant + oral decitabine / cedazuridine) in subjects with R / R PTCL. Additionally, oral decitabine / cedazuridine as a single agent will be evaluated for safety and tolerability in this patient population.

[0098] The Phase 2 study will evaluate trinapant in combination with oral decitabine / cedazuridine for preliminary efficacy as well as PK and PD in this patient population.

[0099] The induction phase will occur prior to the start of Phase 1 to confirm that the US-approved dosing of oral decitabine / cedazuridine as a single agent is tolerated in this population. As many as six subjects will receive oral decitabine / cedazuridine as a single agent on days 1-5 of a 28-day cycle. Subjects will be evaluated for myelosuppression and other dose-limiting toxicities (DLTs), and dose adjustments will be made as appropriate. Enrollment in the induction phase will be halted if two or more DLTs occur in cycle 1, and dose adjustments will be made for both arms of the Phase 1 trial.

[0100] Phase 1 begins after the induction phase is complete. Subjects are randomized (1:1) to receive trinapant at three consecutive dose levels (120, 150, and 180 mg / day on days 1-7 and 15-21 of a 28-day cycle) in combination with fixed-dose oral decitabine / cedazuridine (Arm A) or fixed-dose oral decitabine / cedazuridine as single agents (Arm B). The starting dose of oral decitabine / cedazuridine in both arms is the standard FDC tablet (35 mg decitabine / 100 mg cedazuridine) with the dosing regimen determined during the induction phase. Trinapant will be escalated to the next higher dose level, if applicable.

[0101] The starting dose of trinapant in Arm A will be escalated in successive cohorts of 3-6 evaluable subjects at each dose level until the RP2D is determined. The dose escalation phase will identify the RP2D, defined as the dose demonstrating adequate clinical activity and safety and clinical activity. The decision to escalate or decrement will be based on the occurrence of DLT during the first cycle of each dose level. The trinapant dose will not exceed 180 mg per dose, and oral decitabine / cedazuridine dosing will not exceed 5 days per cycle.

[0102] Specific inclusion criteria are as follows: male or female, aged 18 years or older; expected life expectancy >12 weeks; subject must have histologically confirmed R / R PTCL (local pathology report) as defined by the 2016 World Health Organization (WHO) classification. The following subtypes are eligible for the study: adult T-cell lymphoma / leukemia, extranodal natural killer (NK) / T-cell lymphoma, nasal type, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, unspecified peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, follicular T-cell lymphoma, nodal peripheral T-cell lymphoma with follicular helper (TFH) cell phenotype, and anaplastic large cell lymphoma. Subjects must have documented evidence of relapsed or refractory disease.

[0103] Specific exclusion criteria include: prior treatment with trinapant or any hypomethylating agent; hypersensitivity to trinapant or oral decitabine / cedazuridine, pharmaceutical excipients (vehicles), or other components of the study treatment regimen; poor medical risk due to systemic illness (e.g., uncontrolled infection) in addition to the limited illness being studied; life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator's opinion, may compromise the subject's safety or the integrity of the study outcome, or may interfere with the absorption or metabolism of trinapant; history of or risk for cardiac disease. ****

[0104] 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 invention belongs.

[0105] The invention illustratively described herein can 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. In addition, the terms and expressions used herein are used as terms of description and not of limitation, and in the use of such terms and expressions, there is no intention to exclude 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 invention as claimed.

[0106] 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 individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0107] While the present disclosure has been described in conjunction with the above embodiments, it should be understood that the foregoing description and examples are intended to illustrate, but not limit, the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which this disclosure pertains.

Claims

1. A combination medicine, trinapant or a pharmaceutically acceptable salt thereof, Cedazuridine or a pharmaceutically acceptable salt thereof, and decitabine or a pharmaceutically acceptable salt thereof, A combination medicine comprising:

2. 1. A pharmaceutical combination for use in the treatment of T-cell lymphoma, comprising: trinapant or a pharmaceutically acceptable salt thereof, Cedazuridine or a pharmaceutically acceptable salt thereof, and decitabine or a pharmaceutically acceptable salt thereof, A combination medicine comprising:

3. The combination pharmaceutical of claim 2, wherein the T-cell lymphoma is relapsed or refractory T-cell lymphoma.

4. 3. The pharmaceutical combination of claim 2, wherein the T-cell lymphoma has been previously treated with a hypomethylating agent.

5. 3. The pharmaceutical combination of claim 2, wherein the T-cell lymphoma has not been previously treated with an agent for treating T-cell lymphoma.

6. 6. The combination pharmaceutical of any one of claims 2 to 5, wherein the T-cell lymphoma is selected from peripheral T-cell lymphoma, non-specified peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, follicular T-cell lymphoma, nodal peripheral T-cell lymphoma with follicular helper (TFH) cell phenotype, adult T-cell lymphoma / leukemia, anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, nasal-type NK / T-cell lymphoma, hepatosplenic T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and cutaneous (skin) T-cell lymphoma.

7. 3. The method of claim 2, wherein the T-cell lymphoma is relapsed or refractory peripheral T-cell lymphoma (R / R PTCL).

8. The combined pharmaceutical composition of any one of claims 2 to 5, wherein the T-cell lymphoma is non-specific peripheral T-cell lymphoma.

9. The combined pharmaceutical composition of any one of claims 2 to 5, wherein the T-cell lymphoma is angioimmunoblastic lymphoma.

10. The combined pharmaceutical composition of any one of claims 2 to 5, wherein the T-cell lymphoma is anaplastic large cell lymphoma (ALCL).

11. The combined pharmaceutical composition of any one of claims 2 to 5, wherein the T-cell lymphoma is hepatosplenic T-cell lymphoma.

12. The pharmaceutical combination of any one of claims 2 to 5, wherein the T-cell lymphoma is enteropathy-associated T-cell lymphoma.

13. The combined pharmaceutical composition of any one of claims 2 to 5, wherein the T-cell lymphoma is cutaneous T-cell lymphoma.

14. The combined pharmaceutical composition of any one of claims 2 to 5, wherein the cutaneous T-cell lymphoma is mycosis fungoides or Sézary syndrome.

15. 3. The combination pharmaceutical of claim 2, wherein the T-cell lymphoma is T-lymphoblastic lymphoma / leukemia or adult T-cell lymphoma / leukemia.

16. A combination pharmaceutical according to any one of claims 1 to 5, wherein the trinapant, the cedazuridine and the decitabine are administered individually or in combination.

17. 17. The pharmaceutical combination of claim 16, wherein the trinapant is administered once daily for seven consecutive days every other week of each 28-day cycle.

18. 18. The combination pharmaceutical of claim 17, wherein the dose of trinapant is 30 mg or 90 mg per day.

19. 17. The pharmaceutical combination of claim 16, wherein the cedazuridine and decitabine are administered once daily on days 1 through 5 of each 28-day cycle.

20. 20. The pharmaceutical combination of claim 19, wherein the dose of cedazuridine is 100 mg per day and the dose of decitabine is 35 mg per day.

21. 17. The pharmaceutical combination of claim 16, wherein the subject is not being treated with any compound that is metabolized by cytidine deaminase.

22. 17. The pharmaceutical combination of claim 16, wherein the trinapant, the cedazuridine, and the decitabine are administered orally.

23. A pharmaceutical composition for use in the treatment of T-cell lymphoma, comprising trinapant or a pharmaceutically acceptable salt thereof, in combination with cedazuridine or a pharmaceutically acceptable salt thereof, and decitabine or a pharmaceutically acceptable salt thereof.

24. The pharmaceutical composition described in claim 23, wherein the T-cell lymphoma is relapsed or refractory T-cell lymphoma.

25. The pharmaceutical composition of claim 23, wherein the T-cell lymphoma has previously been treated with a hypomethylating agent.

26. The pharmaceutical composition of claim 23, wherein the T-cell lymphoma has not been previously treated with a drug for treating T-cell lymphoma.

27. The pharmaceutical composition of any one of claims 23 to 26, wherein the T-cell lymphoma is selected from peripheral T-cell lymphoma, non-specified peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, follicular T-cell lymphoma, nodal peripheral T-cell lymphoma with follicular helper (TFH) cell phenotype, adult T-cell lymphoma / leukemia, anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, nasal-type NK / T-cell lymphoma, hepatosplenic T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and cutaneous (skin) T-cell lymphoma.

28. The pharmaceutical composition of claim 23, wherein the T-cell lymphoma is relapsed or refractory peripheral T-cell lymphoma (R / R PTCL).

29. A pharmaceutical composition described in any one of claims 23 to 26, wherein the T-cell lymphoma is non-specific peripheral T-cell lymphoma.

30. A pharmaceutical composition described in any one of claims 23 to 26, wherein the T-cell lymphoma is angioimmunoblastic lymphoma.

31. The pharmaceutical composition described in any one of claims 23 to 26, wherein the T-cell lymphoma is anaplastic large cell lymphoma (ALCL).

32. The pharmaceutical composition described in any one of claims 23 to 26, wherein the T-cell lymphoma is hepatosplenic T-cell lymphoma.

33. A pharmaceutical composition described in any one of claims 23 to 26, wherein the T-cell lymphoma is enteropathy-associated T-cell lymphoma.

34. A pharmaceutical composition described in any one of claims 23 to 26, wherein the T-cell lymphoma is cutaneous T-cell lymphoma.

35. A pharmaceutical composition described in any one of claims 23 to 26, wherein the cutaneous T-cell lymphoma is mycosis fungoides or Sézary syndrome.

36. The pharmaceutical composition described in claim 23, wherein the T-cell lymphoma is T-lymphoblastic lymphoma / leukemia or adult T-cell lymphoma / leukemia.

37. The pharmaceutical composition of claim 23, wherein the trinapant is administered once daily for 7 consecutive days every other week of each 28-day cycle.

38. 38. The pharmaceutical composition of claim 37, wherein the dose of trinapant is 30 mg or 90 mg per day.

39. 24. The pharmaceutical composition of claim 23, wherein the cedazuridine and decitabine are administered once daily on days 1 through 5 of each 28-day cycle.

40. 40. The pharmaceutical composition of claim 39, wherein the dose of cedazuridine is 100 mg daily and the dose of decitabine is 35 mg daily.

41. 24. The pharmaceutical composition of claim 23, wherein the subject is not being treated with any compound that is metabolized by cytidine deaminase.

42. 24. The pharmaceutical composition of claim 23, wherein the trinapant, the cedazuridine, and the decitabine are administered orally.

43. A pharmaceutical composition for use in the treatment of T-cell lymphoma, comprising cedazuridine or a pharmaceutically acceptable salt thereof, and decitabine or a pharmaceutically acceptable salt thereof, in combination with trinapant or a pharmaceutically acceptable salt thereof.

44. The pharmaceutical composition described in claim 43, wherein the T-cell lymphoma is relapsed or refractory T-cell lymphoma.

45. The pharmaceutical composition of claim 43, wherein the T-cell lymphoma has previously been treated with a hypomethylating agent.

46. ​​The pharmaceutical composition of claim 43, wherein the T-cell lymphoma has not been previously treated with a drug for treating T-cell lymphoma.

47. The pharmaceutical composition of any one of claims 43 to 46, wherein the T-cell lymphoma is selected from peripheral T-cell lymphoma, non-specified peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, follicular T-cell lymphoma, nodal peripheral T-cell lymphoma with follicular helper (TFH) cell phenotype, adult T-cell lymphoma / leukemia, anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, nasal-type NK / T-cell lymphoma, hepatosplenic T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and cutaneous (skin) T-cell lymphoma.

48. The pharmaceutical composition of claim 43, wherein the T-cell lymphoma is relapsed or refractory peripheral T-cell lymphoma (R / R PTCL).

49. A pharmaceutical composition described in any one of claims 43 to 46, wherein the T-cell lymphoma is non-specific peripheral T-cell lymphoma.

50. A pharmaceutical composition described in any one of claims 43 to 46, wherein the T-cell lymphoma is angioimmunoblastic lymphoma.

51. A pharmaceutical composition described in any one of claims 43 to 46, wherein the T-cell lymphoma is anaplastic large cell lymphoma (ALCL).

52. A pharmaceutical composition described in any one of claims 43 to 46, wherein the T-cell lymphoma is hepatosplenic T-cell lymphoma.

53. A pharmaceutical composition described in any one of claims 43 to 46, wherein the T-cell lymphoma is enteropathy-associated T-cell lymphoma.

54. A pharmaceutical composition described in any one of claims 43 to 46, wherein the T-cell lymphoma is cutaneous T-cell lymphoma.

55. A pharmaceutical composition described in any one of claims 43 to 46, wherein the cutaneous T-cell lymphoma is mycosis fungoides or Sézary syndrome.

56. The pharmaceutical composition described in claim 43, wherein the T-cell lymphoma is T-lymphoblastic lymphoma / leukemia or adult T-cell lymphoma / leukemia.

57. The pharmaceutical composition of claim 43, wherein the trinapant is administered once daily for 7 consecutive days every other week of each 28-day cycle.

58. A pharmaceutical composition described in claim 57, wherein the dose of trinapant is 30 mg or 90 mg per day.

59. The pharmaceutical composition of claim 43, wherein the cedazuridine and decitabine are administered once daily on days 1 to 5 of each 28-day cycle.

60. The pharmaceutical composition described in claim 59, wherein the dose of cedazuridine is 100 mg per day and the dose of decitabine is 35 mg per day.

61. The pharmaceutical composition of claim 43, wherein the subject is not being treated with any compound that is metabolized by cytidine deaminase.

62. The pharmaceutical composition described in claim 43, wherein the trinapant, the cedazuridine, and the decitabine are administered orally.

63. Trinapant or a pharmaceutically acceptable salt thereof. Cedazuridine or a pharmaceutically acceptable salt thereof, and 1. Use of a medicament for the manufacture of a combination medicament for the treatment of T-cell lymphoma, for administering decitabine or a pharmaceutically acceptable salt thereof, either individually or in combination, wherein the medicament comprises: trinapant or a pharmaceutically acceptable salt thereof, Cedazuridine or a pharmaceutically acceptable salt thereof, and decitabine or a pharmaceutically acceptable salt thereof, The use comprising at least one selected from the group consisting of:

64. 64. The use of claim 63, wherein the T-cell lymphoma is relapsed or refractory T-cell lymphoma.

65. 64. The use of claim 63, wherein the T-cell lymphoma has been previously treated with a hypomethylating agent.

66. 64. The use of claim 63, wherein the T-cell lymphoma has not been previously treated with an agent for treating T-cell lymphoma.

67. 64. The use of claim 63, wherein the T-cell lymphoma is selected from peripheral T-cell lymphoma, non-specified peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, follicular T-cell lymphoma, nodal peripheral T-cell lymphoma with follicular helper (TFH) cell phenotype, adult T-cell lymphoma / leukemia, anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, nasal-type NK / T-cell lymphoma, hepatosplenic T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and cutaneous T-cell lymphoma.

68. 64. The use of claim 63, wherein the T-cell lymphoma is relapsed or refractory peripheral T-cell lymphoma (R / R PTCL).

69. 64. The use of claim 63, wherein the T-cell lymphoma is peripheral T-cell lymphoma not otherwise specified.

70. 64. The use of claim 63, wherein the T-cell lymphoma is angioimmunoblastic lymphoma.

71. 64. The use of claim 63, wherein the T-cell lymphoma is anaplastic large cell lymphoma (ALCL).

72. 64. The use of claim 63, wherein the T-cell lymphoma is hepatosplenic T-cell lymphoma.

73. 64. The use of claim 63, wherein the T-cell lymphoma is enteropathy-associated T-cell lymphoma.

74. 64. The use of claim 63, wherein the T-cell lymphoma is cutaneous T-cell lymphoma.

75. 64. The use of claim 63, wherein the cutaneous T-cell lymphoma is mycosis fungoides or Sézary syndrome.

76. 64. The use of claim 63, wherein the T-cell lymphoma is T-lymphoblastic lymphoma / leukemia or adult T-cell lymphoma / leukemia.

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