Combination therapy for treating malignancies

Abstract

Provided are methods and compositions for treating solid tumors in patients carrying an IDH1 and / or IDH2 mutation using a combination of a dual inhibitor of a mutant IDH1 or IDH2 enzyme and a DNA demethylating agent.

Description

COMBINATION THERAPY FOR TREATING MALIGNANCIESCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No.: 63 / 523,161, filed on June 26, 2023, the content of which is incorporated herein by reference in its entirety.FIELD

[0002] Provided herein are combination therapies for treating solid tumors, in particular brain tumors, more particularly glioma. In one embodiment, the therapies involve treatment with dual IDH1 / IDH2 inhibitor and a DNA demethylating agent.BACKGROUND

[0003] Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (z.e., a-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+) -dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+) -dependent isozyme is a homodimer.

[0004] IDH1 (isocitrate dehydrogenase 1 (NADP+), cytosolic) is also known as IDH; IDP; IDCD; IDPC or PICD. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 (peroxisomal targeting signal- 1) sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production.

[0005] The human IDH1 gene encodes a protein of 414 amino acids. The nucleotide and amino acid sequences for human IDH1 can be found as GenBank entries NM 005896.2 and NP_005887.2 respectively. The nucleotide and amino acid sequences for IDH1 are also described in, e.g., Nekrutenko et al., Mol. Biol. Evol. 15: 1674-1684(1998); Geisbrecht et al., J. Biol. Chem. 274:30527-30533(1999); Wiemann et al., Genome Res. 11:422-435(2001); The MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec et al., Submitted (DEC2008) to UniProtKB; Kullmann et al., Submitted (JUN- 1996) to the EMBL / GenBank / DDBJ databases; and Sjoeblom etal., Science 314:268-274(2006).

[0006] Non-mutant, e.g., wild type, IDH1 catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate thereby reducing NAD+(NADP+) to NADH (NADPH), e.g., in the forward reaction:Isocitrate + NAD+(NADP+) a-KG + CO2+ NADH (NADPH) + H+.

[0007] It has been discovered that mutations of IDH1 present in certain cancer cells result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of a- ketoglutarate to / ?(-)-2-hydroxyglutaratc (2HG). The production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al, Nature 2009, 462:739- 44).

[0008] IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial) is also known as IDH; IDP; IDHM; IDPM; ICD-M; or mNADP-IDH. The protein encoded by this gene is the NADP(+) -dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex. Human IDH2 gene encodes a protein of 452 amino acids. The nucleotide and amino acid sequences for IDH2 can be found as GenBank entries NM_002168.2 and NP_002159.2 respectively. The nucleotide and amino acid sequence for human IDH2 are also described in, e.g. Huh et al., Submitted (NOV-1992) to the EMBL-GenBank / DDBJ databases; and the MGC Project team, Genome Res. 14:2121- 2127(2004).

[0009] Non-mutant, e.g. wild type, IDH2 catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate (a-KG).

[0010] It has been discovered that mutations of IDH2 present in certain cancer cells result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of a-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 2HG is not formed by wild-type IDH2. The production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al, Nature 2009, 462:739-44). The inhibition of mutant IDH1 and / or mutant IDH2 and their neomorphic activity is therefore a potential therapeutic treatment for cancer.

[0011] Oligodendrogliomas and astrocytomas are primary brain tumors and represent subtypes of gliomas (e.g., adult-type diffuse gliomas). Traditionally, oligodendrogliomas and astrocytomas have been classified in accordance with their histopathological phenotypes, but more recent classification guidelines have moved toward an increased role of molecularmarkers in CNS tumor taxonomy. Per 2021 WHO (World Health Organization) classification of CNS tumors (WHO CNS5), adult-type diffuse gliomas are classified into three subtypes: oligodendroglioma, astrocytoma and glioblastoma. Oligodendroglioms harbor IDH1 or IDH2 mutations and lpl9q co-deletion. Per CNS5, oligodendrogliomas occur as grade 2 or 3 tumors. Astrocytomas harbor IDH1 or IDH2 mutations but lacklpl9q co-deletion. Per CNS5, astrocytomas occur as grade 2, 3 or 4 tumors. Finally, glioblastomas are characterized by a lack of IDH mutations (z.e., wild-type IDH). (Louis, D. N. et al., Neuro-Oncology, 23: 1231- 1251(2021)).

[0012] Recurrent or progressive IDH-mutant gliomas are oligodendrogliomas and astrocytomas that harbor IDH1 or IDH2 gene mutation and have recurred or progressed after receiving standard of care therapy including surgery, radiation and / or chemotherapy.

[0013] Vorasidenib is an orally available, brain penetrant second-generation dual mutant isocitrate dehydrogenase 1 and 2 (mIDHl / 2) inhibitor currently being evaluated in clinical trials for the treatment of IDH-mutant gliomas.Vorasidenib

[0014] Vorasidenib or (6-(6-chloropyridin-2-yl)-N2,N4-bis((R)- 1,1,1 -trifluoropropan-2- yl)-l,3,5-triazine-2,4-diamine) is disclosed in U.S. Patent No. 9,579,324, which is incorporated herein by reference in its entirety.SUMMARY

[0015] In one embodiment, provided is a combination of vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate, or cocrystal thereof, and azacitidine for use in a method of treating solid tumors, in particular a brain tumor, wherein vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate, or cocrystal thereof, and azacitidine are administered sequentially or concurrently.

[0016] In one embodiment, provided is a combination for use in a method of treating a brain tumor, wherein the brain tumor is glioma.

[0017] In some embodiments, the solid tumor is characterized by the presence of an isocitrate dehydrogenase (IDH) mutation.

[0018] In some embodiments, the brain tumor (e.g., glioma) is characterized by the presence of an isocitrate dehydrogenase (IDH) mutation.

[0019] In some embodiments, the solid tumor is characterized by the presence of anIDH1 mutation, wherein the IDH1 mutation results in accumulation of R(-)-2- hydroxyglutarate in a patient.

[0020] In some embodiments, the brain tumor (e.g., glioma) is characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in accumulation of R(-)-2- hydroxyglutarate in a patient.

[0021] In some embodiments, the IDH1 mutation is an R132X mutation.

[0022] In some embodiments, the IDH1 mutation is an R132H, R132C, R132S, R132G or R132L mutation.

[0023] In some embodiments, the solid tumor is characterized by the presence of anIDH2 mutation, wherein the IDH2 mutation results in accumulation of R(-)-2- hydroxyglutarate in a patient.

[0024] In some embodiments, the brain tumor (e.g., glioma) is characterized by the presence of an IDH2 mutation, wherein the IDH2 mutation results in accumulation of R(-)-2- hydroxyglutarate in a patient.

[0025] In some embodiments, the IDH2 mutation is an R140X mutation.

[0026] In some embodiments, the IDH2 mutation is an R140Q, R140W, or R140L mutation.

[0027] In some embodiments, the IDH2 mutation is an R172X mutation.

[0028] In some embodiments, the IDH2 mutation is an R172K or R172G mutation.

[0029] In some embodiments, the solid tumor is characterized by the presence of anIDH1 mutation and an IDH2 mutation, wherein the IDH1 and IDH2 mutations collectively result in accumulation of R(-)-2 -hydroxyglutarate in a patient.

[0030] In some embodiments, the brain tumor (e.g., glioma) is characterized by the presence of an IDH1 mutation and an IDH2 mutation, wherein the IDH1 and IDH2 mutations collectively result in accumulation of R(-)-2 -hydroxyglutarate in a patient.

[0031] In some embodiments, vorasidenib is administered in non-salt form.

[0032] In some embodiments, vorasidenib is administered in the form of a pharmaceutically acceptable salt.

[0033] In some embodiments, vorasidenib is administered as a cocrystal.

[0034] In some embodiments, vorasidenib is administered as a cocrystal with citric acid.

[0035] In some embodiments, vorasidenib is administered at a dose between about 10 mg / day and about 100 mg / day.

[0036] In some embodiments, azacitidine is administered at a dose between about 50 mg / m2 / day and about 2,000 mg / m2 / day.

[0037] In some embodiments, azacitidine is administered at a dose between about 5 mg / day and about 2,000 mg / day.

[0038] In one embodiment, provided is a method of treating a brain tumor in a patient in need thereof comprising administering to the patient a combination of a vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and a DNA demethylating agent.

[0039] In one embodiment, provided is a method of treating a solid tumor, in particular a brain tumor in a patient in need thereof comprising administering to the patient a combination of a vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and a DNA demethylating agent.

[0040] In one embodiment, provided is a method of treating a solid tumor, in particular a brain tumor in a patient in need thereof comprising administering to the patient a combination of a vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and a DNA demethylating agent, wherein the DNA demethylating agent is a cytidine analog.

[0041] In one embodiment, provided is a method of treating a solid tumor, in particular a brain tumor in a patient in need thereof comprising administering to the patient a combination of a vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and a DNA demethylating agent, wherein the DNA demethylating agent is azacitidine.

[0042] In one embodiment, provided is a method of treating glioma in a patient in need thereof comprising administering to the patient a combination of a vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and a DNA demethylating agent.

[0043] In one embodiment, provided is a method of treating glioma in a patient in need thereof comprising administering to the patient a combination of a vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and a DNA demethylating agent, wherein the DNA demethylating agent is a cytidine analog.

[0044] In one embodiment, provided is a method of treating glioma in a patient in need thereof comprising administering to the patient a combination of a vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and a DNA demethylating agent, wherein the DNA demethylating agent is azacitidine.

[0045] In some embodiments, the brain tumor (e.g., glioma) is recurrent or progressive.

[0046] In some embodiments, the solid tumor is characterized by the presence of an isocitrate dehydrogenase (IDH) mutation.

[0047] In some embodiments, the brain tumor (e.g., glioma) is characterized by the presence of an isocitrate dehydrogenase (IDH) mutation.

[0048] In some embodiments, the solid tumor is characterized by the presence of anIDH1 mutation, wherein the IDH1 mutation results in accumulation of R(-)-2- hydroxyglutarate in a patient.

[0049] In some embodiments, the brain tumor (e.g., glioma) is characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in accumulation of R(-)-2- hydroxyglutarate in a patient.

[0050] In some embodiments, the IDH1 mutation is an R132X mutation.

[0051] In some embodiments, the IDH1 mutation is an R132H, R132C, R132S, R132G or R132L mutation.

[0052] In some embodiments, the solid tumor is characterized by the presence of anIDH2 mutation, wherein the IDH2 mutation results in accumulation of R(-)-2- hydroxyglutarate in a patient.

[0053] In some embodiments, the brain tumor (e.g., glioma) is characterized by the presence of an IDH2 mutation, wherein the IDH2 mutation results in accumulation of R(-)-2- hydroxyglutarate in a patient.

[0054] In some embodiments, the IDH2 mutation is an R140X mutation.

[0055] In some embodiments, the IDH2 mutation is an R140Q, R140W, or R140L mutation.

[0056] In some embodiments, the IDH2 mutation is an R172X mutation.

[0057] In some embodiments, the IDH2 mutation is an R172K or R172G mutation.

[0058] In some embodiments, the solid tumor is characterized by the presence of anIDH1 mutation and an IDH2 mutation, wherein the IDH1 and IDH2 mutations collectively result in accumulation of R(-)-2 -hydroxyglutarate in a patient.

[0059] In some embodiments, the brain tumor (e.g., glioma) is characterized by the presence of an IDH1 mutation and an IDH2 mutation, wherein the IDH1 and IDH2 mutations collectively result in accumulation of R(-)-2 -hydroxyglutarate in a patient.

[0060] In some embodiments, vorasidenib is administered in non-salt form (z.e., as a free base).

[0061] In some embodiments, vorasidenib is administered in a salt form (z.e., as a salt of a pharmaceutically acceptable acid)

[0062] In some embodiments, vorasidenib is administered as a cocrystal.

[0063] In some embodiments, vorasidenib is administered as a cocrystal with citric acid.

[0064] In some embodiments, vorasidenib is administered at a dose between about 10 mg / day and about 100 mg / day.

[0065] In some embodiments, vorasidenib is administered at a dose of about 40 mg / day.

[0066] In some embodiments, vorasidenib is administered once or twice daily.

[0067] In some embodiments, vorasidenib is administered once daily.

[0068] In one embodiment, provided is a method of treating a brain tumor in a patient in need thereof comprising administering to the patient a combination of a vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and azacitidine.

[0069] In one embodiment, provided is a method of treating glioma in a patient in need thereof comprising administering to the patient a combination of a vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and azacitidine.

[0070] In one embodiment, provided herein is a method of treating brain tumors, such as glioma characterized by the presence of a mutant allele of IDH1 and / or IDH2, comprising administering to a subject a therapeutically effective amount of vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and azacitidine.

[0071] In one embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and azacitidine.

[0072] In one embodiment, provided herein is a method of treating brain tumors, such as glioma characterized by the presence of a mutant allele of IDH1 and / or IDH2, comprising administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and azacitidine.BRIEF DESCRIPTION OF THE DRAWINGS

[0073] FIG. 1. Study plan of preclinical (in vitro) study of Example 1DETAILED DESCRIPTION

[0074] The details of construction and the arrangement of components set forth in the following description or illustrated in the drawings are not meant to be limiting. Other embodiments and different ways to practice the invention are expressly included. Also, thephraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having,” “containing”, “involving”, and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.Definitions:

[0075] The term a “mutant IDH1 / IDH2 inhibitor” or “inhibitor of IDH1 / IDH2 mutant(s)” means a molecule e.g., a polypeptide, peptide, or small molecule (e.g., a molecule of less than 1,000 daltons), or aptomer, that binds to an IDH1 / IDH2 mutant subunit and inhibits neoactivity, e.g., by inhibiting formation of a dimer, e.g., a homodimer of mutant IDH1 / IDH2 subunits or a heterodimer of a mutant and a wildype subunit. In some embodiments, the neoactivity inhibition is at least about 60%, 70%, 80%, 90%, 95% or 99% as compared to the activity in the absence of the mutant IDH1 / IDH2 inhibitor. In one embodiment, the mutant IDH1 / IDH2 inhibitor is vorasidenib.

[0076] The term “elevated levels of 2HG” means 10%, 20% 30%, 50%, 75%, 100%, 200%, 500% or more 2HG is present in a subject that carries a mutant IDH1 / IDH2 allele than is present in a subject that does not carry a mutant IDH1 / IDH2 allele. The term “elevated levels of 2HG” may refer to the amount of 2HG within a cell, within a tumor, within an organ comprising a tumor, or within a bodily fluid.

[0077] The term “bodily fluid” includes one or more of amniotic fluid surrounding a fetus, aqueous humour, blood (e.g., blood plasma), serum, cerebrospinal fluid, cerumen, chyme, Cowper’s fluid, female ejaculate, interstitial fluid, lymph, breast milk, mucus (e.g., nasal drainage or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretion, or vomit.

[0078] The terms “inhibit” or “prevent” include both complete and partial inhibition and prevention. An inhibitor may completely or partially inhibit the intended target.

[0079] The term “subject” is intended to include human and non-human animals. Exemplary human subjects include a human patient (referred to as a patient) having a disorder, e.g., a disorder described herein or a normal subject. The term “non-human animals” of one aspect of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and / or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.

[0080] The term “treat” means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease / disorder (e.g., a solid tumor, including glioma,characterized by the presence of a mutant allele of IDH1 / IDH2), lessen the severity of the disease / disorder or improve the symptoms associated with the disease / disorder.

[0081] The term “solid tumor” here refers to any a bnormal malignant mass of tissue that does not contain cysts or liquid areas, such as breast, lung, prostate, pancreatic, colon, bladder, brain or skin tumor. Examples of solid tumors include glioma, melanoma, chondrosarcoma, cholangiocarcinoma (including intrahepatic cholangiocarcinoma (IHCC)), prostate cancer, pancreatic dual adenocarcinoma (PDAC), colon cancer or non-small cell lung cancer (NSCLC).

[0082] An amount of a compound, including a pharmaceutically acceptable salt, cocrystal, solvate, tautomer, stereoisomer, isotopologue, prodrug or a polymorph thereof, effective to treat a disorder, or a “therapeutically effective amount” or “therapeutically effective dose” refers to an amount of the compound, including a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, or a polymorph thereof, which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder beyond that expected in the absence of such treatment.

[0083] The term “co-administering” as used herein with respect to additional cancer therapeutic agents means that the additional cancer therapeutic agent may be administered together with a compound provided herein as part of a single dosage form (such as a composition comprising a compound and a second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional cancer therapeutic agent may be administered prior to, consecutively with, or following the administration of a compound provided herein. In such combination therapy treatment, both the compounds provided herein and the second therapeutic agent(s) are administered by conventional methods. The administration of a composition comprising both a compound provided herein and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound provided herein to said subject at another time during a course of treatment. The term “co-administering” as used herein with respect to an additional cancer treatment means that the additional cancer treatment may occur prior to, consecutively with, concurrently with or following the administration of a compound provided herein.

[0084] The term “DNA demethylating agent” refers to an agent that inhibits the transfer of a methyl group to DNA. In one embodiment, the DNA demethylating agent is a cytidine analog.

[0085] The term “a cytidine analog” referred to herein is intended to encompass the free base of the cytidine analog, or a salt, solvate, hydrate, cocrystal, complex, prodrug, precursor, metabolite, and / or derivative thereof. In certain embodiments, a cytidine analog referred to herein encompasses the free base of the cytidine analog, or a salt, solvate, hydrate, cocrystal or complex thereof. In certain embodiments, a cytidine analog referred to herein encompasses the free base of the cytidine analog, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0086] The term “substantially free of other stereoisomers” as used herein means a preparation enriched in a compound having a selected stereochemistry at one or more selected stereocenters by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.

[0087] The term “enriched” means that at least the designated percentage of a preparation is the compound having a selected stereochemistry at one or more selected stereocenters.

[0088] The term “crystalline” refers to a solid having a highly regular chemical structure. In particular, a crystalline vorasidenib may be produced as one or more single crystalline forms of vorasidenib. For the purposes of this application, the terms “crystalline form”, “single crystalline form” and “polymorph” are synonymous; the terms distinguish between crystals that have different properties (e.g., different XRPD patterns and / or different DSC scan results). The term “polymorph” includes pseudopolymorphs, which are typically different solvates of a material, and thus their properties differ from one another. Thus, each distinct polymorph and pseudopolymorph of vorasidenib is considered to be a distinct single crystalline form herein.

[0089] The term “substantially crystalline” refers to forms that may be at least a particular weight percent crystalline. Particular weight percentages are 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and 100%. In some embodiments, substantially crystalline refers to a vorasidenib that is at least 70% crystalline. In other embodiments, substantially crystalline refers to a vorasidenib that is at least 90% crystalline.

[0090] The term “isolated” refers to forms that may be at least a particular weight percent of a particular crystalline form of compound . Particular weight percentages are 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 90% and 100%.

[0091] The term “cocrystal” refers to a crystalline solid made up of two or more neutral chemical species in a defined stoichiometric ratio that possesses distinct crystallographic and spectroscopic properties when compared to the species individually. A “cocrystal” is distinct from a “salt,” which is made up of charged-balanced charged species. The species making up a cocrystal typically are linked by hydrogen bonding and other non-covalent and non-ionic interactions. Thus, a pharmaceutical cocrystal of a drug typically comprises the drug and one or more coformers. The combinations of drug and coformer(s) that will form cocyrstals generally cannot be predicted ab initio, and cocrystal formation typically affects the physicochemical properties of a drug in unpredictable ways.

[0092] The term “solvate or solvated” means a physical association of a compound, including a crystalline form thereof, of this invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate or solvated” encompasses both solution-phase and isolable solvates. Representative solvates include, for example, a hydrate, ethanolates or a methanolate.

[0093] The term “hydrate” is a solvate wherein the solvent molecule is H2O that is present in a defined stoichiometric amount, and may, for example, include hemihydrate, monohydrate, dihydrate, or trihydrate.

[0094] The term “mixture” is used to refer to the combined elements of the mixture regardless of the phase-state of the combination (e.g., liquid or liquid / crystalline).

[0095] The term “seeding” is used to refer to the addition of a crystalline material to initiate recrystallization or crystallization.

[0096] The term “antisolvent” is used to refer to a solvent in which compounds, including crystalline forms thereof, are poorly soluble.

[0097] The term “pharmaceutically acceptable carrier or adjuvant” refers to a carrier or adjuvant that may be administered to a subject, together with a compound of one aspect of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

[0098] The term “a pharmaceutically-acceptable salt ” as used herein refers to non-toxic acid or base addition salts of the compound to which the term refers. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts." J. Pharm. Set. Vol. 66, pp. 1-19.

[0099] The term “about” means approximately, in the region of, roughly, or around.When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10%.CompoundsVorasidenib

[0100] Vorasidenib is 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-l,l,l-trifluoropropan-2-yl)- l,3,5-triazine-2,4-diamine, a pharmaceutically acceptable salt, cocrystal, solvate, tautomer, stereoisomer, isotopologue, prodrug, or a polymorph thereof. Vorasidenib has the following chemical structure:vorasidenib

[0101] Vorasidenib is also known as AG-881, S095032 or S95032.

[0102] Vorasidenib can be prepared by the method described in paragraphs

[1032] -

[1036] of U.S. Publication No. 2015 / 0018328 Al, which paragraphs are incorporated herein by reference.

[0103] As used herein, the terms “compound” and “pharmaceutically acceptable salt,” when referring to vorasidenib and pharmaceutically acceptable salts thereof, include vorasidenib and pharmaceutically acceptable salts in any form, including any tautomer or rotamer thereof, any solid form thereof (including any polymorphic form thereof), any solvate or hydrate form thereof, any cocrystal thereof, and any solution thereof.

[0104] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” of the vorasidenib includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, vorasidenib. Pharmaceuticallyacceptable salts are described in detail in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.

[0105] As used herein, the term “cocrystal” refers to a crystalline solid made up of two or more neutral chemical species in a defined stoichiometric ratio that possesses distinct crystallographic and spectroscopic properties when compared to the species individually. A “cocrystal” is distinct from a “salt,” which is made up of charged-balanced charged species. The species making up a cocrystal typically are linked by hydrogen bonding and other non- covalent and non-ionic interactions. Thus, a pharmaceutical cocrystal of a drug typically comprises the drug and one or more coformers. Cocrystals of vorasidenib (e.g. , cocrystals of vorasidenib and citric acid) have been described in U.S. Publication No. 2021 / 0198234 Al.

[0106] In some embodiments, vorasidenib is administered in non-salt form (i.e., free base form). In some embodiments, vorasidenib is administered as a cocrystal (e.g., a cocrystal with citric acid). In some embodiments, vorasidenib is administered in the form of a pharmaceutically acceptable salt.

[0107] Vorasidenib may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form (“Isotopologues”), including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and the like. For example, vorasidenib is enriched in a specific isotopic form of H, C and / or O by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.DNA Demethylating Agents

[0108] In one embodiment, the methods provided herein comprise administration or co-administration of one or more DNA demethylating agents. In one embodiment, the DNA demethylating agents are cytidine analogs. In certain embodiments, the cytidine analog is azacitidine or 5 -aza-2’ -deoxy cytidine (decitabine). In certain embodiments, the cytidine analog is azacitidine. In certain embodiments, the cytidine analog is 5 -aza-2 ’-deoxy cytidine (decitabine). In certain embodiments, the cytidine analog is, for example: 1-J3-D- arabinofuranosylcytosine (Cytarabine or ara-C); pseudoiso-cytidine (psi ICR); 5-fluoro-2’- deoxycytidine (FCdR); 2 ’-deoxy-2’, 2 ’-difluorocytidine (Gemcitabine); 5 -aza-2 ’-deoxy-2 ’,2’- difluorocytidine; 5 -aza-2 ’ -deoxy-2 ’ -fluorocytidine ; l-P-D-ribofuranosyl-2( I / / )-py rim idinonc (Zebularine); 2’, 3 ’-dideoxy-5-fluoro-3’ -thiacytidine (Emtriva); 2 ’-cyclocytidine (Ancitabine); l-P-D-arabinofuranosyl-5-azacytosine (Fazarabine or ara-AC); 6-azacitidine (6- aza-CR); 5,6-dihydro-5-azacitidine (dH-aza-CR); N4-pentyloxy-carbonyl-5’-deoxy-5- fluorocytidine (Capecitabine); N4-octadecyl-cytarabine; or elaidic acid cytarabine. In certainembodiments, the cytidine analogs include any compound which is structurally related to cytidine or deoxycytidine and functionally mimics and / or antagonizes the action of cytidine or deoxy cytidine.

[0109] In certain embodiments, exemplary cytidine analogs have the structures provided below:Azacitidine Decitabine Cytarabine (Ara-C)Gemcitabine Zebularine FCdR Emtriva6-Azacytidine 5-6-Dihydro-5-azacytidine

[0110] Cytidine analogs for use in the methods provided herein may be prepared using synthetic methods and procedures referenced herein or otherwise available in the literature. For example, particular methods for synthesizing azacitidine and decitabine are disclosed, e.g., in U.S. Patent No. 7,038,038 and references discussed therein, each of which is incorporated herein by reference. Other cytidine analogs for use in the methods providedherein may be prepared, e.g., using procedures known in the art, or may be purchased from a commercial source. In one embodiment, the cytidine analogs for use in the methods provided herein may be prepared in a particular solid form (e.g., amorphous or crystalline form). See, e.g., U.S. Patent 6,887,855, issued May 8, 2005 and U.S. Patent 6,943,249, issued September 13, 2005, both of which are incorporated herein by reference in their entireties.

[0111] In one embodiment, the cytidine analog used in the methods provided herein is a free base, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the free base or the pharmaceutically acceptable salt or solvate is a solid. In another embodiment, the free base or the pharmaceutically acceptable salt or solvate is a solid in an amorphous form. In yet another embodiment, the free base or the pharmaceutically acceptable salt or solvate is a solid in a crystalline form. For example, particular embodiments provide azacitidine and decitabine in solid forms, which can be prepared, for example, according to the methods described in U.S. Patent Nos. 6,887,855; 6,943,249; 7,038,038; 7,078,518; 7,192,781; 7,772,199 and U.S. Patent Application Publication Nos. 2005 / 027675, each of which is incorporated by reference herein in their entireties. In other embodiments, azacitidine and decitabine in solid forms can be prepared using other methods known in the art.

[0112] In one embodiment, cytidine analog used in the methods provided herein is a pharmaceutically acceptable salt of the cytidine analog, which includes, but is not limited to, acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate (besylate), bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, 1,2-ethanedisulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methane sulfonate (mesylate), 2-naphthalenesulfonate (napsylate), nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, or undecanoate salts.

[0113] Azacitidine is 4-amino- l-P-D-ribofuranozyl-s-triazin-2( l / / )-onc. also known as VID AZA® (Celgene Corporation). Its empirical formula is CsHnNrOs. the molecular weight is 244. Azacitidine is a white to off-white solid that is insoluble in acetone, ethanol and methyl ketone; slightly soluble in ethanol / water (50 / 50), propylene glycol and polyethylene glycol; sparingly soluble in water, water-saturated octanol, 5% dextrose inwater, N-methyl-2 -pyrrolidone, normal saline and 5% Tween 80 in water, and soluble in dimethylsulfoxide (DMSO).

[0114] VIDAZA® is approved in the US for the treatment of different FAB MyeloDysplastic Syndrome (MDS) subtypes in adult patients. It is also approved for the treatment of pediatric patients aged one month and older with newly diagnosed Juvenile Myelomonocytic Leukemia (JMML). In Europe, it is approved for the treatment of certain types of MDS, Chronic MyeloMonocytic Leukemia (CMML) and certain types of Acute Myeloid Leukemia (AML). It is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or reconstitution as a solution with further dilution for intravenous infusion. Vials of VIDAZA® contain 100 mg of azacitidine as a sterile lyophilized powder. The approved dosing schedule is subcutaneous injection on seven consecutive days of a 28- day treatment cycle.

[0115] Oral azacitidine (ONUREG®) is approved in the US for continued treatment of adult patients with AML who achieved first complete remission. In Europe; it is indicated at maintenance therapy in adult patients with AML who achieved complete remission or complete remission with incomplete blood count recovery. It is supplied in 200 mg and 300 mg film-coated tablets. In one embodiment, the dose used in patients is 300 mg once daily based on days 1 through 14 of the 28-day treatment cycle.

[0116] Decitabine is 4-amino-l-(2-deoxy-P-D-erythro-pentofuranosyl)-l,3,5-triazin- 2(U7)one, also known as DACOGEN®. Its empirical formula is CsHnN-iOi. the molecular weight is 228.21. Decitabine is a fine, white to almost white powder that is slightly soluble in ethanol / water (50 / 50), methanol / water (50 / 50) and methanol; sparingly soluble in water, and soluble in dimethylsulfoxide (DMSO).

[0117] DACOGEN™ is approved for treatment in patients with myelodysplastic syndromes. It is supplied in a clear colorless glass vial as white sterile lyophilized powder for injection. Each 20 mL, as a single dose, glass vial contains 50 mg decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate) and 11.6 mg sodium hydrochloride.Compositions and routes of administration

[0118] In one embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a mutant IDH1 / IDH2 dual inhibitor and a DNA demethylating agent. In one embodiment, the mutant IDH1 / IDH2 dual inhibitor is vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof.

[0119] In one embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and azacitidine.

[0120] In one embodiment, vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and azacitidine are formulated as one composition. In another embodiment, vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof and azacitidine are formulated as separate compositions.

[0121] In another embodiment, such pharmaceutically acceptable compositions further comprise additional therapeutic agents in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein.

[0122] The pharmaceutical compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0123] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their poly oxyethylated versions. These oil solutions or suspensions may also contain a long -chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such asemulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0124] The pharmaceutical compositions may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase and combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0125] The pharmaceutical compositions may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compound of formula (I), or a pharmaceutically acceptable salt thereof, with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[0126] The pharmaceutical compositions may be administered topically to the skin. The pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of one aspect of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of one aspect of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in one aspect of this invention.

[0127] The pharmaceutical compositions may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art ofpharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0128] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound. In one embodiment, provided are dosage forms comprising the pharmaceutical compositions described herein. In one embodiment, the dosage form (e.g., the dosage form for vorasidenib) is an oral dosage form. In one embodiment, the dosage form for vorasidenib is a tablet or a capsule. In one embodiment, the dosage form for vorasidenib is a tablet. In one embodiment the dosage form for vorasidenib is a capsule.

[0129] In one embodiment, the dosage form for vorasidenib comprises between about 1 mg and about 500 mg of vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 200 mg vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 150 mg vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 100 mg vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 90 mg vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 80 mg vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 70 mg vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 60 mg vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 50 mg vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 40 mg vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 30 mg vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 20 mg vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 10 mg vorasidenib. In one embodiment, the dosage form comprises between about 1 mg and about 5 mg vorasidenib. In one embodiment, the dosage form comprises between about 5 mg and about 200 mg vorasidenib. In one embodiment, the dosage form comprises between about 5 mg and about 150 mg vorasidenib. In one embodiment, the dosage form comprises between about 5 mg and about 100 mg vorasidenib. In one embodiment, the dosage form comprises between about 5 mg and about 90 mg vorasidenib. In one embodiment, the dosage form comprises between about 5 mg and about 80 mg vorasidenib. In one embodiment, the dosage form comprises betweenabout 5 mg and about 70 mg vorasidenib. In one embodiment, the dosage form comprises between about 5 mg and about 60 mg vorasidenib. In one embodiment, the dosage form comprises between about 5 mg and about 50 mg vorasidenib. In one embodiment, the dosage form comprises between about 5 mg and about 40 mg vorasidenib. In one embodiment, the dosage form comprises between about 5 mg and about 30 mg vorasidenib. In one embodiment, the dosage form comprises between about 5 mg and about 20 mg vorasidenib. In one embodiment, the dosage form comprises between about 5 mg and about 10 mg vorasidenib. In one embodiment, the dosage form comprises between about 10 mg and about 200 mg vorasidenib. In one embodiment, the dosage form comprises between about 10 mg and about 150 mg vorasidenib. In one embodiment, the dosage form comprises between about 10 mg and about 100 mg vorasidenib. In one embodiment, the dosage form comprises between about 10 mg and about 90 mg vorasidenib. In one embodiment, the dosage form comprises between about 10 mg and about 80 mg vorasidenib. In one embodiment, the dosage form comprises between about 10 mg and about 70 mg vorasidenib. In one embodiment, the dosage form comprises between about 10 mg and about 60 mg vorasidenib. In one embodiment, the dosage form comprises between about 10 mg and about 50 mg vorasidenib. In one embodiment, the dosage form comprises between about 10 mg and about 40 mg vorasidenib. In one embodiment, the dosage form comprises between about 10 mg and about 30 mg vorasidenib. In one embodiment, the dosage form comprises between about 10 mg and about 20 mg vorasidenib. In one embodiment, the dosage form comprises between about 20 mg and about 200 mg vorasidenib. In one embodiment, the dosage form comprises between about 20 mg and about 150 mg vorasidenib. In one embodiment, the dosage form comprises between about 20 mg and about 100 mg vorasidenib. In one embodiment, the dosage form comprises between about 20 mg and about 90 mg vorasidenib. In one embodiment, the dosage form comprises between about 20 mg and about 80 mg vorasidenib. In one embodiment, the dosage form comprises between about 20 mg and about 70 mg vorasidenib. In one embodiment, the dosage form comprises between about 20 mg and about 60 mg vorasidenib. In one embodiment, the dosage form comprises between about 20 mg and about 50 mg vorasidenib. In one embodiment, the dosage form comprises between about 20 mg and about 40 mg vorasidenib. In one embodiment, the dosage form comprises between about 20 mg and about 30 mg vorasidenib. In one embodiment, the dosage form comprises between about 30 mg and about 200 mg vorasidenib. In one embodiment, the dosage form comprises between about 30 mg and about 150 mg vorasidenib. In one embodiment, the dosage form comprises between about 30 mg and about100 mg vorasidenib. In one embodiment, the dosage form comprises between about 30 mg and about 90 mg vorasidenib. In one embodiment, the dosage form comprises between about 30 mg and about 80 mg vorasidenib. In one embodiment, the dosage form comprises between about 30 mg and about 70 mg vorasidenib. In one embodiment, the dosage form comprises between about 30 mg and about 60 mg vorasidenib. In one embodiment, the dosage form comprises between about 30 mg and about 50 mg vorasidenib. In one embodiment, the dosage form comprises between about 30 mg and about 40 mg vorasidenib. In one embodiment, the dosage form comprises between about 40 mg and about 200 mg vorasidenib. In one embodiment, the dosage form comprises between about 40 mg and about 150 mg vorasidenib. In one embodiment, the dosage form comprises between about 40 mg and about 100 mg vorasidenib. In one embodiment, the dosage form comprises between about 40 mg and about 90 mg vorasidenib. In one embodiment, the dosage form comprises between about 40 mg and about 80 mg vorasidenib. In one embodiment, the dosage form comprises between about 40 mg and about 70 mg vorasidenib. In one embodiment, the dosage form comprises between about 40 mg and about 60 mg vorasidenib. In one embodiment, the dosage form comprises between about 40 mg and about 50 mg vorasidenib. In one embodiment, the dosage form comprises between about 50 mg and about 200 mg vorasidenib. In one embodiment, the dosage form comprises between about 50 mg and about 150 mg vorasidenib. In one embodiment, the dosage form comprises between about 50 mg and about 100 mg vorasidenib. In one embodiment, the dosage form comprises between about 50 mg and about 90 mg vorasidenib. In one embodiment, the dosage form comprises between about 50 mg and about 80 mg vorasidenib. In one embodiment, the dosage form comprises between about 50 mg and about 70 mg vorasidenib. In one embodiment, the dosage form comprises between about 50 mg and about 60 mg vorasidenib. In one embodiment, the dosage form comprises between about 60 mg and about 200 mg vorasidenib. In one embodiment, the dosage form comprises between about 60 mg and about 150 mg vorasidenib. In one embodiment, the dosage form comprises between about 60 mg and about 100 mg vorasidenib. In one embodiment, the dosage form comprises between about 60 mg and about 90 mg vorasidenib. In one embodiment, the dosage form comprises between about 60 mg and about 80 mg vorasidenib. In one embodiment, the dosage form comprises between about 60 mg and about 70 mg vorasidenib. In one embodiment, the dosage form comprises between about 70 mg and about 200 mg vorasidenib. In one embodiment, the dosage form comprises between about 70 mg and about 150 mg vorasidenib. In one embodiment, the dosage form comprises between about 70 mg and about100 mg vorasidenib. In one embodiment, the dosage form comprises between about 70 mg and about 90 mg vorasidenib. In one embodiment, the dosage form comprises between about 70 mg and about 80 mg vorasidenib. In one embodiment, the dosage form comprises between about 80 mg and about 200 mg vorasidenib. In one embodiment, the dosage form comprises between about 80 mg and about 150 mg vorasidenib. In one embodiment, the dosage form comprises between about 80 mg and about 100 mg vorasidenib. In one embodiment, the dosage form comprises between about 80 mg and about 90 mg vorasidenib. In one embodiment, the dosage form comprises between about 90 mg and about 200 mg vorasidenib. In one embodiment, the dosage form comprises between about 90 mg and about 150 mg vorasidenib. In one embodiment, the dosage form comprises between about 90 mg and about 100 mg vorasidenib. In one embodiment, the dosage form comprises between about 100 mg and about 200 mg vorasidenib. In one embodiment, the dosage form comprises between about 100 mg and about 150 mg vorasidenib.

[0130] In one embodiment, the dosage form comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg vorasidenib. In one embodiment, the dosage form comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg vorasidenib. In one embodiment, the dosage form comprises about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg vorasidenib. In one embodiment, the dosage form comprises about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg or about 50 mg vorasidenib.

[0131] In one embodiment, the dosage form comprises about 1 mg vorasidenib. In one embodiment, the dosage form comprises about 2 mg vorasidenib. In one embodiment, the dosage form comprises about 3 mg vorasidenib. In one embodiment, the dosage form comprises about 4 mg vorasidenib. In one embodiment, the dosage form comprises about 5 mg vorasidenib. In one embodiment, the dosage form comprises about 6 mg vorasidenib. Inone embodiment, the dosage form comprises about 7 mg vorasidenib. In one embodiment, the dosage form comprises about 8 mg vorasidenib. In one embodiment, the dosage form comprises about 9 mg vorasidenib. In one embodiment, the dosage form comprises about 10 mg vorasidenib. In one embodiment, the dosage form comprises about 15 mg vorasidenib. In one embodiment, the dosage form comprises about 20 mg vorasidenib. In one embodiment, the dosage form comprises about 25 mg vorasidenib. In one embodiment, the dosage form comprises about 30 mg vorasidenib. In one embodiment, the dosage form comprises about 35 mg vorasidenib. In one embodiment, the dosage form comprises about 40 mg vorasidenib. In one embodiment, the dosage form comprises about 45 mg vorasidenib. In one embodiment, the dosage form comprises about 50 mg vorasidenib. In one embodiment, the dosage form comprises about 55 mg vorasidenib. In one embodiment, the dosage form comprises about 60 mg vorasidenib. In one embodiment, the dosage form comprises about 65 mg vorasidenib. In one embodiment, the dosage form comprises about 70 mg vorasidenib. In one embodiment, the dosage form comprises about 75 mg vorasidenib. In one embodiment, the dosage form comprises about 80 mg vorasidenib. In one embodiment, the dosage form comprises about 85 mg vorasidenib. In one embodiment, the dosage form comprises about 90 mg vorasidenib. In one embodiment, the dosage form comprises about 95 mg vorasidenib. In one embodiment, the dosage form comprises about 100 mg vorasidenib. In one embodiment, the dosage form comprises about 110 mg vorasidenib. In one embodiment, the dosage form comprises about 120 mg vorasidenib. In one embodiment, the dosage form comprises about 130 mg vorasidenib. In one embodiment, the dosage form comprises about 140 mg vorasidenib. In one embodiment, the dosage form comprises about 150 mg vorasidenib. In one embodiment, the dosage form comprises about 160 mg vorasidenib. In one embodiment, the dosage form comprises about 170 mg vorasidenib. In one embodiment, the dosage form comprises about 180 mg vorasidenib. In one embodiment, the dosage form comprises about 190 mg vorasidenib. In one embodiment, the dosage form comprises about 200 mg vorasidenib. In one embodiment, the dosage form comprises about 250 mg vorasidenib. In one embodiment, the dosage form comprises about 300 mg vorasidenib. In one embodiment, the dosage form comprises about 350 mg vorasidenib. In one embodiment, the dosage form comprises about 400 mg vorasidenib. In one embodiment, the dosage form comprises about 450 mg vorasidenib. In one embodiment, the dosage form comprises about 500 mg vorasidenib.

[0132] In one embodiment, the amount of azacitidine in the pharmaceutical composition or dosage form provided herein may range, e.g., between about 5 mg and about 2,000 mg. Inone embodiment, the range is between about 10 mg and about 2,000 mg. In one embodiment, the range is between about 20 mg and about 2,000 mg. In one embodiment, the range is between about 50 mg and about 1,000 mg. In one embodiment, the range is between about 50 mg and about 500 mg. In one embodiment, the range is between about 50 mg and about 250 mg. In one embodiment, the range is between about 100 mg and about 500 mg. In one embodiment, the range is between about 150 mg and about 500 mg. In one embodiment, the range is between about 150 mg and about 250 mg. In certain embodiments, the particular amount is about 10 mg. In one embodiment, the particular amount is about 20 mg. In one embodiment, the particular amount is about 50 mg. In one embodiment, the particular amount is about 75 mg. In one embodiment, the particular amount is about 100 mg. In one embodiment, the particular amount is about 120 mg. In one embodiment, the particular amount is about 150 mg. In one embodiment, the particular amount is about 200 mg. In one embodiment, the particular amount is about 250 mg. In one embodiment, the particular amount is about 300 mg. In one embodiment, the particular amount is about 350 mg. In one embodiment, the particular amount is about 400 mg. In one embodiment, the particular amount is about 450 mg. In one embodiment, the particular amount is about 500 mg. In one embodiment, the particular amount is about 600 mg. In one embodiment, the particular amount is about 700 mg. In one embodiment, the particular amount is about 800 mg. In one embodiment, the particular amount is about 900 mg. In one embodiment, the particular amount is about 1,000 mg. In one embodiment, the particular amount is about 1,200 mg. In one embodiment, the particular amount is about 1,500 mg. In certain embodiments, the particular amount is up to about 10 mg. In one embodiment, the particular amount is up to about 20 mg. In one embodiment, the particular amount is up to about 50 mg. In one embodiment, the particular amount is up to about 75 mg. In one embodiment, the particular amount is up to about 100 mg. In one embodiment, the particular amount is up to about 120 mg. In one embodiment, the particular amount is up to about 150 mg. In one embodiment, the particular amount is up to about 200 mg. In one embodiment, the particular amount is up to about 250 mg. In one embodiment, the particular amount is up to about 300 mg. In one embodiment, the particular amount is up to about 350 mg. In one embodiment, the particular amount is up to about 400 mg. In one embodiment, the particular amount is up to about 450 mg. In one embodiment, the particular amount is up to about 500 mg. In one embodiment, the particular amount is up to about 600 mg. In one embodiment, the particular amount is up to about 700 mg. In one embodiment, the particular amount is up to about 800 mg. In one embodiment, the particular amount is up to about 900 mg. In one embodiment, the particularamount is up to about 1,000 mg. In one embodiment, the particular amount is up to about 1,200 mg. In one embodiment, the particular amount is up to about 1,500 mg.

[0133] In one embodiment, the dosage form is a combination comprising vorasidenib and azacitidine.DosageVorasidenib

[0134] Vorasidenib can be administered at a dose between about 1 mg / day and about 1000 mg / day. Vorasidenib can be administered at a dose between about 1 mg and about 500 mg one, two, three or four times a day. In one embodiment, vorasidenib is administered one time a day (once a day, or QD). In one embodiment, vorasidenib is administered two times a day (twice daily, or BID). In one embodiment, vorasidenib is administered three times a day (TID). In one embodiment, vorasidenib is administered four times a day (QID).

[0135] In one embodiment, the dose is between about 1 mg / day and about 500 mg / day. In one embodiment, the dose is between about 1 mg / day and about 200 mg / day. In one embodiment, the dose is between about 1 mg / day and about 150 mg / day. In one embodiment, the dose is between about 1 mg / day and about 100 mg / day. In one embodiment, the dose is between about 1 mg / day and about 90 mg / day. In one embodiment, the dose is between about 1 mg / day and about 80 mg / day. In one embodiment, the dose is between about 1 mg / day and about 70 mg / day. In one embodiment, the dose is between about 1 mg / day and about 60 mg / day. In one embodiment, the dose is between about 1 mg / day and about 50 mg / day. In one embodiment, the dose is between about 1 mg / day and about 40 mg / day. In one embodiment, the dose is between about 1 mg / day and about 30 mg / day. In one embodiment, the dose is between about 1 mg / day and about 20 mg / day. In one embodiment, the dose is between about 1 mg / day and about 10 mg / day. In one embodiment, the dose is between about 1 mg / day and about 5 mg / day. In one embodiment, the dose is between about 5 mg / day and about 500 mg / day. In one embodiment, the dose is between about 5 mg / day and about 200 mg / day. In one embodiment, the dose is between about 5 mg / day and about 150 mg / day. In one embodiment, the dose is between about 5 mg / day and about 100 mg / day. In one embodiment, the dose is between about 5 mg / day and about 90 mg / day. In one embodiment, the dose is between about 5 mg / day and about 80 mg / day. In one embodiment, the dose is between about 5 mg / day and about 70 mg / day. Inone embodiment, the dose is between about 5 mg / day and about 60 mg / day. In one embodiment, the dose is between about 5 mg / day and about 50 mg / day. In one embodiment, the dose is between about 5 mg / day and about 40 mg / day. In one embodiment, the dose is between about 5 mg / day and about 30 mg / day. In one embodiment, the dose is between about 5 mg / day and about 20 mg / day. In one embodiment, the dose is between about 5 mg / day and about 10 mg / day. In one embodiment, the dose is between about 10 mg / day and about 500 mg / day. In one embodiment, the dose is between about 10 mg / day and about 200 mg / day. In one embodiment, the dose is between about 10 mg / day and about 150 mg / day. In one embodiment, the dose is between about 10 mg / day and about 100 mg / day. In one embodiment, the dose is between about 10 mg / day and about 90 mg / day. In one embodiment, the dose is between about 10 mg / day and about 80 mg / day. In one embodiment, the dose is between about 10 mg / day and about 70 mg / day. In one embodiment, the dose is between about 10 mg / day and about 60 mg / day. In one embodiment, the dose is between about 10 mg / day and about 50 mg / day. In one embodiment, the dose is between about 10 mg / day and about 40 mg / day. In one embodiment, the dose is between about 10 mg / day and about 30 mg / day. In one embodiment, the dose is between about 10 mg / day and about 20 mg / day. In one embodiment, the dose is between about 20 mg / day and about 500 mg / day. In one embodiment, the dose is between about 20 mg / day and about 200 mg / day. In one embodiment, the dose is between about 20 mg / day and about 150 mg / day. In one embodiment, the dose is between about 20 mg / day and about 100 mg / day. In one embodiment, the dose is between about 20 mg / day and about 90 mg / day. In one embodiment, the dose is between about 20 mg / day and about 80 mg / day. In one embodiment, the dose is between about 20 mg / day and about 70 mg / day. In one embodiment, the dose is between about 20 mg / day and about 60 mg / day. In one embodiment, the dose is between about 20 mg / day and about 50 mg / day. In one embodiment, the dose is between about 20 mg / day and about 40 mg / day. In one embodiment, the dose is between about 20 mg / day and about 30 mg / day. In one embodiment, the dose is between about 30 mg / day and about 500 mg / day. In one embodiment, the dose is between about 30 mg / day and about 200 mg / day. In one embodiment, the dose is between about 30 mg / day and about 150 mg / day. In one embodiment, the dose is between about 30 mg / day and about 100 mg / day. In one embodiment, the dose is between about 30 mg / day and about 90 mg / day. In one embodiment, the dose is between about 30 mg / day and about 80 mg / day. In oneembodiment, the dose is between about 30 mg / day and about 70 mg / day. In one embodiment, the dose is between about 30 mg / day and about 60 mg / day. In one embodiment, the dose is between about 30 mg / day and about 50 mg / day. In one embodiment, the dose is between about 30 mg / day and about 40 mg / day. In one embodiment, the dose is between about 40 mg / day and about 500 mg / day. In one embodiment, the dose is between about 40 mg / day and about 200 mg / day. In one embodiment, the dose is between about 40 mg / day and about 150 mg / day. In one embodiment, the dose is between about 40 mg / day and about 100 mg / day. In one embodiment, the dose is between about 40 mg / day and about 90 mg / day. In one embodiment, the dose is between about 40 mg / day and about 80 mg / day. In one embodiment, the dose is between about 40 mg / day and about 70 mg / day. In one embodiment, the dose is between about 40 mg / day and about 60 mg / day. In one embodiment, the dose is between about 40 mg / day and about 50 mg / day. In one embodiment, the dose is between about 50 mg / day and about 500 mg / day. In one embodiment, the dose is between about 50 mg / day and about 200 mg / day. In one embodiment, the dose is between about 50 mg / day and about 150 mg / day. In one embodiment, the dose is between about 50 mg / day and about 100 mg / day. In one embodiment, the dose is between about 50 mg / day and about 90 mg / day. In one embodiment, the dose is between about 50 mg / day and about 80 mg / day. In one embodiment, the dose is between about 50 mg / day and about 70 mg / day. In one embodiment, the dose is between about 50 mg / day and about 60 mg / day. In one embodiment, the dose is between about 60 mg / day and about 500 mg / day. In one embodiment, the dose is between about 60 mg / day and about 200 mg / day. In one embodiment, the dose is between about 60 mg / day and about 150 mg / day. In one embodiment, the dose is between about 60 mg / day and about 100 mg / day. In one embodiment, the dose is between about 60 mg / day and about 90 mg / day. In one embodiment, the dose is between about 60 mg / day and about 80 mg / day. In one embodiment, the dose is between about 60 mg / day and about 70 mg / day. In one embodiment, the dose is between about 70 mg / day and about 500 mg / day. In one embodiment, the dose is between about 70 mg / day and about 200 mg / day. In one embodiment, the dose is between about 70 mg / day and about 150 mg / day. In one embodiment, the dose is between about 70 mg / day and about 100 mg / day. In one embodiment, the dose is between about 70 mg / day and about 90 mg / day. In one embodiment, the dose is between about 70 mg / day and about 80 mg / day. In oneembodiment, the dose is between about 80 mg / day and about 500 mg / day. In one embodiment, the dose is between about 80 mg / day and about 200 mg / day. In one embodiment, the dose is between about 80 mg / day and about 150 mg / day. In one embodiment, the dose is between about 80 mg / day and about 100 mg / day. In one embodiment, the dose is between about 80 mg / day and about 90 mg / day. In one embodiment, the dose is between about 90 mg / day and about 500 mg / day. In one embodiment, the dose is between about 90 mg / day and about 200 mg / day. In one embodiment, the dose is between about 90 mg / day and about 150 mg / day. In one embodiment, the dose is between about 90 mg / day and about 100 mg / day. In one embodiment, the dose is between about 100 mg / day and about 500 mg / day. In one embodiment, the dose is between about 100 mg / day and about 200 mg / day. In one embodiment, the dose is between about 100 mg / day and about 150 mg / day. In one embodiment, the dose is about 1 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day, about 60 mg / day, about 65 mg / day, about 70 mg / day, about 75 mg / day, about 80 mg / day, about 85 mg / day, about 90 mg / day, about 95 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 130 mg / day, about 140 mg / day, about 150 mg / day, about 160 mg / day, about 170 mg / day, about 180 mg / day, about 190 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 450 mg / day, about 500 mg / day or about 1000 mg / day. In one embodiment, the dose is about 1 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day or about 10 mg / day. In one embodiment, the dose is about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day, about 60 mg / day, about 65 mg / day, about 70 mg / day, about 75 mg / day, about 80 mg / day, about 85 mg / day, about 90 mg / day, about 95 mg / day or about 100 mg / day. In one embodiment, the dose is about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day or about 50 mg / day.

[0136] In one embodiment, the dose is about 1 mg / day. In one embodiment, the dose is about 2 mg / day. In one embodiment, the dose is about 3 mg / day. In one embodiment, the dose is about 4 mg / day. In one embodiment, the dose is about 5 mg / day. In one embodiment, the dose is about 6 mg / day. In one embodiment, the dose is about 7 mg / day. Inone embodiment, the dose is about 8 mg / day. In one embodiment, the dose is about 9 mg / day. In one embodiment, the dose is about 10 mg / day. In one embodiment, the dose is about 15 mg / day. In one embodiment, the dose is about 20 mg / day. In one embodiment, the dose is about 25 mg / day. In one embodiment, the dose is about 30 mg / day. In one embodiment, the dose is about 35 mg / day. In one embodiment, the dose is about 40 mg / day. In one embodiment, the dose is about 45 mg / day. In one embodiment, the dose is about 50 mg / day. In one embodiment, the dose is about 55 mg / day. In one embodiment, the dose is about 60 mg / day. In one embodiment, the dose is about 65 mg / day. In one embodiment, the dose is about 70 mg / day. In one embodiment, the dose is about 75 mg / day. In one embodiment, the dose is about 80 mg / day. In one embodiment, the dose is about 85 mg / day. In one embodiment, the dose is about 90 mg / day. In one embodiment, the dose is about 95 mg / day. In one embodiment, the dose is about 100 mg / day. In one embodiment, the dose is about 110 mg / day. In one embodiment, the dose is about 120 mg / day. In one embodiment, the dose is about 130 mg / day. In one embodiment, the dose is about 140 mg / day. In one embodiment, the dose is about 150 mg / day. In one embodiment, the dose is about 160 mg / day. In one embodiment, the dose is about 170 mg / day. In one embodiment, the dose is about 180 mg / day. In one embodiment, the dose is about 190 mg / day. In one embodiment, the dose is about 200 mg / day. In one embodiment, the dose is about 250 mg / day. In one embodiment, the dose is about 300 mg / day. In one embodiment, the dose is about 350 mg / day. In one embodiment, the dose is about 400 mg / day. In one embodiment, the dose is about 450 mg / day. In one embodiment, the dose is about 500 mg / day. In one embodiment, the dose is about 600 mg / day. In one embodiment, the dose is about 700 mg / day. In one embodiment, the dose is about 800 mg / day. In one embodiment, the dose is about 900 mg / day. In one embodiment, the dose is about 1000 mg / day.

[0137] In one embodiment, the dose is between about 1 mg and about 200 mg once daily. In one embodiment, the dose is between about 1 mg and about 150 mg once daily. In one embodiment, the dose is between about 1 mg and about 100 mg once daily. In one embodiment, the dose is between about 1 mg and about 90 mg once daily. In one embodiment, the dose is between about 1 mg and about 80 mg once daily. In one embodiment, the dose is between about 1 mg and about 70 mg once daily. In one embodiment, the dose is between about 1 mg and about 60 mg once daily. In one embodiment, the dose is between about 1 mg and about 50 mg once daily. In one embodiment, the dose is between about 1 mg and about 40 mg once daily. In one embodiment, the dose is between about 1 mg and about 30 mg once daily. In oneembodiment, the dose is between about 1 mg and about 20 mg once daily. In one embodiment, the dose is between about 1 mg and about 10 mg once daily. In one embodiment, the dose is between about 1 mg and about 5 mg once daily. In one embodiment, the dose is between about 5 mg and about 200 mg once daily. In one embodiment, the dose is between about 5 mg and about 150 mg once daily. In one embodiment, the dose is between about 5 mg and about 100 mg once daily. In one embodiment, the dose is between about 5 mg and about 90 mg once daily, In one embodiment, the dose is between about 5 mg and about 80 mg once daily, In one embodiment, the dose is between about 5 mg and about 70 mg once daily, In one embodiment, the dose is between about 5 mg and about 60 mg once daily, In one embodiment, the dose is between about 5 mg and about 50 mg once daily, In one embodiment, the dose is between about 5 mg and about 40 mg once daily, In one embodiment, the dose is between about 5 mg and about 30 mg once daily, In one embodiment, the dose is between about 5 mg and about 20 mg once daily, In one embodiment, the dose is between about 5 mg and about 10 mg once daily. In one embodiment, the dose is between about 10 mg and about 200 mg once daily. In one embodiment, the dose is between about 10 mg and about 150 mg once daily. In one embodiment, the dose is between about 10 mg and about 100 mg once daily. In one embodiment, the dose is between about 10 mg and about 90 mg once daily, In one embodiment, the dose is between about 10 mg and about 80 mg once daily, In one embodiment, the dose is between about 10 mg and about 70 mg once daily, In one embodiment, the dose is between about 10 mg and about 60 mg once daily, In one embodiment, the dose is between about 10 mg and about 50 mg once daily, In one embodiment, the dose is between about 10 mg and about 40 mg once daily, In one embodiment, the dose is between about 10 mg and about 30 mg once daily, In one embodiment, the dose is between about 10 mg and about 20 mg once daily. In one embodiment, the dose is between about 20 mg and about 200 mg once daily. In one embodiment, the dose is between about 20 mg and about 150 mg once daily. In one embodiment, the dose is between about 20 mg and about 100 mg once daily. In one embodiment, the dose is between about 20 mg and about 90 mg once daily, In one embodiment, the dose is between about 20 mg and about 80 mg once daily, In one embodiment, the dose is between about 20 mg and about 70 mg once daily, In one embodiment, the dose is between about 20 mg and about 60 mg once daily, In one embodiment, the dose is between about 20 mg and about 50 mg once daily. In oneembodiment, the dose is between about 20 mg and about 40 mg once daily. In one embodiment, the dose is between about 20 mg and about 30 mg once daily. In one embodiment, the dose is between about 30 mg and about 200 mg once daily. In one embodiment, the dose is between about 30 mg and about 150 mg once daily. In one embodiment, the dose is between about 30 mg and about 100 mg once daily. In one embodiment, the dose is between about 30 mg and about 90 mg once daily, In one embodiment, the dose is between about 30 mg and about 80 mg once daily, In one embodiment, the dose is between about 30 mg and about 70 mg once daily, In one embodiment, the dose is between about 30 mg and about 60 mg once daily, In one embodiment, the dose is between about 30 mg and about 50 mg once daily, In one embodiment, the dose is between about 30 mg and about 40 mg once daily. In one embodiment, the dose is between about 40 mg and about 200 mg once daily. In one embodiment, the dose is between about 40 mg and about 150 mg once daily. In one embodiment, the dose is between about 40 mg and about 100 mg once daily. In one embodiment, the dose is between about 40 mg and about 90 mg once daily, In one embodiment, the dose is between about 40 mg and about 80 mg once daily, In one embodiment, the dose is between about 40 mg and about 70 mg once daily, In one embodiment, the dose is between about 40 mg and about 60 mg once daily, In one embodiment, the dose is between about 40 mg and about 50 mg once daily. In one embodiment, the dose is between about 50 mg and about 200 mg once daily. In one embodiment, the dose is between about 50 mg and about 150 mg once daily. In one embodiment, the dose is between about 50 mg and about 100 mg once daily. In one embodiment, the dose is between about 50 mg and about 90 mg once daily, In one embodiment, the dose is between about 50 mg and about 80 mg once daily, In one embodiment, the dose is between about 50 mg and about 70 mg once daily, In one embodiment, the dose is between about 50 mg and about 60 mg once daily. In one embodiment, the dose is between about 60 mg and about 200 mg once daily. In one embodiment, the dose is between about 60 mg and about 150 mg once daily. In one embodiment, the dose is between about 60 mg and about 100 mg once daily. In one embodiment, the dose is between about 60 mg and about 90 mg once daily, In one embodiment, the dose is between about 60 mg and about 80 mg once daily, In one embodiment, the dose is between about 60 mg and about 70 mg once daily. In one embodiment, the dose is between about 70 mg and about 200 mg once daily. In one embodiment, the dose is between about 70 mg and about 150 mg once daily. In oneembodiment, the dose is between about 70 mg and about 100 mg once daily. In one embodiment, the dose is between about 70 mg and about 90 mg once daily. In one embodiment, the dose is between about 70 mg and about 80 mg once daily. In one embodiment, the dose is between about 80 mg and about 200 mg once daily. In one embodiment, the dose is between about 80 mg and about 150 mg once daily. In one embodiment, the dose is between about 80 mg and about 100 mg once daily. In one embodiment, the dose is between about 80 mg and about 90 mg once daily. In one embodiment, the dose is between about 90 mg and about 200 mg once daily. In one embodiment, the dose is between about 90 mg and about 150 mg once daily. In one embodiment, the dose is between about 90 mg and about 100 mg once daily. In one embodiment, the dose is between about 100 mg and about 200 mg once daily. In one embodiment, the dose is between about 100 mg and about 150 mg once daily. In one embodiment, the dose is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg once daily. In one embodiment, the dose is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg once daily. In one embodiment, the dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg once daily. In one embodiment, the dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg or about 50 mg once daily.

[0138] In one embodiment, the dose is about 1 mg once daily. In one embodiment, the dose is about 2 mg once daily. In one embodiment, the dose is about 3 mg once daily. In one embodiment, the dose is about 4 mg once daily. In one embodiment, the dose is about 5 mg once daily. In one embodiment, the dose is about 6 mg once daily. In one embodiment, the dose is about 7 mg once daily. In one embodiment, the dose is about 8 mg once daily. In one embodiment, the dose is about 9 mg once daily. In one embodiment, the dose is about 10 mg once daily. In one embodiment, the dose is about 15 mg once daily. In one embodiment, thedose is about 20 mg once daily. In one embodiment, the dose is about 25 mg once daily. In one embodiment, the dose is about 30 mg once daily. In one embodiment, the dose is about 35 mg once daily. In one embodiment, the dose is about 40 mg once daily. In one embodiment, the dose is about 45 mg once daily. In one embodiment, the dose is about 50 mg once daily. In one embodiment, the dose is about 55 mg once daily. In one embodiment, the dose is about 60 mg once daily. In one embodiment, the dose is about 65 mg once daily. In one embodiment, the dose is about 70 mg once daily. In one embodiment, the dose is about 75 mg once daily. In one embodiment, the dose is about 80 mg once daily. In one embodiment, the dose is about 85 mg once daily. In one embodiment, the dose is about 90 mg once daily. In one embodiment, the dose is about 95 mg once daily. In one embodiment, the dose is about 100 mg once daily. In one embodiment, the dose is about 110 mg once daily. In one embodiment, the dose is about 120 mg once daily. In one embodiment, the dose is about 130 mg once daily. In one embodiment, the dose is about 140 mg once daily. In one embodiment, the dose is about 150 mg once daily. In one embodiment, the dose is about 160 mg once daily. In one embodiment, the dose is about 170 mg once daily. In one embodiment, the dose is about 180 mg once daily. In one embodiment, the dose is about 190 mg once daily. In one embodiment, the dose is about 200 mg once daily. In one embodiment, the dose is about 250 mg once daily. In one embodiment, the dose is about 300 mg once daily. In one embodiment, the dose is about 350 mg once daily. In one embodiment, the dose is about 400 mg once daily. In one embodiment, the dose is about 450 mg once daily. In one embodiment, the dose is about 500 mg once daily.

[0139] In one embodiment, the dose is between about 1 mg and about 200 mg twice daily. In one embodiment, the dose is between about 1 mg and about 150 mg twice daily. In one embodiment, the dose is between about 1 mg and about 100 mg twice daily. In one embodiment, the dose is between about 1 mg and about 90 mg twice daily. In one embodiment, the dose is between about 1 mg and about 80 mg twice daily. In one embodiment, the dose is between about 1 mg and about 70 mg twice daily. In one embodiment, the dose is between about 1 mg and about 60 mg twice daily. In one embodiment, the dose is between about 1 mg and about 50 mg twice daily. In one embodiment, the dose is between about 1 mg and about 40 mg twice daily. In one embodiment, the dose is between about 1 mg and about 30 mg twice daily. In one embodiment, the dose is between about 1 mg and about 20 mg twice daily. In one embodiment, the dose is between about 1 mg and about 10 mg twice daily. In one embodiment, the dose is between about 1 mg and about 5 mg twice daily. In oneembodiment, the dose is between about 5 mg and about 200 mg twice daily. In one embodiment, the dose is between about 5 mg and about 150 mg twice daily. In one embodiment, the dose is between about 5 mg and about 100 mg twice daily. In one embodiment, the dose is between about 5 mg and about 90 mg twice daily. In one embodiment, the dose is between about 5 mg and about 80 mg twice daily. In one embodiment, the dose is between about 5 mg and about 70 mg twice daily. In one embodiment, the dose is between about 5 mg and about 60 mg twice daily. In one embodiment, the dose is between about 5 mg and about 50 mg twice daily. In one embodiment, the dose is between about 5 mg and about 40 mg twice daily. In one embodiment, the dose is between about 5 mg and about 30 mg twice daily. In one embodiment, the dose is between about 5 mg and about 20 mg twice daily. In one embodiment, the dose is between about 5 mg and about 10 mg twice daily. In one embodiment, the dose is between about 10 mg and about 200 mg twice daily. In one embodiment, the dose is between about 10 mg and about 150 mg twice daily. In one embodiment, the dose is between about 10 mg and about 100 mg twice daily. In one embodiment, the dose is between about 10 mg and about 90 mg twice daily. In one embodiment, the dose is between about 10 mg and about 80 mg twice daily. In one embodiment, the dose is between about 10 mg and about 70 mg twice daily. In one embodiment, the dose is between about 10 mg and about 60 mg twice daily. In one embodiment, the dose is between about 10 mg and about 50 mg twice daily. In one embodiment, the dose is between about 10 mg and about 40 mg twice daily. In one embodiment, the dose is between about 10 mg and about 30 mg twice daily. In one embodiment, the dose is between about 10 mg and about 20 mg twice daily. In one embodiment, the dose is between about 20 mg and about 200 mg twice daily. In one embodiment, the dose is between about 20 mg and about 150 mg twice daily. In one embodiment, the dose is between about 20 mg and about 100 mg twice daily. In one embodiment, the dose is between about 20 mg and about 90 mg twice daily. In one embodiment, the dose is between about 20 mg and about 80 mg twice daily. In one embodiment, the dose is between about 20 mg and about 70 mg twice daily. In one embodiment, the dose is between about 20 mg and about 60 mg twice daily. In one embodiment, the dose is between about 20 mg and about 50 mg twice daily. In one embodiment, the dose is between about 20 mg and about 40 mg twice daily. In one embodiment, the dose is between about 20 mg and about 30 mg twice daily. In one embodiment, the dose is between about 30 mg and about 200 mg twice daily. In oneembodiment, the dose is between about 30 mg and about 150 mg twice daily. In one embodiment, the dose is between about 30 mg and about 100 mg twice daily. In one embodiment, the dose is between about 30 mg and about 90 mg twice daily. In one embodiment, the dose is between about 30 mg and about 80 mg twice daily. In one embodiment, the dose is between about 30 mg and about 70 mg twice daily. In one embodiment, the dose is between about 30 mg and about 60 mg twice daily. In one embodiment, the dose is between about 30 mg and about 50 mg twice daily. In one embodiment, the dose is between about 30 mg and about 40 mg twice daily. In one embodiment, the dose is between about 40 mg and about 200 mg twice daily. In one embodiment, the dose is between about 40 mg and about 150 mg twice daily. In one embodiment, the dose is between about 40 mg and about 100 mg twice daily. In one embodiment, the dose is between about 40 mg and about 90 mg twice daily. In one embodiment, the dose is between about 40 mg and about 80 mg twice daily. In one embodiment, the dose is between about 40 mg and about 70 mg twice daily. In one embodiment, the dose is between about 40 mg and about 60 mg twice daily. In one embodiment, the dose is between about 40 mg and about 50 mg twice daily. In one embodiment, the dose is between about 50 mg and about 200 mg twice daily. In one embodiment, the dose is between about 50 mg and about 150 mg twice daily. In one embodiment, the dose is between about 50 mg and about 100 mg twice daily. In one embodiment, the dose is between about 50 mg and about 90 mg twice daily. In one embodiment, the dose is between about 50 mg and about 80 mg twice daily. In one embodiment, the dose is between about 50 mg and about 70 mg twice daily. In one embodiment, the dose is between about 50 mg and about 60 mg twice daily. In one embodiment, the dose is between about 60 mg and about 200 mg twice daily. In one embodiment, the dose is between about 60 mg and about 150 mg twice daily. In one embodiment, the dose is between about 60 mg and about 100 mg twice daily. In one embodiment, the dose is between about 60 mg and about 90 mg twice daily. In one embodiment, the dose is between about 60 mg and about 80 mg twice daily. In one embodiment, the dose is between about 60 mg and about 70 mg twice daily. In one embodiment, the dose is between about 70 mg and about 200 mg twice daily. In one embodiment, the dose is between about 70 mg and about 150 mg twice daily. In one embodiment, the dose is between about 70 mg and about 100 mg twice daily. In one embodiment, the dose is between about 70 mg and about 90 mg twice daily. In one embodiment, the dose is between about 70 mg and about 80 mg twice daily. In oneembodiment, the dose is between about 80 mg and about 200 mg twice daily. In one embodiment, the dose is between about 80 mg and about 150 mg twice daily. In one embodiment, the dose is between about 80 mg and about 100 mg twice daily. In one embodiment, the dose is between about 80 mg and about 90 mg twice daily. In one embodiment, the dose is between about 90 mg and about 200 mg twice daily. In one embodiment, the dose is between about 90 mg and about 150 mg twice daily. In one embodiment, the dose is between about 90 mg and about 100 mg twice daily. In one embodiment, the dose is between about 100 mg and about 200 mg twice daily. In one embodiment, the dose is between about 100 mg and about 150 mg twice daily. In one embodiment, the dose is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg twice daily. In one embodiment, the dose is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg twice daily. In one embodiment, the dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg twice daily. In one embodiment, the dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg or about 50 mg twice daily.In one embodiment, the dose is about 1 mg twice daily. In one embodiment, the dose is about 2 mg twice daily. In one embodiment, the dose is about 3 mg twice daily. In one embodiment, the dose is about 4 mg twice daily. In one embodiment, the dose is about 5 mg twice daily. In one embodiment, the dose is about 6 mg twice daily. In one embodiment, the dose is about 7 mg twice daily. In one embodiment, the dose is about 8 mg twice daily. In one embodiment, the dose is about 9 mg twice daily. In one embodiment, the dose is about 10 mg twice daily. In one embodiment, the dose is about 15 mg twice daily. In one embodiment, the dose is about 20 mg twice daily. In one embodiment, the dose is about 25 mg twice daily. In one embodiment, the dose is about 30 mg twice daily. In one embodiment, the dose is about 35 mg twice daily. In one embodiment, the dose is about 40mg twice daily. In one embodiment, the dose is about 45 mg twice daily. In one embodiment, the dose is about 50 mg twice daily. In one embodiment, the dose is about 55 mg twice daily. In one embodiment, the dose is about 60 mg twice daily. In one embodiment, the dose is about 65 mg twice daily. In one embodiment, the dose is about 70 mg twice daily. In one embodiment, the dose is about 75 mg twice daily. In one embodiment, the dose is about 80 mg twice daily. In one embodiment, the dose is about 85 mg twice daily. In one embodiment, the dose is about 90 mg twice daily. In one embodiment, the dose is about 95 mg twice daily. In one embodiment, the dose is about 100 mg twice daily. In one embodiment, the dose is about 110 mg twice daily. In one embodiment, the dose is about 120 mg twice daily. In one embodiment, the dose is about 130 mg twice daily. In one embodiment, the dose is about 140 mg twice daily. In one embodiment, the dose is about 150 mg twice daily. In one embodiment, the dose is about 160 mg twice daily. In one embodiment, the dose is about 170 mg twice daily. In one embodiment, the dose is about 180 mg twice daily. In one embodiment, the dose is about 190 mg twice daily. In one embodiment, the dose is about 200 mg twice daily. In one embodiment, the dose is about 250 mg twice daily. In one embodiment, the dose is about 300 mg twice daily. In one embodiment, the dose is about 350 mg twice daily. In one embodiment, the dose is about 400 mg twice daily. In one embodiment, the dose is about 450 mg twice daily. In one embodiment, the dose is about 500 mg twice daily.Azacitidine

[0140] In one embodiment, depending on the disease to be treated and the subject’s condition, azacitidine may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. Azacitidine may be formulated, alone or together with vorasidenib and / or one or more active agent(s), in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.

[0141] In one embodiment, azacitidine is administered by, e.g, intravenous (IV), subcutaneous (SC) or oral routes. Certain embodiments herein provide co-administration of azacitidine with vorasidenib and / or one or more additional active agents to provide a synergistic therapeutic effect in subjects in need thereof. The co-administered active agent(s) may be cancer therapeutic agents, as described herein. In certain embodiments, the coadministered active agent(s) may be dual inhibitors of IDH1 and IDH2. In certainembodiments, the co-administered agent(s) may be dosed, e.g., orally or by injection (e.g., IV or SC).

[0142] In certain embodiments, treatment cycles comprise multiple doses of azacitidine administered to a subject in need thereof over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or greater than 14 days), optionally followed by treatment dosing holidays (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or greater than 28 days). Suitable dosage amounts for the methods provided herein include, e.g., therapeutically effective amounts and prophylactically effective amounts. For example, in certain embodiments, the amount of azacitidine administered in the methods provided herein may range, e.g., between about 50 mg / m2 / day and about 2,000 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 100 mg / m2 / day and about 1,000 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 100 mg / m2 / day and about 500 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 50 mg / m2 / day and about 500 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 50 mg / m2 / day and about 200 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 50 mg / m2 / day and about 100 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 50 mg / m2 / day and about 75 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 120 mg / m2 / day and about 250 mg / m2 / day. In certain embodiments, the particular dosage is about 50 mg / m2 / day. In one embodiment, the particular dosage is about 60 mg / m2 / day. In one embodiment, the particular dosage is about 75 mg / m2 / day. In one embodiment, the particular dosage is about 80 mg / m2 / day. In one embodiment, the particular dosage is about 100 mg / m2 / day. In one embodiment, the particular dosage is about 120 mg / m2 / day. In one embodiment, the particular dosage is about 140 mg / m2 / day. In one embodiment, the particular dosage is about 150 mg / m2 / day. In one embodiment, the particular dosage is about 180 mg / m2 / day. In one embodiment, the particular dosage is about 200 mg / m2 / day. In one embodiment, the particular dosage is about 220 mg / m2 / day. In one embodiment, the particular dosage is about 240 mg / m2 / day. In one embodiment, the particular dosage is about 250 mg / m2 / day. In one embodiment, the particular dosage is about 260 mg / m2 / day. In one embodiment, the particular dosage is about 280 mg / m2 / day. In one embodiment, the particular dosage is about 300 mg / m2 / day. In one embodiment, the particular dosage is about 320 mg / m2 / day. In one embodiment, the particular dosage is about 350 mg / m2 / day. In one embodiment, the particular dosage is about 380 mg / m2 / day. In one embodiment, the particular dosage is about 400 mg / m2 / day. In one embodiment, theparticular dosage is about 450 mg / m2 / day. In one embodiment, the particular dosage is about 500 mg / m2 / day. In certain embodiments, the particular dosage is up to about 100 mg / m2 / day. In one embodiment, the particular dosage is up to about 120 mg / m2 / day. In one embodiment, the particular dosage is up to about 140 mg / m2 / day. In one embodiment, the particular dosage is up to about 150 mg / m2 / day. In one embodiment, the particular dosage is up to about 180 mg / m2 / day. In one embodiment, the particular dosage is up to about 200 mg / m2 / day. In one embodiment, the particular dosage is up to about 220 mg / m2 / day. In one embodiment, the particular dosage is up to about 240 mg / m2 / day. In one embodiment, the particular dosage is up to about 250 mg / m2 / day. In one embodiment, the particular dosage is up to about 260 mg / m2 / day. In one embodiment, the particular dosage is up to about 280 mg / m2 / day. In one embodiment, the particular dosage is up to about 300 mg / m2 / day. In one embodiment, the particular dosage is up to about 320 mg / m2 / day. In one embodiment, the particular dosage is up to about 350 mg / m2 / day. In one embodiment, the particular dosage is up to about 380 mg / m2 / day. In one embodiment, the particular dosage is up to about 400 mg / m2 / day. In one embodiment, the particular dosage is up to about 450 mg / m2 / day. In one embodiment, the particular dosage is up to about 500 mg / m2 / day. In one embodiment, the particular dosage is up to about 750 mg / m2 / day. In one embodiment, the particular dosage is up to about 1000 mg / m2 / day.

[0143] In one embodiment, the amount of azacitidine administered in the methods provided herein may range, e.g., between about 5 mg / day and about 2,000 mg / day. In one embodiment, the range is between about 10 mg / day and about 2,000 mg / day. In one embodiment, the range is between about 20 mg / day and about 2,000 mg / day. In one embodiment, the range is between about 50 mg / day and about 1,000 mg / day. In one embodiment, the range is between about 100 mg / day and about 1,000 mg / day. In one embodiment, the range is between about 100 mg / day and about 500 mg / day. In one embodiment, the range is between about 150 mg / day and about 500 mg / day. In one embodiment, the range is between about 150 mg / day and about 250 mg / day. In certain embodiments, the particular dosage is about 10 mg / day. In one embodiment, the particular dosage is about 20 mg / day. In one embodiment, the particular dosage is about 50 mg / day. In one embodiment, the particular dosage is about 75 mg / day. In one embodiment, the particular dosage is about 100 mg / day. In one embodiment, the particular dosage is about 120 mg / day. In one embodiment, the particular dosage is about 150 mg / day. In one embodiment, the particular dosage is about 200 mg / day. In one embodiment, the particular dosage is about 250 mg / day. In one embodiment, the particular dosage is about 300 mg / day. In one embodiment,the particular dosage is about 350 mg / day. In one embodiment, the particular dosage is about 400 mg / day. In one embodiment, the particular dosage is about 450 mg / day. In one embodiment, the particular dosage is about 500 mg / day. In one embodiment, the particular dosage is about 600 mg / day. In one embodiment, the particular dosage is about 700 mg / day. In one embodiment, the particular dosage is about 800 mg / day. In one embodiment, the particular dosage is about 900 mg / day. In one embodiment, the particular dosage is about 1,000 mg / day. In one embodiment, the particular dosage is about 1,200 mg / day. In one embodiment, the particular dosage is about 1,500 mg / day. In certain embodiments, the particular dosage is up to about 10 mg / day. In one embodiment, the particular dosage is up to about 20 mg / day. In one embodiment, the particular dosage is up to about 50 mg / day. In one embodiment, the particular dosage is up to about 75 mg / day. In one embodiment, the particular dosage is up to about 100 mg / day. In one embodiment, the particular dosage is up to about 120 mg / day. In one embodiment, the particular dosage is up to about 150 mg / day. In one embodiment, the particular dosage is up to about 200 mg / day,. In one embodiment, the particular dosage is up to about 250 mg / day. In one embodiment, the particular dosage is up to about 300 mg / day. In one embodiment, the particular dosage is up to about 350 mg / day. In one embodiment, the particular dosage is up to about 400 mg / day. In one embodiment, the particular dosage is up to about 450 mg / day. In one embodiment, the particular dosage is up to about 500 mg / day. In one embodiment, the particular dosage is up to about 600 mg / day. In one embodiment, the particular dosage is up to about 700 mg / day. In one embodiment, the particular dosage is up to about 800 mg / day. In one embodiment, the particular dosage is up to about 900 mg / day. In one embodiment, the particular dosage is up to about 1,000 mg / day. In one embodiment, the particular dosage is up to about 1,200 mg / day. In one embodiment, the particular dosage is up to about 1,500 mg / day.

[0144]

[0145] In one embodiment, azacitidine can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time. In one embodiment, azacitidine can be administered repetitively if necessary, for example, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient’s symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CT, PET, or MRI scan and other commonly accepted evaluation modalities.

[0146] In one embodiment, azacitidine can be administered once daily or divided into multiple daily doses such as twice daily, three times daily, and four times daily. In one embodiment, the administration can be continuous (z.e., daily for consecutive days or every day), intermittent, e.g., in cycles (z.e., including days, weeks, or months of rest when no drug is administered). In one embodiment, azacitidine is administered daily, for example, once or more than once each day for a period of time. In one embodiment, azacitidine is administered daily for an uninterrupted period of at least 7 days. In some embodiments, azacitidine is administered up to 52 weeks. In one embodiment, azacitidine is administered intermittently, z.e., stopping and starting at either regular or irregular intervals. In one embodiment, azacitidine is administered for one to six days per week. In one embodiment, azacitidine is administered on alternate days. In one embodiment, azacitidine is administered in cycles (e.g., administered daily or continuously for a certain period interrupted with a rest period). In one embodiment, azacitidine is administered daily for two to eight consecutive weeks, then a rest period with no administration for up to one week; or e.g. , daily administration for one week, then a rest period with no administration for up to three weeks).

[0147] In one embodiment, the frequency of administration ranges from about daily to about monthly In one embodiment, azacitidine is administered once a day. In another embodiment, azacitidine is administered twice a day. In yet another embodiment, azacitidine is administered three times a day. In still another embodiment, azacitidine is administered four times a day. In one embodiment, azacitidine is administered once every other day. In one embodiment, azacitidine is administered twice a week. In one embodiment, azacitidine is administered once every week. In one embodiment, azacitidine is administered once every two weeks. In one embodiment, azacitidine is administered once every three weeks. In one embodiment, azacitidine is administered once every four weeks.

[0148] In one embodiment, azacitidine is administered once per day from one day to six months. In one embodiment, azacitidine is administered from one week to three months. In one embodiment, azacitidine is administered from one week to four weeks. In one embodiment, azacitidine is administered from one week to three weeks. In one embodiment, azacitidine is administered from one week to two weeks. In one embodiment, azacitidine is administered once per day for about one week. In one embodiment, azacitidine is administered once per day for about two weeks. In one embodiment, azacitidine is administered once per day for about three weeks. In one embodiment, azacitidine is administered once per day for about four weeks. In one embodiment, azacitidine is administered once per day for about 6 weeks. In one embodiment, azacitidine is administeredonce per day for about 9 weeks. In one embodiment, azacitidine is administered once per day for about 12 weeks. In one embodiment, azacitidine is administered once per day for about 15 weeks. In one embodiment, azacitidine is administered once per day for about 18 weeks. In one embodiment, azacitidine is administered once per day for about 21 weeks. In one embodiment, azacitidine is administered once per day for about 26 weeks. In certain embodiments, azacitidine is administered intermittently. In certain embodiments, azacitidine is administered intermittently in the amount of between about 50 mg / m2 / day and about 2,000 mg / m2 / day. In certain embodiments, azacitidine is administered continuously. In certain embodiments, azacitidine is administered continuously in the amount of between about 50 mg / m2 / day and about 1,000 mg / m2 / day.

[0149] In certain embodiments, azacitidine is administered to a patient in cycles (e.g., daily administration for one week, then a rest period with no administration for up to three weeks). Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance, avoid or reduce the side effects, and / or improves the efficacy of the treatment.

[0150] In one embodiment, a method provided herein comprises administering azacitidine in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or greater than 40 cycles. In one embodiment, the median number of cycles administered in a group of patients is about 1. In one embodiment, the median number of cycles is about 2. In one embodiment, the median number of cycles is about 3. In one embodiment, the median number of cycles is about 4. In one embodiment, the median number of cycles is about 5. In one embodiment, the median number of cycles is about 6. In one embodiment, the median number of cycles is about 7. In one embodiment, the median number of cycles is about 8. In one embodiment, the median number of cycles is about 9. In one embodiment, the median number of cycles is about 10. In one embodiment, the median number of cycles is about 11. In one embodiment, the median number of cycles is about 12. In one embodiment, the median number of cycles is about 13. In one embodiment, the median number of cycles is about 14. In one embodiment, the median number of cycles is about 15. In one embodiment, the median number of cycles is about 16. In one embodiment, the median number of cycles is about 17. In one embodiment, the median number of cycles is about 18. In one embodiment, the median number of cycles is about 19. In one embodiment, the median number of cycles is about 20. In one embodiment, the median number of cycles is about 21. In one embodiment, the median number of cycles isabout 22. In one embodiment, the median number of cycles is about 23. In one embodiment, the median number of cycles is about 24. In one embodiment, the median number of cycles is about 25. In one embodiment, the median number of cycles is about 26. In one embodiment, the median number of cycles is about 27. In one embodiment, the median number of cycles is about 28. In one embodiment, the median number of cycles is about 29. In one embodiment, the median number of cycles is about 30. In one embodiment, the median number of cycles is greater than about 30 cycles.

[0151] In one embodiment, azacitidine is administered to a patient at a dose provided herein over a cycle of 28 days which consists of a 7-day treatment period and a 21-day resting period. In one embodiment, azacitidine is administered to a patient at a dose provided herein each day from day 1 to day 7, followed with a resting period from day 8 to day 28 with no administration of azacitidine. In one embodiment, azacitidine is administered to a patient in cycles, each cycle consisting of a 7-day treatment period followed with a 21-day resting period. In particular embodiments, azacitidine is administered to a patient at a dose of about 50, about 60, about 70, about 75, about 80, about 90, or about 100 mg / m2 / day, for 7 days, followed with a resting period of 21 days. In one embodiment, azacitidine is administered intravenously. In one embodiment, azacitidine is administered subcutaneously.

[0152] In other embodiments, azacitidine is administered orally in cycles. In one embodiment, azacitidine is administered daily in single or divided doses for about one week. In one embodiment, azacitidine is administered daily for about two weeks. In one embodiment, azacitidine is administered daily for about three weeks. In one embodiment, azacitidine is administered daily for about four weeks. In one embodiment, azacitidine is administered daily for about five weeks. In one embodiment, azacitidine is administered daily for about six weeks. In one embodiment, azacitidine is administered daily for about eight weeks. In one embodiment, azacitidine is administered daily for about ten weeks. In one embodiment, azacitidine is administered daily for about fifteen weeks. In one embodiment, azacitidine is administered daily for or about twenty weeks. The administration is followed by a rest period of about 1 day to about ten weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about one week. In one embodiment, the methods provided herein contemplate cycling treatments of about two weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about three weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about four weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about five weeks. In one embodiment, the methodsprovided herein contemplate cycling treatments of about six weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about eight weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about ten weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about fifteen weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about twenty weeks. In some embodiments, azacitidine is administered daily in single or divided doses for about one week. In one embodiment, azacitidine is administered daily for about two weeks. In one embodiment, azacitidine is administered daily for about three weeks. In one embodiment, azacitidine is administered daily for about four weeks. In one embodiment, azacitidine is administered daily for about five weeks. In one embodiment, azacitidine is administered daily for about six weeks. In one embodiment, the resting period of about 1, 3, 5, 7, 9, 12, 14, 16, 18, 20, 22, 24, 26, 28, 29, or 30 days. In some embodiments, the rest period is 1 day. In some embodiments, the rest period is 3 days. In some embodiments, the rest period is 7 days. In some embodiments, the rest period is 14 days. In some embodiments, the rest period is 28 days. The frequency, number and length of dosing cycles can be increased or decreased.Methods of Use

[0153] In one embodiment, provided herein is a method of treating brain tumors by administering to a subject a combination of a mutant IDH1 / IDH2 dual inhibitor and a DNA demethylating agent.

[0154] In one embodiment, the mutant IDH1 / IDH2 dual inhibitor is vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof.

[0155] In one embodiment, the DNA demethylating agent is azacitidine.

[0156] In one embodiment, provided herein is a method of treating a solid tumor, such as a barin tumor, characterized by the presence of a mutant allele of IDH1 and / or IDH2, comprising administering to a subject a therapeutically effective amount of vorasidenib, or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof, and azacitidine.

[0157] In one embodiment, provided herein is a method of treating a brain tumor, such as glioma, characterized by the presence of a mutant allele of IDH1 and / or IDH2, comprising administering to a subject a therapeutically effective amount of vorasidenib, or a pharmaceutically acceptable salt, hydrate, solvate or cocrystal thereof, and azacitidine.

[0158] The methods of the invention are useful for treating solid tumors, in particular brain tumors.

[0159] In some embodiments, the brain tumor is a glioma. In some embodiments, the brain tumor is an oligodendroglioma or astrocytoma. In some embodiments, the brain tumor is an oligodendroglioma. In some embodiments, the brain tumor is an astrocytoma.

[0160] In some embodiments, the brain tumor is a recurrent or progressive glioma. In some embodiments, the brain tumor is a recurrent or progressive oligodendroglioma or a recurrent or progressive astrocytoma. In some embodiments, the brain tumor is a recurrent or progressive oligodendroglioma. In some embodiments, the brain tumor is a recurrent or progressive astrocytoma.

[0161] In some embodiments, the solid tumor to be treated is characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in accumulation of R(-)-2- hydroxyglutarate in a patient. In one aspect of these embodiments, the IDH1 mutation results in accumulation of R(-)-2 -hydroxyglutarate in a patient by providing a new ability of the enzyme to catalyze the NADPH-dependent reduction of a-ketoglutarate to R(-)-2- hydroxyglutarate in a patient. In another aspect of these embodiments, the IDH1 mutation is an R132X mutation. In another aspect of these embodiments, the R132X mutation is selected from R132H, R132C, R132L, R132S and R132G. In another aspect of these embodiments, the R132X mutation is R132H or R132C. In yet another aspect of these embodiments, the R132X mutation is R132H. In still another aspect of these embodiments, at least 30, 40, 50, 60, 70, 80 or 90% of the solid tumor cells carry an IDH1 R132X mutation, such as an R132H, R132C, R132L, R132S or R132G mutation, at the time of diagnosis or treatment. A solid tumor can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 132 of IDH1.

[0162] In other embodiments, the solid tumor to be treated is characterized by the presence of an IDH2 mutation, wherein the IDH2 mutation results in accumulation of R(-)-2- hydroxyglutarate in a patient. In one aspect of these embodiments, the IDH2 mutation results in accumulation of R(-)-2 -hydroxyglutarate in a patient by providing a new ability of the enzyme to catalyze the NADPH-dependent reduction of a-ketoglutarate to R(-)-2-hydroxyglutarate in a patient. In another aspect of these embodiments, the mutant IDH2 has an R140X mutation. In another aspect of these embodiments, the R140X mutation is a R140Q mutation. In another aspect of these embodiments, the R140X mutation is a R140W mutation. In another aspect of these embodiments, the R140X mutation is a R140L mutation. In another aspect of these embodiments, the mutant IDH2 has an R172X mutation. In another aspect of these embodiments, the R172X mutation is a R172K mutation. In another aspect of these embodiments, the R172X mutation is a R172G mutation. In stillanother aspect of these embodiments, at least 30, 40, 50, 60, 70, 80 or 90% of the solid tumor cells carry an IDH2 R140X and / or R172X mutation, such as an R140Q, R140W, or R140L and / or R172K or R172G mutation, at the time of diagnosis or treatment. A solid tumor an be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 140 and / or 172 of IDH2.

[0163] In still other embodiments, the solid tumor to be treated is characterized by the presence of an IDH1 mutation and an IDH2 mutation, wherein the IDH1 and IDH2 mutations collectively result in accumulation of R(-)-2 -hydroxyglutarate in a patient. In one aspect of these embodiments, the IDH1 and IDH2 mutations result in accumulation of / ?(-)-2- hydroxyglutarate in a patient by providing a new ability of the enzyme to catalyze the NADPH-dependent reduction of a-ketoglutarate to / ?(-)-2-hydroxyglutaratc in a patient. In various aspects of these embodiments, the IDH1 mutation is an R132X mutation selected from R132H, R132C, R132L, R132V, R132S and R132G. In various aspects of these embodiments, the IDH2 mutation is an R140Q, R140W, R140L, R172K or R172G mutation. In various other aspects of these embodiments, the solid tumor to be treated is characterized by any combination of the foregoing IDH1 and IDH2 mutations. In still other aspects of these embodiments, at least 30, 40, 50, 60, 70, 80 or 90% of the solid tumor cells carry an IDH1 R132X mutation, such as an R132H, R132C, R132L, R132S or R132G mutation, and an IDH2 R140X and / or R172X mutation, such as an R140Q, R140W, or R140L and / or R172K or R172G mutation, at the time of diagnosis or treatment. A solid tumor can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 132 of IDH1 and at amino acid 140 and / or 172 of IDH2.

[0164] In still other embodiments, the solid tumor to be treated is characterized by the presence of an IDH1 allele that does not include an R132X mutation and an IDH2 allele that does not include an R140X or R172X mutation. In one aspect of these embodiments, at least 90% of the solid tumor cells do not include a mutation at amino acid 132 of IDH1 or at amino acid 140 or 172 of IDH2 at the time of diagnosis or treatment. A solid tumor can be analyzed by sequencing cell samples to determine the presence or absence of a mutation at amino acid 132 of IDH1 and at amino acid 140 and / or 172 of IDH2.

[0165] In one embodiment, the efficacy of treatment of the solid tumor is monitored by measuring the levels of 2HG in the subject. Typically, levels of 2HG are measured prior to treatment, wherein an elevated level is indicated for the use of the methods of treatment described herein. Once the elevated levels are established, the level of 2HG is determinedduring the course of and / or following termination of treatment to establish efficacy. In certain embodiments, the level of 2HG is only determined during the course of and / or following termination of treatment. A reduction of 2HG levels during the course of treatment and following treatment is indicative of efficacy. Similarly, a determination that 2HG levels are not elevated during the course of or following treatment is also indicative of efficacy. Typically, 2HG measurements are utilized together with other well-known determinations of efficacy of solid tumor treatment, such as reduction in number and size of tumors and / or other cancer-associated lesions, improvement in the general health of the subject, and alterations in other biomarkers that are associated with solid tumor treatment efficacy.

[0166] In some embodiments, the brain tumor (e.g., glioma) to be treated is characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in accumulation of / ?(-)-2-hydroxyglutaratc in a patient. In one aspect of these embodiments, the IDH1 mutation results in accumulation of / ?(-)-2-hydroxyglutaratc in a patient by providing a new ability of the enzyme to catalyze the NADPH-dependent reduction of a-ketoglutarate to R(-)-2- hydroxyglutarate in a patient. In another aspect of these embodiments, the IDH1 mutation is an R132X mutation. In another aspect of these embodiments, the R132X mutation is selected from R132H, R132C, R132L, R132S and R132G. In another aspect of these embodiments, the R132X mutation is R132H or R132C. In yet another aspect of these embodiments, the R132X mutation is R132H. In still another aspect of these embodiments, at least 30, 40, 50, 60, 70, 80 or 90% of the brain tumor (e.g., glioma) cells carry an IDH1 R132X mutation, such as an R132H, R132C, R132L, R132S or R132G mutation, at the time of diagnosis or treatment. A brain tumor (e.g., glioma) can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 132 of IDH1.

[0167] In other embodiments, the brain tumor (e.g. , glioma) to be treated is characterized by the presence of an IDH2 mutation, wherein the IDH2 mutation results in accumulation of / ?(-)-2-hydroxyglutaratc in a patient. In one aspect of these embodiments, the IDH2 mutation results in accumulation of / ?(-)-2-hydroxyglutaratc in a patient by providing a new ability of the enzyme to catalyze the NADPH-dependent reduction of a-ketoglutarate to / ?(-)-2-hydroxyglutaratc in a patient. In another aspect of these embodiments, the mutant IDH2 has an R140X mutation. In another aspect of these embodiments, the R140X mutation is a R140Q mutation. In another aspect of these embodiments, the R140X mutation is a R140W mutation. In another aspect of these embodiments, the R140X mutation is a R140L mutation. In another aspect of these embodiments, the mutant IDH2 has an R172X mutation.In another aspect of these embodiments, the R172X mutation is a R172K mutation. In another aspect of these embodiments, the R172X mutation is a R172G mutation. In still another aspect of these embodiments, at least 30, 40, 50, 60, 70, 80 or 90% of the brain tumor (e.g., glioma) cells carry an IDH2 R140X and / or R172X mutation, such as an R140Q, R140W, or R140L and / or R172K or R172G mutation, at the time of diagnosis or treatment. A brain tumor (e.g., glioma) can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g, the changed amino acid present at) a mutation at amino acid 140 and / or 172 of IDH2.

[0168] In still other embodiments, the brain tumor (e.g. , glioma) to be treated is characterized by the presence of an IDH1 mutation and an IDH2 mutation, wherein the IDH1 and IDH2 mutations collectively result in accumulation of R(-)-2 -hydroxyglutarate in a patient. In one aspect of these embodiments, the IDH1 and IDH2 mutations result in accumulation of R(-)-2 -hydroxyglutarate in a patient by providing a new ability of the enzyme to catalyze the NADPH-dependent reduction of a-ketoglutarate to / ?(-)-2-hydroxyglutaratc in a patient. In various aspects of these embodiments, the IDH1 mutation is an R132X mutation selected from R132H, R132C, R132L, R132V, R132S and R132G. In various aspects of these embodiments, the IDH2 mutation is an R140Q, R140W, R140L, R172K or R172G mutation. In various other aspects of these embodiments, the brain tumor (e.g. , glioma) to be treated is characterized by any combination of the foregoing IDH1 and IDH2 mutations. In still other aspects of these embodiments, at least 30, 40, 50, 60, 70, 80 or 90% of the brain tumor (e.g., glioma) cells carry an IDH1 R132X mutation, such as an R132H, R132C, R132L, R132S or R132G mutation, and an IDH2 R140X and / or R172X mutation, such as an R140Q, R140W, or R140L and / or R172K or R172G mutation, at the time of diagnosis or treatment. A brain tumor (e.g., glioma) can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 132 of IDH1 and at amino acid 140 and / or 172 of IDH2.

[0169] In still other embodiments, the brain tumor (e.g. , glioma) to be treated is characterized by the presence of an IDH1 allele that does not include an R132X mutation and an IDH2 allele that does not include an R140X or R172X mutation. In one aspect of these embodiments, at least 90% of the brain tumor (e.g., glioma) cells do not include a mutation at amino acid 132 of IDH1 or at amino acid 140 or 172 of IDH2 at the time of diagnosis or treatment. A brain tumor (e.g., glioma) can be analyzed by sequencing cell samples to determine the presence or absence of a mutation at amino acid 132 of IDH1 and at amino acid 140 and / or 172 of IDH2.

[0170] In one embodiment, the efficacy of treatment of the brain tumor is monitored by measuring the levels of 2HG in the subject. Typically, levels of 2HG are measured prior to treatment, wherein an elevated level is indicated for the use of the methods of treatment described herein. Once the elevated levels are established, the level of 2HG is determined during the course of and / or following termination of treatment to establish efficacy. In certain embodiments, the level of 2HG is only determined during the course of and / or following termination of treatment. A reduction of 2HG levels during the course of treatment and following treatment is indicative of efficacy. Similarly, a determination that 2HG levels are not elevated during the course of or following treatment is also indicative of efficacy. Typically, 2HG measurements are utilized together with other well-known determinations of efficacy of brain tumor treatment, such as reduction in number and size of tumors and / or other cancer-associated lesions, improvement in the general health of the subject, and alterations in other biomarkers that are associated with brain tumor treatment efficacy.

[0171] 2HG can be detected in a sample by the methods of PCT Publication No. WO 2011 / 050210 and US Publication No. US2012 / 0121515 hereby incorporated by reference in their entirety, or by analogous methods. In an exemplary method, 2HG can be detected in a sample by LC / MS. The sample is mixed 80:20 with methanol and centrifuged at 3,000 rpm for 20 minutes at 4 degrees Celsius. The resulting supernatant can be collected and stored at -80 degrees Celsius prior to LC-MS / MS to assess 2-hydroxyglutarate levels. A variety of different liquid chromatography (LC) separation methods can be used. Each method can be coupled by negative electrospray ionization (ESI, -3.0 kV) to triple-quadrupole mass spectrometers operating in multiple reaction monitoring (MRM) mode, with MS parameters optimized on infused metabolite standard solutions. Metabolites can be separated by reversed phase chromatography using 10 mM tributyl-amine as an ion pairing agent in the aqueous mobile phase, according to a variant of a previously reported method (Luo et al. J Chromatogr A 1147, 153-64, 2007). One method allows resolution of TCA metabolites: t = 0, 50% B; t = 5, 95% B; t= 7, 95% B; t= 8, 0% B, where B refers to an organic mobile phase of 100% methanol. Another method is specific for 2-hydroxyglutarate, running a fast linear gradient from 50% -95% B (buffers as defined above) over 5 minutes. A Synergi Hydro-RP, 100mm x 2 mm, 2. 1 pm particle size (Phenomonex) can be used as the column, as described above. Metabolites can be quantified by comparison of peak areas with pure metabolite standards at known concentration. Metabolite flux studies from13C-glutamine can be performed as described, e.g., in Munger et al. Nat Biotechnol 26, 1179-86, 2008.

[0172] In one embodiment, 2HG is directly evaluated.

[0173] In another embodiment, a derivative of 2HG formed in the process of performing the analytic method is evaluated. By way of example such a derivative can be a derivative formed in MS analysis. Derivatives can include a salt adduct, e.g., a Na adduct, a hydration variant, or a hydration variant which is also a salt adduct, e.g. , a Na adduct, e.g. , as formed in MS analysis.In another embodiment a metabolic derivative of 2HG is evaluated. Examples include species that build up or are elevated, or reduced, as a result of the presence of 2HG, such as glutarate or glutamate that will be correlated to 2HG, e.g., R-2HG.

[0174] Exemplary 2HG derivatives include dehydrated derivatives such as the compounds provided below, or a salt adduct thereof:

[0175] Treatment methods described herein can additionally comprise various evaluation steps prior to and / or following treatment with vorasidenib and azacitidine.

[0176] In one embodiment, prior to and / or after treatment with vorasidenib and azacitidine, the method further comprises the step of evaluating the growth, size, weight, invasiveness, stage and / or other phenotype of the solid tumor.

[0177] In one embodiment, prior to and / or after treatment with vorasidenib and azacitidine, the method further comprises the step of evaluating the IDH1 genotype of the solid tumor. This may be achieved by ordinary methods in the art, such as DNA sequencing, immuno analysis, and / or evaluation of the presence, distribution or level of 2HG.

[0178] In one embodiment, prior to and / or after treatment with vorasidenib and azacitidine, the method further comprises the step of evaluating the growth, size, weight, invasiveness, stage and / or other phenotype of the brain tumor.

[0179] In one embodiment, prior to and / or after treatment with vorasidenib and azacitidine, the method further comprises the step of evaluating the IDH1 genotype of the brain tumor. This may be achieved by ordinary methods in the art, such as DNA sequencing, immuno analysis, and / or evaluation of the presence, distribution or level of 2HG.

[0180] In one embodiment, prior to and / or after treatment with vorasidenib and azacitidine, the method further comprises the step of determining the 2HG level in the subject. This may be achieved by spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and / or MRS measurement, sample analysis of bodily fluid, such as serum or spinal cord fluid analysis, or by analysis of surgical material, e.g., by mass-spectroscopy.

[0181] In one embodiment, vorasidenib and azacitidine are administered concurrently. In one embodiment, vorasidenib and azacitidine are administered sequentially.

[0182] In one embodiment, depending on the disease to be treated and the subject’s condition, vorasidenib may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration, vorasidenib may be formulated alone or together with one or more active agent(s), in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.

[0183] In one embodiment, the amount of vorasidenib administered in the methods provided herein may range, e.g., between about 5 mg / day and about 2,000 mg / day. In one embodiment, the range is between about 10 mg / day and about 2,000 mg / day. In one embodiment, the range is between about 20 mg / day and about 2,000 mg / day. In one embodiment, the range is between about 50 mg / day and about 1,000 mg / day. In one embodiment, the range is between about 100 mg / day and about 1,000 mg / day. In one embodiment, the range is between about 100 mg / day and about 500 mg / day. In one embodiment, the range is between about 150 mg / day and about 500 mg / day. In one embodiment, the range is or between about 150 mg / day and about 250 mg / day. In certain embodiments, particular dosages are, e.g., about 10 mg / day. In one embodiment, the dose is about 20 mg / day. In one embodiment, the dose is about 50 mg / day. In one embodiment, the dose is about 75 mg / day. In one embodiment, the dose is about 100 mg / day. In one embodiment, the dose is about 120 mg / day. In one embodiment, the dose is about 150 mg / day. In one embodiment, the dose is about 200 mg / day. In one embodiment, the dose is about 250 mg / day. In one embodiment, the dose is about 300 mg / day. In one embodiment, the dose is about 350 mg / day. In one embodiment, the dose is about 400 mg / day. In one embodiment, the dose is about 450 mg / day. In one embodiment, the dose is about 500 mg / day. In one embodiment, the dose is about 600 mg / day. In one embodiment, the dose is about 700 mg / day. In one embodiment, the dose is about 800 mg / day. In one embodiment, the dose is about 900 mg / day. In one embodiment, the dose is about 1,000 mg / day. In one embodiment, the dose is about 1,200 mg / day. In one embodiment, the dose is or about 1,500 mg / day. In certain embodiments, particular dosages are, e.g., up to about 10 mg / day. In one embodiment, the particular dose is up to about 20 mg / day. In one embodiment, the particular dose is up to about 50 mg / day. In one embodiment, the particular dose is up to about 75 mg / day. In one embodiment, the particular dose is up to about 100 mg / day. In oneembodiment, the particular dose is up to about 120 mg / day. In one embodiment, the particular dose is up to about 150 mg / day. In one embodiment, the particular dose is up to about 200 mg / day. In one embodiment, the particular dose is up to about 250 mg / day. In one embodiment, the particular dose is up to about 300 mg / day. In one embodiment, the particular dose is up to about 350 mg / day. In one embodiment, the particular dose is up to about 400 mg / day. In one embodiment, the particular dose is up to about 450 mg / day. In one embodiment, the particular dose is up to about 500 mg / day. In one embodiment, the particular dose is up to about 600 mg / day. In one embodiment, the particular dose is up to about 700 mg / day. In one embodiment, the particular dose is up to about 800 mg / day. In one embodiment, the particular dose is up to about 900 mg / day. In one embodiment, the particular dose is up to about 1,000 mg / day. In one embodiment, the particular dose is up to about 1,200 mg / day. In one embodiment, the particular dose is up to about 1,500 mg / day.

[0184] In one embodiment, the amount of vorasidenib in the pharmaceutical composition or dosage form provided herein may range, e.g. , between about 5 mg and about 2,000 mg. In one embodiment, the range is between about 10 mg and about 2,000 mg. In one embodiment, the range is between about 20 mg and about 2,000 mg. In one embodiment, the range is between about 50 mg and about 1,000 mg. In one embodiment, the range is between about 50 mg and about 500 mg. In one embodiment, the range is between about 50 mg and about 250 mg. In one embodiment, the range is between about 100 mg and about 500 mg. In one embodiment, the range is between about 150 mg and about 500 mg. In one embodiment, the range is between about 150 mg and about 250 mg. In certain embodiments, particular amounts are, e.g., about 10 mg. In one embodiment, the particular amount is about 20 mg. In one embodiment, the particular amount is about 50 mg. In one embodiment, the particular amount is about 75 mg. In one embodiment, the particular amount is about 100 mg. In one embodiment, the particular amount is about 120 mg. In one embodiment, the particular amount is about 150 mg. In one embodiment, the particular amount is about 200 mg. In one embodiment, the particular amount is about 250 mg. In one embodiment, the particular amount is about 300 mg. In one embodiment, the particular amount is about 350 mg. In one embodiment, the particular amount is about 400 mg. In one embodiment, the particular amount is about 450 mg. In one embodiment, the particular amount is about 500 mg. In one embodiment, the particular amount is about 600 mg. In one embodiment, the particular amount is about 700 mg. In one embodiment, the particular amount is about 800 mg. In one embodiment, the particular amount is about 900 mg. In one embodiment, the particular amount is about 1,000 mg. In one embodiment, the particular amount is about 1,200 mg. Inone embodiment, the particular amount is or about 1,500 mg. In certain embodiments, particular amounts are, e.g., up to about 10 mg. In one embodiment, the particular amount is up to about 20 mg. In one embodiment, the particular amount is up to about 50 mg. In one embodiment, the particular amount is up to about 75 mg. In one embodiment, the particular amount is up to about 100 mg. In one embodiment, the particular amount is up to about 120 mg. In one embodiment, the particular amount is up to about 150 mg. In one embodiment, the particular amount is up to about 200 mg. In one embodiment, the particular amount is up to about 250 mg. In one embodiment, the particular amount is up to about 300 mg. In one embodiment, the particular amount is up to about 350 mg. In one embodiment, the particular amount is up to about 400 mg. In one embodiment, the particular amount is up to about 450 mg. In one embodiment, the particular amount is up to about 500 mg. In one embodiment, the particular amount is up to about 600 mg. In one embodiment, the particular amount is up to about 700 mg. In one embodiment, the particular amount is up to about 800 mg. In one embodiment, the particular amount is up to about 900 mg. In one embodiment, the particular amount is up to about 1,000 mg. In one embodiment, the particular amount is up to about 1,200 mg. In one embodiment, the particular amount is up to about 1,500 mg.

[0185] In one embodiment, vorasidenib can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time. In one embodiment, comound 1 can be administered repetitively if necessary, for example, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient’s symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CT, PET, or MRI scan and other commonly accepted evaluation modalities.

[0186] In certain embodiments, vorasidenib is administered to a patient in cycles (e.g., daily administration for one week, then a rest period with no administration for up to three weeks). Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance, avoid or reduce the side effects, and / or improves the efficacy of the treatment.

[0187] In one embodiment, a method provided herein comprises administering vorasidenib in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or greater than 40 cycles. In oneembodiment, the median number of cycles administered in a group of patients is about 1. In one embodiment, the median number of cycles administered in a group of patients is about 2. In one embodiment, the median number of cycles administered in a group of patients is about 3. In one embodiment, the median number of cycles administered in a group of patients is about 4. In one embodiment, the median number of cycles administered in a group of patients is about 5. In one embodiment, the median number of cycles administered in a group of patients is about 6. In one embodiment, the median number of cycles administered in a group of patients is about 7. In one embodiment, the median number of cycles administered in a group of patients is about 8. In one embodiment, the median number of cycles administered in a group of patients is about 9. In one embodiment, the median number of cycles administered in a group of patients is about 10. In one embodiment, the median number of cycles administered in a group of patients is about 11. In one embodiment, the median number of cycles administered in a group of patients is about 12. In one embodiment, the median number of cycles administered in a group of patients is about 13. In one embodiment, the median number of cycles administered in a group of patients is about 14. In one embodiment, the median number of cycles administered in a group of patients is about 15. In one embodiment, the median number of cycles administered in a group of patients is about 16. In one embodiment, the median number of cycles administered in a group of patients is about 17. In one embodiment, the median number of cycles administered in a group of patients is about 18. In one embodiment, the median number of cycles administered in a group of patients is about 19. In one embodiment, the median number of cycles administered in a group of patients is about 20. In one embodiment, the median number of cycles administered in a group of patients is about 21. In one embodiment, the median number of cycles administered in a group of patients is about 22. In one embodiment, the median number of cycles administered in a group of patients is about 23. In one embodiment, the median number of cycles administered in a group of patients is about 24. In one embodiment, the median number of cycles administered in a group of patients is about 25. In one embodiment, the median number of cycles administered in a group of patients is about 26. In one embodiment, the median number of cycles administered in a group of patients is about 27. In one embodiment, the median number of cycles administered in a group of patients is about 28. In one embodiment, the median number of cycles administered in a group of patients is about 29. In one embodiment, the median number of cycles administered in a group of patients is about 30. In one embodiment, the median number of cycles administered in a group of patients is greater than about 30 cycles.

[0188] In certain embodiments, treatment cycles comprise multiple doses of vorasidenib administered to a subject in need thereof over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or greater than 14 days), optionally followed by treatment dosing holidays (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or greater than 28 days).

[0189] In one embodiment, depending on the disease to be treated and the subject’s condition, azacitidine may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. Azacitidine may be formulated, alone or together with vorasidenib and / or one or more active agent(s), in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.

[0190] In one embodiment, azacitidine is administered by, e.g, intravenous (IV), subcutaneous (SC) or oral routes. Certain embodiments herein provide co-administration of azacitidine with vorasidenib and / or one or more additional active agents to provide a synergistic therapeutic effect in subjects in need thereof. The co-administered active agent(s) may be cancer therapeutic agents, as described herein. In certain embodiments, the coadministered active agent(s) may be inhibitors of IDH1. In certain embodiments, the coadministered agent(s) may be dosed, e.g., orally or by injection (e.g., IV or SC).

[0191] In certain embodiments, treatment cycles comprise multiple doses of azacitidine administered to a subject in need thereof over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or greater than 14 days), optionally followed by treatment dosing holidays (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or greater than 28 days). Suitable dosage amounts for the methods provided herein include, e.g., therapeutically effective amounts and prophylactically effective amounts. For example, in certain embodiments, the amount of azacitidine administered in the methods provided herein may range, e.g., between about 50 mg / m2 / day and about 2,000 mg / m2 / day.In certain embodiments, the amount of azacitidine is between about 100 mg / m2 / day and about 1,000 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 100 mg / m2 / day and about 500 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 50 mg / m2 / day and about 500 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 50 mg / m2 / day and about 200 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 50 mg / m2 / day and about 100 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 50mg / m2 / day and about 75 mg / m2 / day. In certain embodiments, the amount of azacitidine is between about 120 mg / m2 / day and about 250 mg / m2 / day. In certain embodiments, the particular dosage is about 50 mg / m2 / day. In one embodiment, the particular dosage is about 60 mg / m2 / day. In one embodiment, the particular dosage is about 75 mg / m2 / day. In one embodiment, the particular dosage is about 80 mg / m2 / day. In one embodiment, the particular dosage is about 100 mg / m2 / day. In one embodiment, the particular dosage is about 120 mg / m2 / day. In one embodiment, the particular dosage is about 140 mg / m2 / day. In one embodiment, the particular dosage is about 150 mg / m2 / day. In one embodiment, the particular dosage is about 180 mg / m2 / day. In one embodiment, the particular dosage is about 200 mg / m2 / day. In one embodiment, the particular dosage is about 220 mg / m2 / day. In one embodiment, the particular dosage is about 240 mg / m2 / day. In one embodiment, the particular dosage is about 250 mg / m2 / day. In one embodiment, the particular dosage is about 260 mg / m2 / day. In one embodiment, the particular dosage is about 280 mg / m2 / day. In one embodiment, the particular dosage is about 300 mg / m2 / day. In one embodiment, the particular dosage is about 320 mg / m2 / day. In one embodiment, the particular dosage is about 350 mg / m2 / day. In one embodiment, the particular dosage is about 380 mg / m2 / day. In one embodiment, the particular dosage is about 400 mg / m2 / day. In one embodiment, the particular dosage is about 450 mg / m2 / day. In one embodiment, the particular dosage is about 500 mg / m2 / day. In certain embodiments, the particular dosage is up to about 100 mg / m2 / day. In one embodiment, the particular dosage is up to about 120 mg / m2 / day. In one embodiment, the particular dosage is up to about 140 mg / m2 / day. In one embodiment, the particular dosage is up to about 150 mg / m2 / day. In one embodiment, the particular dosage is up to about 180 mg / m2 / day. In one embodiment, the particular dosage is up to about 200 mg / m2 / day. In one embodiment, the particular dosage is up to about 220 mg / m2 / day. In one embodiment, the particular dosage is up to about 240 mg / m2 / day. In one embodiment, the particular dosage is up to about 250 mg / m2 / day. In one embodiment, the particular dosage is up to about 260 mg / m2 / day. In one embodiment, the particular dosage is up to about 280 mg / m2 / day. In one embodiment, the particular dosage is up to about 300 mg / m2 / day. In one embodiment, the particular dosage is up to about 320 mg / m2 / day. In one embodiment, the particular dosage is up to about 350 mg / m2 / day. In one embodiment, the particular dosage is up to about 380 mg / m2 / day. In one embodiment, the particular dosage is up to about 400 mg / m2 / day. In one embodiment, the particular dosage is up to about 450 mg / m2 / day. In one embodiment, the particular dosage is up to about 500 mg / m2 / day. In one embodiment, the particular dosage isup to about 750 mg / m2 / day. In one embodiment, the particular dosage is up to about 1000 mg / m2 / day.

[0192] In one embodiment, the amount of azacitidine administered in the methods provided herein may range, e.g., between about 5 mg / day and about 2,000 mg / day. In one embodiment, the range is between about 10 mg / day and about 2,000 mg / day. In one embodiment, the range is between about 20 mg / day and about 2,000 mg / day. In one embodiment, the range is between about 50 mg / day and about 1,000 mg / day. In one embodiment, the range is between about 100 mg / day and about 1,000 mg / day. In one embodiment, the range is between about 100 mg / day and about 500 mg / day. In one embodiment, the range is between about 150 mg / day and about 500 mg / day. In one embodiment, the range is between about 150 mg / day and about 250 mg / day. In certain embodiments, the particular dosage is about 10 mg / day. In one embodiment, the particular dosage is about 20 mg / day. In one embodiment, the particular dosage is about 50 mg / day. In one embodiment, the particular dosage is about 75 mg / day. In one embodiment, the particular dosage is about 100 mg / day. In one embodiment, the particular dosage is about 120 mg / day. In one embodiment, the particular dosage is about 150 mg / day. In one embodiment, the particular dosage is about 200 mg / day. In one embodiment, the particular dosage is about 250 mg / day. In one embodiment, the particular dosage is about 300 mg / day. In one embodiment, the particular dosage is about 350 mg / day. In one embodiment, the particular dosage is about 400 mg / day. In one embodiment, the particular dosage is about 450 mg / day. In one embodiment, the particular dosage is about 500 mg / day. In one embodiment, the particular dosage is about 600 mg / day. In one embodiment, the particular dosage is about 700 mg / day. In one embodiment, the particular dosage is about 800 mg / day. In one embodiment, the particular dosage is about 900 mg / day. In one embodiment, the particular dosage is about 1,000 mg / day. In one embodiment, the particular dosage is about 1,200 mg / day. In one embodiment, the particular dosage is about 1,500 mg / day. In certain embodiments, the particular dosage is up to about 10 mg / day. In one embodiment, the particular dosage is up to about 20 mg / day. In one embodiment, the particular dosage is up to about 50 mg / day. In one embodiment, the particular dosage is up to about 75 mg / day. In one embodiment, the particular dosage is up to about 100 mg / day. In one embodiment, the particular dosage is up to about 120 mg / day. In one embodiment, the particular dosage is up to about 150 mg / day. In one embodiment, the particular dosage is up to about 200 mg / day,. In one embodiment, the particular dosage is up to about 250 mg / day. In one embodiment, the particular dosage is up to about 300 mg / day. In one embodiment, the particular dosage is up to about 350 mg / day. Inone embodiment, the particular dosage is up to about 400 mg / day. In one embodiment, the particular dosage is up to about 450 mg / day. In one embodiment, the particular dosage is up to about 500 mg / day. In one embodiment, the particular dosage is up to about 600 mg / day. In one embodiment, the particular dosage is up to about 700 mg / day. In one embodiment, the particular dosage is up to about 800 mg / day. In one embodiment, the particular dosage is up to about 900 mg / day. In one embodiment, the particular dosage is up to about 1,000 mg / day. In one embodiment, the particular dosage is up to about 1,200 mg / day. In one embodiment, the particular dosage is up to about 1,500 mg / day.

[0193] In one embodiment, the amount of azacitidine in the pharmaceutical composition or dosage form provided herein may range, e.g., between about 5 mg and about 2,000 mg. In one embodiment, the range is between about 10 mg and about 2,000 mg. In one embodiment, the range is between about 20 mg and about 2,000 mg. In one embodiment, the range is between about 50 mg and about 1,000 mg. In one embodiment, the range is between about 50 mg and about 500 mg. In one embodiment, the range is between about 50 mg and about 250 mg. In one embodiment, the range is between about 100 mg and about 500 mg. In one embodiment, the range is between about 150 mg and about 500 mg. In one embodiment, the range is between about 150 mg and about 250 mg. In certain embodiments, the particular amount is about 10 mg. In one embodiment, the particular amount is about 20 mg. In one embodiment, the particular amount is about 50 mg. In one embodiment, the particular amount is about 75 mg. In one embodiment, the particular amount is about 100 mg. In one embodiment, the particular amount is about 120 mg. In one embodiment, the particular amount is about 150 mg. In one embodiment, the particular amount is about 200 mg. In one embodiment, the particular amount is about 250 mg. In one embodiment, the particular amount is about 300 mg. In one embodiment, the particular amount is about 350 mg. In one embodiment, the particular amount is about 400 mg. In one embodiment, the particular amount is about 450 mg. In one embodiment, the particular amount is about 500 mg. In one embodiment, the particular amount is about 600 mg. In one embodiment, the particular amount is about 700 mg. In one embodiment, the particular amount is about 800 mg. In one embodiment, the particular amount is about 900 mg. In one embodiment, the particular amount is about 1,000 mg. In one embodiment, the particular amount is about 1,200 mg. In one embodiment, the particular amount is about 1,500 mg. In certain embodiments, the particular amount is up to about 10 mg. In one embodiment, the particular amount is up to about 20 mg. In one embodiment, the particular amount is up to about 50 mg. In one embodiment, the particular amount is up to about 75 mg. In one embodiment, the particularamount is up to about 100 mg. In one embodiment, the particular amount is up to about 120 mg. In one embodiment, the particular amount is up to about 150 mg. In one embodiment, the particular amount is up to about 200 mg. In one embodiment, the particular amount is up to about 250 mg. In one embodiment, the particular amount is up to about 300 mg. In one embodiment, the particular amount is up to about 350 mg. In one embodiment, the particular amount is up to about 400 mg. In one embodiment, the particular amount is up to about 450 mg. In one embodiment, the particular amount is up to about 500 mg. In one embodiment, the particular amount is up to about 600 mg. In one embodiment, the particular amount is up to about 700 mg. In one embodiment, the particular amount is up to about 800 mg. In one embodiment, the particular amount is up to about 900 mg. In one embodiment, the particular amount is up to about 1,000 mg. In one embodiment, the particular amount is up to about 1,200 mg. In one embodiment, the particular amount is up to about 1,500 mg.

[0194] In one embodiment, azacitidine can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time. In one embodiment, azacitidine can be administered repetitively if necessary, for example, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient’s symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CT, PET, or MRI scan and other commonly accepted evaluation modalities.

[0195] In one embodiment, azacitidine can be administered once daily or divided into multiple daily doses such as twice daily, three times daily, and four times daily. In one embodiment, the administration can be continuous (z.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest when no drug is administered). In one embodiment, azacitidine is administered daily, for example, once or more than once each day for a period of time. In one embodiment, azacitidine is administered daily for an uninterrupted period of at least 7 days. In some embodiments, azacitidine is administered up to 52 weeks. In one embodiment, azacitidine is administered intermittently, i.e., stopping and starting at either regular or irregular intervals. In one embodiment, azacitidine is administered for one to six days per week. In one embodiment, azacitidine is administered on alternate days. In one embodiment, azacitidine is administered in cycles (e.g., administered daily or continuously for a certain period interrupted with a rest period). In one embodiment, azacitidine is administered daily for two to eight consecutiveweeks, then a rest period with no administration for up to one week; or e.g. , daily administration for one week, then a rest period with no administration for up to three weeks).

[0196] In one embodiment, the frequency of administration ranges from about daily to about monthly. In one embodiment, azacitidine is administered once a day. In another embodiment, azacitidine is administered twice a day. In yet another embodiment, azacitidine is administered three times a day. In still another embodiment, azacitidine is administered four times a day. In one embodiment, azacitidine is administered once every other day. In one embodiment, azacitidine is administered twice a week. In one embodiment, azacitidine is administered once every week. In one embodiment, azacitidine is administered once every two weeks. In one embodiment, azacitidine is administered once every three weeks. In one embodiment, azacitidine is administered once every four weeks.

[0197] In one embodiment, azacitidine is administered once per day from one day to six months. In one embodiment, azacitidine is administered from one week to three months. In one embodiment, azacitidine is administered from one week to four weeks. In one embodiment, azacitidine is administered from one week to three weeks. In one embodiment, azacitidine is administered from one week to two weeks. In one embodiment, azacitidine is administered once per day for about one week. In one embodiment, azacitidine is administered once per day for about two weeks. In one embodiment, azacitidine is administered once per day for about three weeks. In one embodiment, azacitidine is administered once per day for about four weeks. In one embodiment, azacitidine is administered once per day for about 6 weeks. In one embodiment, azacitidine is administered once per day for about 9 weeks. In one embodiment, azacitidine is administered once per day for about 12 weeks. In one embodiment, azacitidine is administered once per day for about 15 weeks. In one embodiment, azacitidine is administered once per day for about 18 weeks. In one embodiment, azacitidine is administered once per day for about 21 weeks. In one embodiment, azacitidine is administered once per day for about 26 weeks. In certain embodiments, azacitidine is administered intermittently. In certain embodiments, azacitidine is administered intermittently in the amount of between about 50 mg / m2 / day and about 2,000 mg / m2 / day. In certain embodiments, azacitidine is administered continuously. In certain embodiments, azacitidine is administered continuously in the amount of between about 50 mg / m2 / day and about 1,000 mg / m2 / day.

[0198] In certain embodiments, azacitidine is administered to a patient in cycles (e.g., daily administration for one week, then a rest period with no administration for up to three weeks). Cycling therapy involves the administration of an active agent for a period of time,followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance, avoid or reduce the side effects, and / or improves the efficacy of the treatment.

[0199] In one embodiment, a method provided herein comprises administering azacitidine in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or greater than 40 cycles. In one embodiment, the median number of cycles administered in a group of patients is about 1. In one embodiment, the median number of cycles is about 2. In one embodiment, the median number of cycles is about 3. In one embodiment, the median number of cycles is about 4. In one embodiment, the median number of cycles is about 5. In one embodiment, the median number of cycles is about 6. In one embodiment, the median number of cycles is about 7. In one embodiment, the median number of cycles is about 8. In one embodiment, the median number of cycles is about 9. In one embodiment, the median number of cycles is about 10. In one embodiment, the median number of cycles is about 11. In one embodiment, the median number of cycles is about 12. In one embodiment, the median number of cycles is about 13. In one embodiment, the median number of cycles is about 14. In one embodiment, the median number of cycles is about 15. In one embodiment, the median number of cycles is about 16. In one embodiment, the median number of cycles is about 17. In one embodiment, the median number of cycles is about 18. In one embodiment, the median number of cycles is about 19. In one embodiment, the median number of cycles is about 20. In one embodiment, the median number of cycles is about 21. In one embodiment, the median number of cycles is about 22. In one embodiment, the median number of cycles is about 23. In one embodiment, the median number of cycles is about 24. In one embodiment, the median number of cycles is about 25. In one embodiment, the median number of cycles is about 26. In one embodiment, the median number of cycles is about 27. In one embodiment, the median number of cycles is about 28. In one embodiment, the median number of cycles is about 29. In one embodiment, the median number of cycles is about 30. In one embodiment, the median number of cycles is greater than about 30 cycles.

[0200] In one embodiment, azacitidine is administered to a patient at a dose provided herein over a cycle of 28 days which consists of a 7-day treatment period and a 21-day resting period. In one embodiment, azacitidine is administered to a patient at a dose provided herein each day from day 1 to day 7, followed with a resting period from day 8 to day 28 with no administration of azacitidine. In one embodiment, azacitidine is administered to a patient in cycles, each cycle consisting of a 7-day treatment period followed with a 21-day restingperiod. In particular embodiments, azacitidine is administered to a patient at a dose of about 50, about 60, about 70, about 75, about 80, about 90, or about 100 mg / m2 / day, for 7 days, followed with a resting period of 21 days. In one embodiment, azacitidine is administered intravenously. In one embodiment, azacitidine is administered subcutaneously.

[0201] In other embodiments, azacitidine is administered orally in cycles. In one embodiment, azacitidine is administered daily in single or divided doses for about one week. In one embodiment, azacitidine is administered daily for about two weeks. In one embodiment, azacitidine is administered daily for about three weeks. In one embodiment, azacitidine is administered daily for about four weeks. In one embodiment, azacitidine is administered daily for about five weeks. In one embodiment, azacitidine is administered daily for about six weeks. In one embodiment, azacitidine is administered daily for about eight weeks. In one embodiment, azacitidine is administered daily for about ten weeks. In one embodiment, azacitidine is administered daily for about fifteen weeks. In one embodiment, azacitidine is administered daily for or about twenty weeks. The administration is followed by a rest period of about 1 day to about ten weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about one week. In one embodiment, the methods provided herein contemplate cycling treatments of about two weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about three weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about four weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about five weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about six weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about eight weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about ten weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about fifteen weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about twenty weeks. In some embodiments, azacitidine is administered daily in single or divided doses for about one week. In one embodiment, azacitidine is administered daily for about two weeks. In one embodiment, azacitidine is administered daily for about three weeks. In one embodiment, azacitidine is administered daily for about four weeks. In one embodiment, azacitidine is administered daily for about five weeks. In one embodiment, azacitidine is administered daily for about six weeks. In one embodiment, the resting period of about 1, 3, 5, 7, 9, 12, 14, 16, 18, 20, 22, 24, 26, 28, 29, or 30 days. In some embodiments, the rest period is 1 day. In some embodiments, the rest period is 3 days. In someembodiments, the rest period is 7 days. In some embodiments, the rest period is 14 days. In some embodiments, the rest period is 28 days. The frequency, number and length of dosing cycles can be increased or decreased.

[0202] In one embodiment, vorasidenib is administered orally once a day. In one embodiment, vorasidenib is administered on days 1-28 of each 28-day cycle. In one embodiment, 50 mg of vorasidenib is administered orally once a day. In another embodiment, 100 mg of vorasidenib is administered orally once a day. In yet another embodiment, 200 mg of vorasidenib is administered orally once a day. In one embodiment, azacitidine is administered subcutaneously for 7 days. In one embodiment, azacitidine is administered on days 1-7 of each 28-day cycle. In one embodiment, 75 mg / m2 / day of azacitidine is administered on days 1-7 of each 28-day cycle.SELECTED EMBODIMENTS

[0203] Embodiment 1. A combination of vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate, or cocrystal thereof, and azacitidine for use in a method of treating a solid tumor, wherein vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate, or cocrystal thereof, and azacitidine are administered sequentially or concurrently.

[0204] Embodiment 2. A combination for use of embodiment 1, wherein the solid tumor is a brain tumor.

[0205] Embodiment 3. The combination for use of embodiment 2, wherein the brain tumor is glioma.

[0206] Embodiment 4. The combination for use of any one of embodiments 1-3, wherein the solid tumor is characterized by the presence of an isocitrate dehydrogenase (IDH) mutation.

[0207] Embodiment s. The combination for use of any one of embodiments 1-4, wherein the solid tumor is characterized by the presence of an IDH1 mutation.

[0208] Embodiment 6. The combination for use of embodiment 5, wherein the IDH1 mutation results in accumulation of R(-)-2 -hydroxyglutarate in a patient.

[0209] Embodiment 7. The combination for use of embodiment 5 or embodiment 6, wherein the IDH1 mutation is an R132X mutation.

[0210] Embodiment 8. The combination for use of embodiment 7, wherein the IDH1 mutation is an R132H, R132C, R132S, R132G or R132L mutation.

[0211] Embodiment 9. The combination for use of any one of embodiments 1 to 8, wherein the solid tumor is characterized by the presence of an IDH2 mutation.

[0212] Embodiment 10. The combination for use of embodiment 9, wherein the IDH2 mutation results in accumulation of R(-)-2 -hydroxyglutarate in a patient.

[0213] Embodiment 11. The combination for use of embodiment 9 or embodiment 10, wherein the IDH2 mutation is an R140X mutation.

[0214] Embodiment 12. The combination for use of embodiment 11, wherein the IDH2 mutation is an R140Q, R140W, or R140L mutation.

[0215] Embodiment 13. The combination for use of embodiment 9 or embodiment 10, wherein the IDH2 mutation is an R172X mutation.

[0216] Embodiment 14. The combination for use of embodiment 13, wherein the IDH2 mutation is an R172K or R172G mutation.

[0217] Embodiment 15. The combination for use of any one of embodiments 1 to 14, wherein the brain tumor is characterized by the presence of an IDH1 mutation and an IDH2 mutation.

[0218] Embodiment 16. The combination for use of embodiment 15, wherein the IDH1 and IDH2 mutations collectively result in accumulation of R(-)-2 -hydroxyglutarate in a patient.

[0219] Embodiment 17. The combination for use of any one of embodiments 1 to 16, wherein vorasidenib is administered in non-salt form.

[0220] Embodiment 18. The combination for use of any one of embodiments 1 to 16, wherein vorasidenib is administered in the form of a pharmaceutically acceptable salt.

[0221] Embodiment 19. The combination for use of any one of embodiments 1 to 16, wherein vorasidenib is administered as a cocrystal.

[0222] Embodiment 20. The combination for use of embodiment 19, wherein vorasidenib is administered as a cocrystal with citric acid.

[0223] Embodiment 21. The combination for use of any one of embodiments 1 to 20, wherein vorasidenib is administered at a dose between about 10 mg / day and about 100 mg / day.

[0224] Embodiment 22. The combination for use of any one of embodiments 1 to 20, wherein vorasidenib is administered at a dose between about 10 mg / day and about 50 mg / day.

[0225] Embodiment 23. The combination for use of any one of embodiments 1 to 20, wherein vorasidenib is administered at a dose between about 20 mg / day and about 40 mg / day.

[0226] Embodiment 24. The combination for use of any one of embodiments 1 to 20, wherein vorasidenib is administered at a dose of about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day or about 50 mg / day.

[0227] Embodiment 25. The combination for use of any one of embodiments 1 to 20, wherein vorasidenib is administered at a dose of about 10 mg / day, about 20 mg / day or about 40 mg / day.

[0228] Embodiment 26. The combination for use of any one of embodiments 1 to 20, wherein vorasidenib is administered at a dose of about 20 mg / day or about 40 mg / day.

[0229] Embodiment 27. The combination for use of any one of embodiments 1 to 20, wherein vorasidenib is administered at a dose of about 40 mg / day.

[0230] Embodiment 28. The combination for use of any one of embodiments 1 to 27, wherein vorasidenib is administered once or twice daily.

[0231] Embodiment 29. The combination for use of any one of embodiments 1 to 27, wherein vorasidenib is administered once daily.

[0232] Embodiment 30. The combination for use of embodiment 29, wherein vorasidenib is administered at a dose between about 10 mg and about 100 mg once daily.

[0233] Embodiment 31. The combination for use of embodiment 29, wherein vorasidenib is administered at a dose between about 10 mg and about 50 mg once daily.

[0234] Embodiment 32. The combination for use of embodiment 29, wherein vorasidenib is administered at a dose between about 20 mg and about 40 mg once daily.

[0235] Embodiment 33. The combination for use of embodiment 29, wherein vorasidenib is administered at a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg or about 50 mg once daily.

[0236] Embodiment 34. The combination for use of embodiment 29, wherein vorasidenib is administered at a dose of about 10 mg, about 20 mg or about 40 mg once daily.

[0237]

[0238] Embodiment 35. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 2,000 mg / m2 / day.

[0239] Embodiment 36. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 2,000 mg / m2 / day.

[0240] Embodiment 37. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 100 mg / m2 / day and about 1,000 mg / m2 / day.

[0241] Embodiment 38. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 100 mg / m2 / day and about 500 mg / m2 / day.

[0242] Embodiment 39. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 500 mg / m2 / day.

[0243] Embodiment 40. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 200 mg / m2 / day.

[0244] Embodiment 41. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 75 mg / m2 / day.

[0245] Embodiment 42. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 120 mg / m2 / day and about 250 mg / m2 / day.

[0246] Embodiment 43. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose of about 50 mg / m2 / day, about 75 mg / m2 / day, about 80 mg / m2 / day, about 100 mg / m2 / day, about 120 mg / m2 / day, about 140 mg / m2 / day, about 150 mg / m2 / day, about 180 mg / m2 / day, about 200 mg / m2 / day, about 220 mg / m2 / day, about 240 mg / m2 / day, about 250 mg / m2 / day, about 260 mg / m2 / day, about 280 mg / m2 / day, about 300 mg / m2 / day, about 350 mg / m2 / day, about 380 mg / m2 / day, about 400 mg / m2 / day, about 450 mg / m2 / day or about 500 mg / m2 / day.

[0247] Embodiment 44. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 5 mg / day and about 2,000 mg / day.

[0248] Embodiment 45. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 10 mg / day and about 2,000 mg / day.

[0249] Embodiment 46. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 20 mg / day and about 2,000 mg / day.

[0250] Embodiment 47. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 100 mg / day and about 1,000 mg / day.

[0251] Embodiment 48. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 100 mg / day and about 500 mg / day.

[0252] Embodiment 49. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 150 mg / day and about 250 mg / day.

[0253] Embodiment 50. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose between about 120 mg / m2 / day and about 250 mg / m2 / day.

[0254] Embodiment 51. The combination for use of any one of embodiments 1 to 34, wherein azacitidine is administered at a dose of about 10 mg / day, about 20 mg / day, about 50 mg / day, about 75 mg / day, about 100 mg / day, about 120 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 4500 mg / day, about 500 mg / day, about 600 mg / day, about 700 mg / day, about 800 mg / day, about 1,000 mg / day, about 1,200 mg / day or about 1,500 mg / day.

[0255] Embodiment 52. The combination for use of any one of embodiments 1 to 51, wherein vorasidenib and azacitidine are administered sequentially.

[0256] Embodiment 53. The combination for use of any one of embodiments 1 to 51 wherein vorasidenib and azacitidine are administered concurrently.

[0257] Embodiment 54. A method of treating a solid tumor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate, or cocrystal thereof, and azacitidine.

[0258] Embodiment 55. The method of embodiment 54, wherein the solid tumor is a brain tumor.

[0259] Embodiment 56. The method of embodiment 55, wherein the brain tumor is a glioma.

[0260] Embodiment 57. The method of any one of embodiments 54 to 56, wherein the solid tumor is characterized by the presence of an isocitrate dehydrogenase (IDH) mutation.

[0261] Embodiment 58. The method of embodiment 57, wherein the solid tumor is characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in accumulation of R(-)-2-hydroxyglutarate in a patient.

[0262] Embodiment 59. The method of embodiment 57 or 58, wherein the IDH1 mutation is an R132X mutation.

[0263] Embodiment 60. The method of embodiment 59, wherein the IDH1 mutation is an R132H, R132C, R132S, R132G or R132L mutation.

[0264] Embodiment 61. The method of any one of embodiments 54 to 56, wherein the solid tumor is characterized by the presence of an IDH2 mutation.

[0265] Embodiment 62. The method of embodiment 61, wherein the IDH2 mutation results in accumulation of R(-)-2 -hydroxyglutarate in a patient.

[0266] Embodiment 63. The method of embodiment 61 or embodiment 62, wherein theIDH2 mutation is an R140X mutation.

[0267] Embodiment 64. The method of embodiment 63, wherein the IDH2 mutation is an R140Q, R140W, or R140L mutation.

[0268] Embodiment 65. The method of embodiment 61 or embodiment 62, wherein theIDH2 mutation is an R172X mutation.

[0269] Embodiment 66. The method of embodiment 65, wherein the IDH2 mutation is an R172K or R172G mutation.

[0270] Embodiment 67. The method of any one of embodiments 54 to 66, wherein the solid tumor is characterized by the presence of an IDH1 mutation and an IDH2 mutation.

[0271] Embodiment 68. The method of embodiment 67, , wherein the IDH1 and IDH2 mutations collectively result in accumulation of R(-)-2-hydroxyglutarate in a patient.

[0272] Embodiment 69. The method of any one of embodiments 54 to 68, wherein vorasidenib is administered in non-salt form.

[0273] Embodiment 70. The method of any one of embodiments 54 to 68, wherein vorasidenib is administered in the form of a pharmaceutically acceptable salt.

[0274] Embodiment 71. The method of any one of embodiments 54 to 68, wherein vorasidenib is administered as a cocrystal.

[0275] Embodiment 72. The method of embodiment 71, wherein vorasidenib is administered as a cocrystal with citric acid.

[0276] Embodiment 73. The method of any one of embodiments 54 to 72, wherein vorasidenib is administered at a dose between about 10 mg / day and about 100 mg / day.

[0277] Embodiment 74. The method of any one of embodiments 54 to 72, wherein vorasidenib is administered at a dose between about 10 mg / day and about 50 mg / day.

[0278] Embodiment 75. The method of any one of embodiments 54 to 72, wherein vorasidenib is administered at a dose between about 20 mg / day and about 40 mg / day.

[0279] Embodiment 76. The method of any one of embodiments 54 to 72, wherein vorasidenib is administered at a dose of about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day or about 50 mg / day.

[0280] Embodiment 77. The method of any one of embodiments 54 to 72, wherein vorasidenib is administered at a dose of about 10 mg / day, about 20 mg / day or about 40 mg / day.

[0281] Embodiment 78. The method of any one of embodiments 54 to 72, wherein vorasidenib is administered at a dose of about 20 mg / day or about 40 mg / day.

[0282] Embodiment 79. The method of any one of embodiments 54 to 72, wherein vorasidenib is administered at a dose of about 40 mg / day.

[0283] Embodiment 80. The method of any one of embodiments 54 to 79, wherein vorasidenib is administered once or twice daily.

[0284] Embodiment 81. The method of any one of embodiments 54 to 79, wherein vorasidenib is administered once daily.

[0285] Embodiment 82. The method of embodiment 81, wherein vorasidenib is administered at a dose between about 10 mg and about 100 mg once daily.

[0286] Embodiment 83. The method of embodiment 81, wherein vorasidenib is administered at a dose between about 10 mg and about 50 mg once daily.

[0287] Embodiment 84. The method of embodiment 81, wherein vorasidenib is administered at a dose between about 20 mg and about 40 mg once daily.

[0288] Embodiment 85. The method of embodiment 81, wherein vorasidenib is administered at a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg or about 50 mg once daily.

[0289] Embodiment 86. The method of embodiment 81, wherein vorasidenib is administered at a dose of about 10 mg, about 20 mg or about 40 mg once daily.

[0290] Embodiment 87. The method of embodiment 81, wherein vorasidenib is administered at a dose of about 20 mg or about 40 mg once daily.

[0291] Embodiment 88 The method of embodiment 81, wherein vorasidenib is administered at a dose of about 40 mg once daily.

[0292] Embodiment 89. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 2,000 mg / m2 / day.

[0293] Embodiment 90. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 100 mg / m2 / day and about 1,000 mg / m2 / day.

[0294] Embodiment 91. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 100 mg / m2 / day and about 500 mg / m2 / day.

[0295] Embodiment 92. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 500 mg / m2 / day.

[0296] Embodiment 93. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 200 mg / m2 / day.

[0297] Embodiment 94. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 75 mg / m2 / day.

[0298] Embodiment 95. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 120 mg / m2 / day and about 250 mg / m2 / day.

[0299] Embodiment 96. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose of about 50 mg / m2 / day, about 75 mg / m2 / day, about 80 mg / m2 / day, about 100 mg / m2 / day, about 120 mg / m2 / day, about 140 mg / m2 / day, about 150 mg / m2 / day, about 180 mg / m2 / day, about 200 mg / m2 / day, about 220 mg / m2 / day, about 240 mg / m2 / day, about 250 mg / m2 / day, about 260 mg / m2 / day, about 280 mg / m2 / day, about 300 mg / m2 / day, about 350 mg / m2 / day, about 380 mg / m2 / day, about 400 mg / m2 / day, about 450 mg / m2 / day or about 500 mg / m2 / day.

[0300] Embodiment 97. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 5 mg / day and about 2,000 mg / day.

[0301] Embodiment 98. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 10 mg / day and about 2,000 mg / day.

[0302] Embodiment 99. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 20 mg / day and about 2,000 mg / day.

[0303] Embodiment 100. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 100 mg / day and about 1,000 mg / day.

[0304] Embodiment 101. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 100 mg / day and about 500 mg / day.

[0305] Embodiment 102. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 150 mg / day and about 250 mg / day.

[0306] Embodiment 103. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose between about 120 mg / m2 / day and about 250 mg / m2 / day.

[0307] Embodiment 104. The method of any one of embodiments 54 to 88, wherein azacitidine is administered at a dose of about 10 mg / day, about 20 mg / day, about 50 mg / day, about 75 mg / day, about 100 mg / day, about 120 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 4500 mg / day, about 500 mg / day, about 600 mg / day, about 700 mg / day, about 800 mg / day, about 1,000 mg / day, about 1,200 mg / day or about 1,500 mg / day.

[0308] Embodiment 105. The method of any one of embodiments 54 to 104, wherein vorasidenib and azacitidine are administered sequentially.

[0309] Embodiment 106. The method of any one of embodiments 54 to 104 wherein vorasidenib and azacitidine are administered concurrently.

[0310] Embodiment 107. A method of treating a solid tumor in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate, or cocrystal thereof, and azacitidine.EXAMPLESExample 1. Preclinical study (in vitro) to explore combination effect for vorasidenib and azacitidine in TS603 neurosphere model system

[0311] This study will be performed in TS603 neurosphere model (in vitro) to access the Target engagement, cellular differentiation and efficacy analyzed by Colony formation

[0312] Compounds: vorasidenib dissolved in DMSO. Azacitidine (AZA) dissolved in DMSO.

[0313] Neurosphere: TS603 IDHR132H heterozygous mutant cell line

[0314] Study plan: the study plan is detailed in Figi .

[0315] Experiment 1: First step of the study is Target Engagement i.e. 2-HG analysis The study will be performed in 3D Neurosphere culture of TS603 cells. In this study 3 doses of Vorasidenib (0.1, 0.25, 0.75 nM) will be tested as single agent and the matrix combination with 1000 nM AZA (Vora / AZA: 0.1 / 1000, 0.25 / 1000, 0.75 / 1000 nM). Study will be performed in duplicate therefore a total of 14 samples will be collected and analyzed for target engagement i.e. 2HG reduction.

[0316] Experiment 2: Second set of experiments will be to analyze PD (Pharmacodynamic) biomarkers i.e. Cell Differentiation genes and protein markers.This study will be performed in 3D Neurosphere culture of TS603 cells. In this study 3 doses of vorasidenib will be tested as single agent and AZA combination. The dose levels of vorasidenib dose will be selected based on the target engagement analysis (30, 60 and 90% target engagement) performed in Experiment 1 (paragraph

[0194] , AZA will also be tested at 3 dose levels (100, 500 and 1000 nM) for PD biomarkers. A combination run for vorasidenib and AZA will be performed as vorasidenib / AZA: 30% / 100, 60% / 100, 90% / 100, 30 % / 500, 60 % / 500, 90 % / 500, 30 % / 1000, 60 % / 1000, 90 % / 1000 nM. Total 16 combinations will be performed in duplicates for mRNA analysis of GFAP, AQP4, ATP1A2, CNP and NG2. All 16 combinations will also be tested as single sample for Protein estimation of DNMT1, GFAP, protein loading control.

[0317] Experiment 3: Third set of experiments will be to analyze combination efficacy of vorasidenib and AZA in colony formation assayThis study will be performed with TS603 cells in soft agar to analyze combination efficacy of vorasidenib and AZA in Colony formation assay, vorasidenib dose will be selected based on the target engagement analysis (100%) performed in Experiment 1 (paragraph

[0194] and AZA will be tested at lOOOnM. Vorasidenib and AZA will be tested as single agent as well as combinations (vorasidenib / AZA: 100% Target engagement / 1000 nM). This study will be performed as 4 per triplicate, total 12 samples.Example 2. Preclinical study (in vivo) to explore combination effect for vorasidenib and azacitidine in TS603 xenograft model.

[0318] This study will be performed to explore the Tumor Efficacy response of vorasidenib in combination with azacitidine (AZA), with BID dosing of vorasidenib at 2 different concentrations (5mpk and 50mpk) as a combo with AZA in a xenograft model of human glioma utilizing TS603 cells (IDH1R132C) in ICR SCID mice

[0319] Vorasidenib will be used as a solution in 0.5% methyl cellulose (cP400) and 0.2% Tween 80 in water.

[0320] Azacitidine will be used as a solution in 5% DMSO and 30% PEG 300 in water.

[0321] Mice: Fox Chase SCID male mice, 5-6 weeks will be used

[0322] Test System: Inoculation of le6TS603 cells with Matrigel into the flanks of male SCID mice

[0323] Study plan: the study plan is detailed in Table 1 below. Each group comprises 10 mice (N).Dosing for vorasidenib is BID x 28 per oral and AZA is Q3D x 4 intraperitoneal.The dosing schedule for azacitidine is with second dose of vorasidenib in groups 5 and 6. Sample collections were performed after azacitidine treatment in groups 2, 5 and 6 and / or after second dose of vorasidenib in groups 3 and 4.Sampling will be done post last dose at 3 time points (1 and 3 hr survival and 8 hr Terminal).Table 1. Preclinical (in vivo) study plan

[0324] Tumor volume and body weight measurements will be performed twice weekly

[0325] Study will be terminated at day 28 and tumor growth inhibition will be analyzed.

Claims

Claims1. A method of treating a solid tumor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate, or cocrystal thereof, and azacitidine.

2. The method of claim 1, wherein the solid tumor is a brain tumor.

3. The method of claim 2, wherein the brain tumor is a glioma.

4. The method of any one of claims 1 to 3, wherein the solid tumor is characterized by the presence of an isocitrate dehydrogenase (IDH) mutation.

5. The method of claim 4, wherein the solid tumor is characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in accumulation of R(-)-2- hydroxyglutarate in a patient.

6. The method of claim 4 or 5, wherein the IDH1 mutation is an R132X mutation.

7. The method of claim 6, wherein the IDH1 mutation is an R132H, R132C, R132S, R132G or R132L mutation.

8. The method of any one of claims 1 to 3, wherein the solid tumor is characterized by the presence of an IDH2 mutation.

9. The method of claim 8, wherein the IDH2 mutation results in accumulation of R(-)-2 -hydroxyglutarate in a patient.

10. The method of claim 8 or claim 9, wherein the IDH2 mutation is an R140X mutation.

11. The method of claim 10, wherein the IDH2 mutation is an R140Q, R140W, or R140L mutation.

12. The method of claim 8 or claim 9, wherein the IDH2 mutation is an R172X mutation.

13. The method of claim 12, wherein the IDH2 mutation is an R172K or R172G mutation.

14. The method of any one of claims 1 to 13, wherein the solid tumor is characterized by the presence of an IDH1 mutation and an IDH2 mutation.

15. The method of claim 14 wherein the IDH1 and IDH2 mutations collectively result in accumulation of R(-)-2 -hydroxyglutarate in a patient.

16. The method of any one of claims 1 to 15, wherein vorasidenib is administered in non-salt form.

17. The method of any one of claims 1 to 15, wherein vorasidenib is administered in the form of a pharmaceutically acceptable salt.

18. The method of any one of claims 1 to 15, wherein vorasidenib is administered as a cocrystal.

19. The method of claim 18, wherein vorasidenib is administered as a cocrystal with citric acid.

20. The method of any one of claims 1 to 19, wherein vorasidenib is administered at a dose between about 10 mg / day and about 100 mg / day.

21. The method of any one of claims 1 to 19, wherein vorasidenib is administered at a dose between about 10 mg / day and about 50 mg / day.

22. The method of any one of claims 1 to 19, wherein vorasidenib is administered at a dose between about 20 mg / day and about 40 mg / day.

23. The method of any one of claims 1 to 19, wherein vorasidenib is administered at a dose of about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day or about 50 mg / day.

24. The method of any one of claims 1 to 19, wherein vorasidenib is administered at a dose of about 10 mg / day, about 20 mg / day or about 40 mg / day.

25. The method of any one of claims 1 to 19, wherein vorasidenib is administered at a dose of about 20 mg / day or about 40 mg / day.

26. The method of any one of claims 1 to 19, wherein vorasidenib is administered at a dose of about 40 mg / day.

27. The method of any one of claims 1 to 26, wherein vorasidenib is administered once or twice daily.

28. The method of any one of claims 1 to 26, wherein vorasidenib is administered once daily.

29. The method of claim 28, wherein vorasidenib is administered at a dose between about 10 mg and about 100 mg once daily.

30. The method of claim 28, wherein vorasidenib is administered at a dose between about 10 mg and about 50 mg once daily.

31. The method of claim 28, wherein vorasidenib is administered at a dose between about 20 mg and about 40 mg once daily.

32. The method of claim 28, wherein vorasidenib is administered at a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg or about 50 mg once daily.

33. The method of claim 28, wherein vorasidenib is administered at a dose of about 10 mg, about 20 mg or about 40 mg once daily.

34. The method of claim 28, wherein vorasidenib is administered at a dose of about 20 mg or about 40 mg once daily.

35. The method of claim 28, wherein vorasidenib is administered at a dose of about 40 mg once daily.

36. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 2,000 mg / m2 / day.

37. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 100 mg / m2 / day and about 1,000 mg / m2 / day.

38. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 100 mg / m2 / day and about 500 mg / m2 / day.

39. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 500 mg / m2 / day.

40. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 200 mg / m2 / day.

41. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 50 mg / m2 / day and about 75 mg / m2 / day.

42. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 120 mg / m2 / day and about 250 mg / m2 / day.

43. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose of about 50 mg / m2 / day, about 75 mg / m2 / day, about 80 mg / m2 / day, about 100 mg / m2 / day, about 120 mg / m2 / day, about 140 mg / m2 / day, about 150 mg / m2 / day, about 180 mg / m2 / day, about 200 mg / m2 / day, about 220 mg / m2 / day, about 240 mg / m2 / day, about 250 mg / m2 / day, about 260 mg / m2 / day, about 280 mg / m2 / day, about 300 mg / m2 / day, about 350 mg / m2 / day, about 380 mg / m2 / day, about 400 mg / m2 / day, about 450 mg / m2 / day or about 500 mg / m2 / day.

44. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 5 mg / day and about 2,000 mg / day.

45. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 10 mg / day and about 2,000 mg / day.

46. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 20 mg / day and about 2,000 mg / day.

47. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 100 mg / day and about 1,000 mg / day.

48. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 100 mg / day and about 500 mg / day.

49. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 150 mg / day and about 250 mg / day.

50. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose between about 120 mg / m2 / day and about 250 mg / m2 / day.

51. The method of any one of claims 1 to 35, wherein azacitidine is administered at a dose of about 10 mg / day, about 20 mg / day, about 50 mg / day, about 75 mg / day, about 100 mg / day, about 120 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 4500 mg / day, about 500 mg / day, about 600 mg / day, about 700 mg / day, about 800 mg / day, about 1,000 mg / day, about 1,200 mg / day or about 1,500 mg / day.

52. The method of any one of claims 1 to 51, wherein vorasidenib and azacitidine are administered sequentially.

53. The method of any one of claims 1 to 51 wherein vorasidenib and azacitidine are administered concurrently.

54. A method of treating a solid tumor in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising vorasidenib or a pharmaceutically acceptable salt, hydrate, solvate, or cocrystal thereof, and azacitidine.

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