METHODS OF TREATMENT OF MALIGNANCIES

1 . A method of treating a hematological malignancy in a subject comprising administering to the subject a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, having the following formula:

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 2), wherein the hematological malignancy is a malignancy characterized by the presence of a mutant allele of IDH1 and the absence of an RAS mutation.

2 - 3 . (canceled)

4 . A method of treating a solid tumor in a subject comprising administering to the subject a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, having the following formula:

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 2), wherein the solid tumor is characterized by the presence of a mutant allele of IDH1 and the absence of an RAS mutation.

5 - 6 . (canceled)

7 . A method of treating a hematological malignancy in a subject comprising administering to the subject a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, having the following formula:

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 2) in combination with a RAS pathway inhibitor, wherein the hematological malignancy is a malignancy characterized by the presence of a mutant allele of IDH1 and a mutant RAS.

8 . The method of claim 7 , wherein the RAS mutation is an NRAS mutation.

9 . The method of claim 7 , wherein the RAS mutation is a KRAS mutation.

10 . A method of treating a solid tumor in a subject comprising administering to the subject a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, having the following formula:

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 2) in combination with a RAS pathway inhibitor, wherein the solid tumor characterized by the presence of a mutant allele of IDH1 and a mutant RAS.

11 . The method of claim 10 , wherein the RAS mutation is an NRAS mutation.

12 . The method of claim 10 , wherein the RAS mutation is a KRAS mutation.

13 . The method of claim 7 , wherein the IDH1 mutation is an IDH1 R132X mutation.

14 . The method of claim 13 , wherein the IDH1 mutation is an IDH1 R132H, R132C, R132L, R132V, R132S or R132G mutation.

15 . The method of claim 7 , wherein the a RAS pathway inhibitor is a MEK kinase inhibitor.

16 . The method of claim 15 , wherein the MEK kinase inhibitor is selected from trametinib, selumetinib, binimetinib, PD-325901, cobimetinib, CI-1040 and PD035901.

17 . The method of claim 1 or 117 , wherein the malignancy is acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS, myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemias (B-ALL), or lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutant allele of IDH1 and the method comprises administering a therapeutically effective amount of COMPOUND 2 to the subject.

18 . The method of claim 17 , wherein the malignancy is acute myelogenous leukemia (AML).

19 . The method of claim 114 or 1110 , wherein the solid tumor is glioma, melanoma, chondrosarcoma, cholangiocarcinoma (including intrahepatic cholangiocarcinoma (IHCC), prostate cancer, colon cancer, or non-small cell lung cancer (NSCLC), each characterized by the presence of a mutant allele of IDH1 and the method comprises administering a therapeutically effective amount of COMPOUND 2 to the subject.

20 . The method of claim 7 , wherein the dose of COMPOUND 2 is about 20 to about 2000 mg/day.

21 . The method of claim 7 , wherein the dose of COMPOUND 2 is about 50 to 500 mg/day.

22 - 26 . (canceled)

27 . A method of identifying a cancer subject suitable for treatment with a combination of an IDH1 inhibitor and a RAS pathway inhibitor, comprising: (a) obtaining a biological sample from a subject having cancer; (b) screening the biological sample for an IDH1 mutation and an RAS mutation; and (c) if the cancer is characterized by the presence of a mutant allele of IDH1 and a mutant RAS, identifying the subject as a cancer subject suitable for treatment with a combination therapy with an IDH1 inhibitor and a RAS pathway inhibitor.

28 . The method of claim 27 , wherein the RAS mutation is an NRAS mutation.

29 . The method of claim 27 , wherein the RAS mutation is a KRAS mutation.

30 . The method of claim 27 , wherein the IDH1 inhibitor is COMPOUND 2.

31 . The method of claim 27 , wherein the RAS pathway inhibitor is selected from trametinib, selumetinib, binimetinib, PD-325901, cobimetinib, CI-1040 and PD035901.

32 . The method of claim 27 , wherein the cancer is a solid tumor or a hematologic malignancy.

33 . The method of claim 32 , wherein the hematologic malignancy is AML.

34 . The method of claim 27 , wherein the cancer is relapsed or refractory.

35 . The method of claim 33 , wherein the AML is relapsed or refractory.

36 . The method of claim 7 , wherein the subject has 3 or less co-occuring mutations.

37 . The method of claim 8 , wherein the NRAS mutation is at a residue G12, G13 or Q61.

38 - 62 . (canceled)

63 . The method of claim 17 , wherein the hematologic malignancy is relapsed or refractory.

64 . The method of claim 18 , wherein the AML is relapsed or refractory.