METHODS OF TREATMENT OF MALIGNANCIES
Provided are methods and compositions for treating cancers in patients carrying an IDH1 mutation or IDH2 mutation.
1 . A method of treating acute myelogenous leukemia (AML) 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 (COMPOUND 2), having the following formula:
or a pharmaceutically acceptable salt, solvate, or a polymorph thereof, wherein the AML is characterized by the presence of a mutant allele of IDH1 and the absence of an RAS mutation.
2 . The method of claim 1 , wherein the RAS mutation is an NRAS mutation.
3 . The method of claim 1 , wherein the RAS mutation is a KRAS mutation.
4 - 6 . (canceled)
7 . A method of treating acute myelogenous leukemia (AML) 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 (COMPOUND 2), having the following formula:
or a pharmaceutically acceptable salt, solvate, or a polymorph thereof in combination with a RAS pathway inhibitor, wherein the AML is characterized by the presence of a mutant allele of IDH1 and the presence of an RAS mutation.
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 - 12 . (canceled)
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 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 . (canceled)
18 . The method of claim 7 , wherein the acute myelogenous leukemia (AML) is relapsed or refractory.
19 . (canceled)
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 - 62 . (canceled)
63 . The method of claim 7 , wherein the dose of COMPOUND 2 is about 500 mg/day.
64 . The method of claim 1 , wherein the IDH1 mutation is an IDH1 R132X mutation.
65 . The method of claim 64 , wherein the IDH1 mutation is an IDH1 R132H, R132C, R132L, R132V, R132S or R132G mutation.
66 . The method of claim 1 , wherein the acute myelogenous leukemia (AML) is relapsed or refractory.
67 . The method of claim 1 , wherein the dose of COMPOUND 2 is about 20 to about 2000 mg/day.
68 . The method of claim 1 , wherein the dose of COMPOUND 2 is about 50 to 500 mg/day.
69 . The method of claim 1 , wherein the dose of COMPOUND 2 is about 500 mg/day.