COMBINATION THERAPY FOR TREATING MALIGNANCIES
Provided are methods and compositions for treating cancers in patients carrying an IDH1 mutation using a combination of an inhibitor of a mutant IDH1 enzyme and a DNA demethylating agent.
1 . A method of treating a hematological malignancy characterized by the presence of a mutant allele of IDH1, comprising administering to a subject in need thereof a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, azacitidine and an additional cancer therapeutic agent, wherein the mutant IDH1 inhibitor is (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 thereof (COMPOUND 2), and wherein the mutant allele of IDH1 has a mutation selected from R132H, R132C, R132L, R132V, R132S and R132GF.
2 - 3 . (canceled)
4 . The method of claim 1 , 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.
5 . The method of claim 1 , wherein the malignancy is acute myelogenous leukemia (AML).
6 . (canceled)
7 . The method of claim 1 , wherein the dose of COMPOUND 2 is about 20 to 2000 mg/day.
8 . The method of claim 1 , wherein the dose of COMPOUND 2 is about 50 to 500 mg/day.
9 . The method of claim 1 , wherein the dose of COMPOUND 2 is about 50 mg/day.
10 . The method of claim 1 , wherein the dose of COMPOUND 2 is about 75 mg/day.
11 . The method of claim 1 , wherein the dose of COMPOUND 2 is about 100 mg/day.
12 . (canceled)
13 . The method of claim 1 , wherein the dose of azacitidine is about 50 to about 500 mg/m 2 /day.
14 . The method of claim 1 , wherein the dose of azacitidine is about 50 to about 200 mg/m 2 /day.
15 . The method of claim 1 , wherein the dose of azacitidine is about 50 mg/m 2 /day.
16 . The method of claim 1 , wherein the dose of azacitidine is about 60 mg/m 2 /day.
17 . The method of claim 1 , wherein the dose of azacitidine is about 75 mg/m 2 /day.
18 . The method of claim 1 , wherein COMPOUND 2 and azacitidine are administered concurrently.
19 . The method of claim 1 , wherein COMPOUND 2 and azacitidine are administered sequentially.
20 - 21 . (canceled)
22 . The method of claim 1 , wherein the dose of COMPOUND 2 is about 500 mg/day.
23 . The method of claim 1 , wherein the azacitidine is administered in cycles.
24 . The method of claim 23 , wherein the azacitidine is administered subcutaneously for 7 days of each 28-day treatment cycle.
25 . The method of claim 5 , wherein the AML is previously untreated AML.
26 . The method of claim 5 , wherein the AML is newly diagnosed AML.