Combination therapy for treating malignancies
Provided are methods and compositions for treating hematological malignancies in patients carrying an IDH1 mutation using a combination of an inhibitor of mutant IDH1 enzyme, (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, or a pharmaceutically acceptable salt thereof (COMPOUND 2) and a DNA demethylating agent.
1. A method of treating acute myelogenous leukemia (AML) 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 and azacitidine, 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. The method of claim 1 , wherein the dose of COMPOUND 2 is about 20 to 2000 mg/day.
3. The method of claim 1 , wherein the dose of COMPOUND 2 is about 50 to 500 mg/day.
4. The method of claim 1 , wherein the dose of COMPOUND 2 is about 50 mg/day.
5. The method of claim 1 , wherein the dose of COMPOUND 2 is about 75 mg/day.
6. The method of claim 1 , wherein the dose of COMPOUND 2 is about 100 mg/day.
7. The method of claim 1 , wherein the dose of azacitidine is about 50 to about 500 mg/m 2 /day.
8. The method of claim 1 , wherein the dose of azacitidine is about 50 to about 200 mg/m 2 /day.
9. The method of claim 1 , wherein the dose of azacitidine is about 50 mg/m 2 /day.
10. The method of claim 1 , wherein the dose of azacitidine is about 60 mg/m 2 /day.
11. The method of claim 1 , wherein the dose of azacitidine is about 75 mg/m 2 /day.
12. The method of claim 1 , wherein COMPOUND 2 and azacitidine are administered concurrently.
13. The method of claim 1 , wherein COMPOUND 2 and azacitidine are administered sequentially.
14. The method of claim 1 , wherein the dose of COMPOUND 2 is about 500 mg/day.
15. The method of claim 1 , wherein the azacitidine is administered in cycles.
16. The method of claim 15 , wherein the azacitidine is administered subcutaneously for 7 days of each 28-day treatment cycle.
17. The method of claim 1 , wherein the AML is previously untreated AML.
18. The method of claim 1 , wherein the AML is newly diagnosed AML.
19. A pharmaceutical composition, comprising (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 or a pharmaceutically acceptable salt thereof, and azacitidine.
20. A method of treating AML characterized by the presence of a mutant allele of IDH1 comprising administering to a patient in need thereof the pharmaceutical composition of claim 19 , wherein the mutant allele of IDH1 has a mutation selected from R132H, R132C, R132L, R132V, R132S and R132GF.