Claims for Patent: 10,653,710

Summary for Patent: 10,653,710

Title:	Combination therapy for treating malignancies
Abstract:	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-oxoethy- l)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-car- boxamide, or a pharmaceutically acceptable salt thereof (COMPOUND 2) and a DNA demethylating agent.
Inventor(s):	Agresta; Samuel V. (Lexington, MA), Viswanadhan; Krishnan (East Hanover, NJ), DiMartino; Jorge (Belmont, CA), Chopra; Vivek Saroj Kumar (South San Francisco, CA), MacBeth; Kyle J. (San Francisco, CA), Knight; Robert Douglas (Berkeley Heights, NJ), Kenvin; Laurie (New Hope, PA), Xu; Qiang (Bernards, NJ)
Assignee:	Agios Pharmaceuticals, Inc. (Cambridge, MA) Celgene Corporation (Summit, NJ)
Application Number:	15/767,822
Patent Claims:	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-oxoethy- l)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-car- boxamide, having the following formula: ##STR00006## 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.sup.2/day. 8. The method of claim 1, wherein the dose of azacitidine is about 50 to about 200 mg/m.sup.2/day. 9. The method of claim 1, wherein the dose of azacitidine is about 50 mg/m.sup.2/day. 10. The method of claim 1, wherein the dose of azacitidine is about 60 mg/m.sup.2/day. 11. The method of claim 1, wherein the dose of azacitidine is about 75 mg/m.sup.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-carb- oxamide 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.