Combination therapy for treating malignancies
Provided are methods and compositions for treating acute myelogenous leukemia (AML) in patients carrying an IDH1 mutation using an inhibitor of a 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 in combination with cytarabine and doxorubicin or idarubicin as an induction therapy and either cytarabine or a combination of combination of mitoxantrone and etoposide as consolidation therapy.
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 therapeutically effective amount of an isocitrate dehydrogenase 1 (IDH1) inhibitor and;
a) an induction therapy regimen consisting of cytarabine and an anthracycline selected from daunorubicin and idarubicin; and
b) a consolidation therapy regimen consisting of cytarabine;
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 is administered during both the induction and the consolidation regimens 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 cytarabine used as an induction therapy is between about 100 mg/m 2 /day and about 500 mg/m 2 /day.
3. The method of claim 2 , wherein the dose of cytarabine is between about 150 mg/m 2 /day and about 300 mg/m 2 /day.
4. The method of claim 3 , wherein the dose of cytarabine is about 200 mg/m 2 /day.
5. The method of claim 1 , wherein the dose of cytarabine used as a consolidation therapy is between about 1 g/m 2 /day and about 10 g/m 2 /day.
6. The method of claim 5 , wherein the dose of cytarabine is between about 1 g/m 2 /day and about 5 g/m 2 /day.
7. The method of claim 6 , wherein the dose of cytarabine is 1 g/m 2 /day, or 1.5 g/m 2 /day, or 2 g/m 2 /day, or 3 g/m 2 /day.
8. The method of claim 1 , wherein the anthracycline is daunorubicin administered at a dose between about 10 mg/m 2 /day and about 300 mg/m 2 /day.
9. The method of claim 8 , wherein the dose of daunorubicin is between about 30 mg/m 2 /day and about 150 mg/m 2 /day.
10. The method of claim 9 , wherein the dose of daunorubicin is about 60 mg/m 2 /day.
11. The Method of claim 1 , wherein the anthracycline is idarubicin administered at a dose between about 1 mg/m 2 /day and about 25 mg/m 2 /day.
12. The method of claim 11 , wherein the dose of idarubicin is between about 3 mg/m 2 /day and about 15 mg/m 2 /day.
13. The method of claim 12 , wherein the dose of idarubicin is about 12 mg/m 2 /day.
14. The method of claim 1 , wherein the dose of COMPOUND 2 is about 20 to 2000 mg/day.
15. The method of claim 1 , wherein the dose of COMPOUND 2 is about 50 to 500 mg/day.
16. The method of claim 1 , wherein the dose of COMPOUND 2 is about 50 mg/day.
17. The method of claim 1 , wherein the dose of COMPOUND 2 is about 75 mg/day.
18. The method of claim 1 , wherein the dose of COMPOUND 2 is about 100 mg/day.
19. The method of claim 1 , wherein AML is selected from newly diagnosed AML, untreated AML, AML arising from myelodysplastic syndrome, AML arising from antecedent hematologic disorder and AML arising after exposure to genotoxic injury.
20. The method of claim 1 wherein the dose of COMPOUND 2 is about 500 mg/day.
21. The method of claim 1 wherein the induction regimen consists of cytarabine administered for 7 days and daunorubicin administered for 3 days.
22. The method of claim 1 wherein the induction regimen consists of cytarabine administered for 7 days and idarubicin administered for 3 days.