COMBINATION THERAPY FOR TREATING MALIGNANCIES
Provided are methods and compositions for treating AML in patients carrying an IDH2 mutation using a combination of an inhibitor of a mutant IDH2 enzyme and an AML induction and consolidation therapy.
1 . A method of treating acute myelogenous leukemia (AML), comprising administering to a subject a therapeutically effective amount of a mutant isocitrate dehydrogenase 2 (IDH2) inhibitor and a combination of Cytarabine and Daunorubicin as an induction therapy, further comprising administering the mutant isocitrate dehydrogenase 2 (IDH2) inhibitor and Cytarabine as a consolidation therapy, wherein the mutant IDH2 inhibitor is 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol, having the following formula:
or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 1), and wherein the AML is characterized by the presence of a mutant allele of IDH2.
2 . A method of treating AML, comprising administering to a subject a therapeutically effective amount of a mutant IDH2 inhibitor and a combination of Cytarabine and Idarubicin as an induction therapy, further comprising administering the mutant isocitrate dehydrogenase 2 (IDH2) inhibitor and Cytarabine as a consolidation therapy, wherein the mutant IDH2 inhibitor is 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol having the following formula:
or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 1), and wherein the AML is characterized by the presence of a mutant allele of IDH2.
3 . (canceled)
4 . A method of treating AML, comprising administering to a subject a therapeutically effective amount of a mutant IDH2 inhibitor and a combination of Cytarabine and Idarubicin as an induction therapy, further comprising administering the mutant isocitrate dehydrogenase 2 (IDH2) inhibitor and a combination of Mitoxantrone and Etoposide as a consolidation therapy, wherein the mutant IDH2 inhibitor is 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol having the following formula:
or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 1), and wherein the AML is characterized by the presence of a mutant allele of IDH2.
5 . The method of claim 1 , wherein the dose of Cytarabine used as an induction therapy is between about 100 mg/m 2 and about 500 mg/m 2 .
6 . The method of claim 5 , wherein the dose of Cytarabine is between about 150 mg/m 2 and about 300 mg/m 2 .
7 . The method of claim 6 , wherein the dose of Cytarabine is about 200 mg/m 2 .
8 . The method of claim 1 , therein the dose of Cytarabine used as a consolidation therapy is between about 1 g/m 2 and about 10 g/m 2 .
9 . The method of claim 8 , wherein the dose of Cytarabine is between about 1 g/m 2 and about 5 g/m 2 .
10 . The method of claim 9 , wherein the dose of Cytarabine is 1 g/m 2 , or 1.5 g/m 2 , or 2 g/m 2 , or 3 g/m 2 .
11 . The method of claim 1 , wherein the dose of Daunorubicin is between about 10 mg/m 2 and about 300 mg/m 2 .
12 . The method of claim 11 , wherein the dose of Daunorubicin is between about 30 mg/m 2 and about 150 mg/m 2 .
13 . The method of claim 12 , wherein the dose of Daunorubicin is about 60 mg/m 2 .
14 . The method of claim 2 , wherein the dose of Idarubicin is between about 1 mg/m 2 and about 25 mg/m 2 .
15 . The method of claim 14 , wherein the dose of Idarubicin is between about 3 mg/m 2 and about 15 mg/m 2 .
16 . The method of claim 15 , wherein the dose of Idarubicin is about 12 mg/m 2 .
17 . The method of claim 4 , wherein the dose of Mitoxantrone is between about 1 mg/m 2 and about 25 mg/m 2 .
18 . The method of claim 17 , wherein the dose of Mitoxantrone is between about 5 mg/m 2 and about 20 mg/m 2 .
19 . The method of claim 18 , wherein the dose of Mitoxantrone is about 10 mg/m 2 .
20 . The method of claim 4 , wherein the dose of Etoposide is between about 50 mg/m 2 and about 500 mg/m 2 .
21 . The method of claim 20 , wherein the dose of Etoposide is between about 75 mg/m 2 and about 250 mg/m 2 .
22 . The method of claim 21 , wherein the dose of Etoposide is about 100 mg/m 2 .
23 . A method of treating AML characterized by the presence of a mutant allele of IDH2, comprising administering to a subject a therapeutically effective amount of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol (COMPOUND 1) and a combination of Cytarabine and Daunorubicin, wherein Cytarabine is administered for 7 days and Daunorubicin is administered for 3 days.
24 . A method of treating AML characterized by the presence of a mutant allele of IDH2, comprising administering to a subject a therapeutically effective amount of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol (COMPOUND 1) and a combination of Cytarabine and Idarubicin, wherein Cytarabine is administered for 7 days and Idarubicin is administered for 3 days.
25 . A method of claim 1 , wherein the dose of COMPOUND 1 is between about 50 mg/m 2 and about 1000 mg/m 2 .
26 . The method of claim 25 , wherein the dose of COMPOUND 1 is between about 150 mg/m 2 and about 300 mg/m 2 .
27 . The method of claim 26 , wherein the dose of COMPOUND 1 is about 200 mg/m 2 .
28 . 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.
29 - 40 . (canceled)