Combination therapy for treating malignancies

Abstract

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)