Combination therapy for treating malignancies

Abstract

Provided are methods and compositions for treating cancers in patients carrying an IDH1 mutation using a combination of an inhibitor of a mutant IDH1 enzyme and a DNA demethylating agent.

1 . A method of treating a hematological malignancy 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, azacitidine and an additional cancer therapeutic agent, 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 - 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the malignancy is acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemias (B-ALL), or lymphoma. 
     
     
         5 . The method of  claim 1 , wherein the malignancy is acute myelogenous leukemia (AML). 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the dose of COMPOUND 2 is about 20 to 2000 mg/day. 
     
     
         8 . The method of  claim 1 , wherein the dose of COMPOUND 2 is about 50 to 500 mg/day. 
     
     
         9 . The method of  claim 1 , wherein the dose of COMPOUND 2 is about 50 mg/day. 
     
     
         10 . The method of  claim 1 , wherein the dose of COMPOUND 2 is about 75 mg/day. 
     
     
         11 . The method of  claim 1 , wherein the dose of COMPOUND 2 is about 100 mg/day. 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the dose of azacitidine is about 50 to about 500 mg/m 2 /day. 
     
     
         14 . The method of  claim 1 , wherein the dose of azacitidine is about 50 to about 200 mg/m 2 /day. 
     
     
         15 . The method of  claim 1 , wherein the dose of azacitidine is about 50 mg/m 2 /day. 
     
     
         16 . The method of  claim 1 , wherein the dose of azacitidine is about 60 mg/m 2 /day. 
     
     
         17 . The method of  claim 1 , wherein the dose of azacitidine is about 75 mg/m 2 /day. 
     
     
         18 . The method of  claim 1 , wherein COMPOUND 2 and azacitidine are administered concurrently. 
     
     
         19 . The method of  claim 1 , wherein COMPOUND 2 and azacitidine are administered sequentially. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . The method of  claim 1 , wherein the dose of COMPOUND 2 is about 500 mg/day. 
     
     
         23 . The method of  claim 1 , wherein the azacitidine is administered in cycles. 
     
     
         24 . The method of  claim 23 , wherein the azacitidine is administered subcutaneously for 7 days of each 28-day treatment cycle. 
     
     
         25 . The method of  claim 5 , wherein the AML is previously untreated AML. 
     
     
         26 . The method of  claim 5 , wherein the AML is newly diagnosed AML.