Methods of treatment of malignancies

Abstract

Provided are methods and compositions for treating cancers in patients carrying an IDH1 mutation or IDH2 mutation.

1 . A method of treating acute myelogenous leukemia (AML) in a subject comprising administering to the subject a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor (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 (COMPOUND 2), having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or a polymorph thereof, wherein the AML is characterized by the presence of a mutant allele of IDH1 and the absence of an RAS mutation. 
       
     
     
         2 . The method of  claim 1 , wherein the RAS mutation is an NRAS mutation. 
     
     
         3 . The method of  claim 1 , wherein the RAS mutation is a KRAS mutation. 
     
     
         4 - 6 . (canceled) 
     
     
         7 . A method of treating acute myelogenous leukemia (AML) in a subject comprising administering to the subject a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor (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 (COMPOUND 2), having the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or a polymorph thereof in combination with a RAS pathway inhibitor, wherein the AML is characterized by the presence of a mutant allele of IDH1 and the presence of an RAS mutation. 
     
     
         8 . The method of  claim 7 , wherein the RAS mutation is an NRAS mutation. 
     
     
         9 . The method of  claim 7 , wherein the RAS mutation is a KRAS mutation. 
     
     
         10 - 12 . (canceled) 
     
     
         13 . The method of  claim 7 , wherein the IDH1 mutation is an IDH1 R132X mutation. 
     
     
         14 . The method of  claim 13 , wherein the IDH1 mutation is an IDH1 R132H, R132C, R132L, R132V, R132S or R132G mutation. 
     
     
         15 . The method of  claim 7 , wherein the RAS pathway inhibitor is a MEK kinase inhibitor. 
     
     
         16 . The method of  claim 15 , wherein the MEK kinase inhibitor is selected from trametinib, selumetinib, binimetinib, PD-325901, cobimetinib, CI-1040 and PD035901. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 7 , wherein the acute myelogenous leukemia (AML) is relapsed or refractory. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 7 , wherein the dose of COMPOUND 2 is about 20 to about 2000 mg/day. 
     
     
         21 . The method of  claim 7 , wherein the dose of COMPOUND 2 is about 50 to 500 mg/day. 
     
     
         22 - 62 . (canceled) 
     
     
         63 . The method of  claim 7 , wherein the dose of COMPOUND 2 is about 500 mg/day. 
     
     
         64 . The method of  claim 1 , wherein the IDH1 mutation is an IDH1 R132X mutation. 
     
     
         65 . The method of  claim 64 , wherein the IDH1 mutation is an IDH1 R132H, R132C, R132L, R132V, R132S or R132G mutation. 
     
     
         66 . The method of  claim 1 , wherein the acute myelogenous leukemia (AML) is relapsed or refractory. 
     
     
         67 . The method of  claim 1 , wherein the dose of COMPOUND 2 is about 20 to about 2000 mg/day. 
     
     
         68 . The method of  claim 1 , wherein the dose of COMPOUND 2 is about 50 to 500 mg/day. 
     
     
         69 . The method of  claim 1 , wherein the dose of COMPOUND 2 is about 500 mg/day.