Idh1 inhibitors for the treatment of haematological malignancies and solid tumors

Abstract

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

1 . A method of treating a hematological malignancy 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, having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 2), wherein the hematological malignancy is a malignancy characterized by the presence of a mutant allele of IDH1 and the absence of a FLT3 mutation. 
       
     
     
         2 . A method of treating a solid tumor 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, having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 2), wherein the solid tumor is characterized by the presence of a mutant allele of IDH1 and the absence of a FLT3 mutation. 
       
     
     
         3 . A method of treating a hematological malignancy 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, having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 2) in combination with a FLT3 inhibitor, wherein the hematological malignancy is a malignancy characterized by the presence of a mutant allele of IDH1 and a mutant FLT3. 
       
     
     
         4 . A method of treating a solid tumor 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, having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 2) in combination with a FLT3 inhibitor, wherein the solid tumor characterized by the presence of a mutant allele of IDH1 and a mutant FLT3. 
       
     
     
         5 . The method of any one of  claims 1  to  4 , wherein the IDH1 mutation is an IDH1 R132X mutation. 
     
     
         6 . The method of  claim 5 , wherein the IDH1 mutation is an IDH1 R132H, R132C, R132L, R132V, R132S or R132G mutation. 
     
     
         7 . The method of any one of  claims 3  to  6 , wherein the FLT3 inhibitor is selected from quizartinib (AC220), sunitinib (SU11248), sorafenib (BAY 43-9006), midostaurin (PKC412), lestaurtinib (CEP-701), crenolanib (CP-868596), PLX3397, E6201, AKN-028, ponatinib (AP24534), ASP2215, KW-2449, famitinib and DCC-2036. 
     
     
         8 . The method of  claim 1  or  3 , 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 (e.g., T-cell lymphoma), each characterized by the presence of a mutant allele of IDH1 and the method comprises administering a therapeutically effective amount of COMPOUND 2 to the subject. 
     
     
         9 . The method of  claim 8 , wherein the malignancy is acute myelogenous leukemia (AML), characterized by the presence of a mutant allele of IDH1. 
     
     
         10 . The method of  claim 2  or  4 , wherein the solid tumor is glioma, melanoma, chondrosarcoma, cholangiocarcinoma (including intrahepatic cholangiocarcinoma (IHCC)), prostate cancer, colon cancer, or non-small cell lung cancer (NSCLC), each characterized by the presence of a mutant allele of IDH1 and the method comprises administering a therapeutically effective amount of COMPOUND 2 to the subject. 
     
     
         11 . The method of any one of  claims 1  to  10 , wherein the dose of COMPOUND 2 is administered at a dose of about 20 to about 2000 mg/day. 
     
     
         12 . The method of any one of  claims 1  to  10 , wherein the dose of COMPOUND 2 is administered at a dose of about 50 to about 500 mg/day. 
     
     
         13 . A method of identifying a cancer subject suitable for treatment with an IDH1 inhibitor, comprising: (a) obtaining a biological sample from a subject having cancer; (b) screening the biological sample for an IDH1 mutation and a FLT3 mutation; and (c) if the cancer is characterized by the presence of a mutant allele of IDH1 and the absence of a FLT3 mutation, identifying the subject as a cancer subject suitable for treatment with an IDH1 inhibitor. 
     
     
         14 . The method of  claim 13 , wherein the IDH1 inhibitor is COMPOUND 2. 
     
     
         15 . A method of identifying a cancer subject suitable for treatment with a combination of an IDH1 inhibitor and a FLT3 pathway inhibitor, comprising: (a) obtaining a biological sample from a subject having cancer; (b) screening the biological sample for an IDH1 mutation and a FLT3 mutation; and (c) if the cancer is characterized by the presence of a mutant allele of IDH1 and a mutant FLT3, identifying the subject as a cancer subject suitable for treatment with a combination therapy with an IDH1 inhibitor and a FLT3 inhibitor. 
     
     
         16 . The method of  claim 15 , wherein the IDH1 inhibitor is COMPOUND 2. 
     
     
         17 . The method of  claim 15  or  16 , wherein the FLT3 inhibitor is selected from quizartinib (AC220), sunitinib (SU11248), sorafenib (BAY 43-9006), midostaurin (PKC412), lestaurtinib (CEP-701), crenolanib (CP-868596), PLX3397, E6201, AKN-028, ponatinib (AP24534), ASP2215, KW-2449, famitinib and DCC-2036. 
     
     
         18 . The method of any one of  claims 13  to  17 , wherein the cancer is a solid tumor or a hematologic malignancy. 
     
     
         19 . The method of  claim 18 , wherein the hematologic malignancy is AML. 
     
     
         20 . The method of  claim 19 , wherein the AML is relapsed or refractory. 
     
     
         21 . The method of any one of  claims 1  to  20 , wherein the mutant FLT3 is FLT3-ITD or FLT3-KDM. 
     
     
         22 . The method of any one of  claims 1  to  21 , wherein the mutant FLT3 is FLT3-ITD. 
     
     
         23 . A compound for use in a method of treating a hematological malignancy in a subject, wherein the compound is 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 having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 2), wherein the hematological malignancy is a malignancy characterized by the presence of a mutant allele of IDH1 and the absence of a FLT3 mutation. 
       
     
     
         24 . A compound for use in a method of treating a solid tumor in a subject, wherein the compound is 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 having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 2), wherein the solid tumor is characterized by the presence of a mutant allele of IDH1 and the absence of a FLT3 mutation. 
       
     
     
         25 . A compound for use in a method of treating a hematological malignancy in a subject, wherein the compound is 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 having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 2) in combination with a FLT3 inhibitor, wherein the hematological malignancy is a malignancy characterized by the presence of a mutant allele of IDH1 and a mutant FLT3. 
       
     
     
         26 . A compound for use in a method of treating a solid tumor in a subject, wherein the compound is 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 having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, metabolite, or a polymorph thereof (COMPOUND 2) in combination with a FLT3 inhibitor, wherein the solid tumor is characterized by the presence of a mutant allele of IDH1 and a mutant FLT3. 
       
     
     
         27 . The compound for use of any one of  claims 23  to  26 , wherein the IDH1 mutation is an IDH1 R132H, R132C, R132L, R132V, R132S or R132G mutation. 
     
     
         28 . The compound for use of any one of  claims 25  to  27 , wherein the FLT3 inhibitor is selected from quizartinib (AC220), sunitinib (SU11248), sorafenib (BAY 43-9006), midostaurin (PKC412), lestaurtinib (CEP-701), crenolanib (CP-868596), PLX3397, E6201, AKN-028, ponatinib (AP24534), ASP2215, KW-2449, famitinib and DCC-2036. 
     
     
         29 . The compound for use of  claim 23  or  25 , 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 (e.g., T-cell lymphoma), each characterized by the presence of a mutant allele of IDH1 and the method comprises administering a therapeutically effective amount of COMPOUND 2 to the subject. 
     
     
         30 . The compound for use of  claim 29 , wherein the malignancy is acute myelogenous leukemia (AML), characterized by the presence of a mutant allele of IDH1. 
     
     
         31 . The compound for use of  claim 30 , wherein the AML is relapsed or refractory. 
     
     
         32 . The compound for use of  claim 24  or  26 , wherein the solid tumor is glioma, melanoma, chondrosarcoma, cholangiocarcinoma (including intrahepatic cholangiocarcinoma (IHCC), prostate cancer, colon cancer, or non-small cell lung cancer (NSCLC), each characterized by the presence of a mutant allele of IDH1 and the method comprises administering a therapeutically effective amount of COMPOUND 2 to the subject. 
     
     
         33 . The compound for use of any one of  claims 23  to  32 , wherein the dose of COMPOUND 2 is about 20 to about 2000 mg/day or about 50 to about 500 mg/day. 
     
     
         34 . The compound for use of any one of  claims 25  to  33 , wherein the mutant FLT3 is FLT3-ITD or FLT3-KDM. 
     
     
         35 . The compound for use of any one of  claims 25  to  34 , wherein the mutant FLT3 is FLT3-ITD.