IDH1 INHIBITORS FOR THE TREATMENT OF HAEMATOLOGICAL MALIGNANCIES AND SOLID TUMORS
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.