Therapy for treating malignancies
Provided are methods and compositions for treating cancers in patients carrying an IDH1 mutation using an inhibitor of a mutant IDH1 enzyme.
1. A method of treating a malignancy characterized by the presence of a mutant allele of IDH1, comprising administering to a subject a once daily 500 mg oral dose of a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor wherein the mutant IGH1 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 1) wherein the compound is administered to a subject that has not ingested a high-fat meal.
2. The method of claim 1 , wherein the oral dose is administered substantially contemporaneously with food, wherein the food is not a high-fat meal.
3. The method of claim 1 wherein the oral dose is administered without food.
4. The method of claim 1 wherein the oral dose is administered to a subject that has not ingested a high-fat meal for at least 60 minutes before administration of the oral dose.
5. The method of claim 1 wherein the oral dose is administered to the subject at least 60 minutes before ingestion of any high-fat meal.
6. The method of claim 1 wherein the C max of COMPOUND 1 is between 1500 ng/mL and 3100 ng/mL.
7. The method of claim 1 wherein the AUC 0-t of COMPOUND 1 is between 110000 hr·ng/mL and 165000 hr·ng/mL.
8. The method of claim 1 wherein the oral dose comprises COMPOUND 1 as part of a solid dispersion.
9. The method of claim 1 wherein the malignancy is a hematologic malignancy.
10. The method of claim 9 wherein the hematologic malignancy is acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemias (B-ALL), or lymphoma.
11. The method of claim 10 , wherein the malignancy is acute myelogenous leukemia (AML).
12. The method of claim 11 wherein the acute myelogenous leukemia (AML) is relapsed or refractory.
13. The method of claim 1 wherein the malignancy is a solid tumor.
14. The method of claim 13 wherein the solid tumor is selected from glioma, intrahepatic cholangiocarcinomas (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, and non-small cell lung cancer (NSCLC).
15. The method of claim 14 wherein the solid tumor is intrahepatic cholangiocarcinoma.
16. The method of claim 13 wherein the solid tumor is advanced.
17. The method of claim 13 wherein the solid tumor is relapsed or refractory.
18. The method of claim 1 wherein the IDH1 mutation is an IDH1 R132X mutation.
19. The method of claim 18 , wherein the IDH1 mutation is an IDH1 R132H, R132C, R132L, R132V, R132S or R132GF mutation.