Inhibiting mutant isocitrate dehydrogenase 1 (mIDH1)
This disclosure relates to compositions and methods for inhibiting mutant IDH1, useful in treatment of mIDH1 cancers including AML, as well as mIDH1-positive solid tumors such as glioma.
1. A Compound I-1 or pharmaceutically acceptable salt thereof:
2. A pharmaceutical composition comprising the compound of claim 1 .
3. The pharmaceutical composition of claim 2 , further comprising Compound I-2 or a pharmaceutically acceptable salt thereof:
4. The pharmaceutical composition of claim 3 , comprising a total of 0.01-0.5% (a/a HPLC) Compound I-1, relative to Compound I-2.
5. The pharmaceutical composition of claim 3 , comprising up to about 1.33 mg of Compound I-1 per 300 mg of Compound I-2.
6. A unit dosage form indicated for oral administration comprising the pharmaceutical composition of claim 4 .
7. The unit dosage form of claim 6 , wherein the unit dosage form is a capsule or tablet comprising 50 mg or 150 mg of Compound I-2.
8. A unit dosage form indicated for oral administration comprising the pharmaceutical composition of claim 5 .
9. The unit dosage form of claim 8 , wherein the unit dosage form is a capsule or tablet comprising 50 mg or 150 mg of Compound I-2.
10. A method of inhibiting mutant isocitrate dehydrogenase 1 (mIDH1) comprising contacting the compound of claim 1 with a cell harboring an IDH1 mutation selected from the group consisting of R132H and R132C.
11. A method of treating a patient diagnosed with acute myeloid leukemia (AML) harboring an IDH1 mutation, the method comprising administering to the patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 3 .
12. The method of claim 11 , comprising administering to the patient up to about 22 mg of Compound I-1 per day.
13. The method of claim 12 , comprising administering to the patient up to about 1.33 mg of Compound I-1 per day.
14. The method of claim 13 , comprising orally administering 150 mg of Compound I-2 to the patient twice a day.
15. A method of treating a patient diagnosed with a glioma harboring an IDH1 mutation, the method comprising administering to the patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 3 .
16. The method of claim 15 , comprising administering to the patient up to about 22 mg of Compound I-1 per day.
17. The method of claim 16 , comprising administering to the patient up to about 1.33 mg of Compound I-1 per day.
18. The method of claim 17 , comprising orally administering 150 mg of Compound I-2 to the patient twice a day.
19. The method of claim 15 , further comprising administering azacitidine to the patient.
20. The method of claim 19 , wherein the pharmaceutical composition is administered to the patient during one or more 28-day treatment cycles, wherein:
(a) the azacitidine is administered intravenously or subcutaneously to the patient in a dose of 75 mg/m 2 for 7 days per every 28-day treatment cycle; and
(b) 150 mg of Compound I-2 is administered twice daily to the patient every day throughout the one or more 28-day treatment cycles.