Compositions comprising PKM2 modulators and methods of treatment using the same
A compound of Structure (I): or a pharmaceutically acceptable salt thereof, alone or in combination with a second therapeutic agent, as well as methods of treating a PKM2-mediated disease or disorder using the same are provided herein.
1. A method of treating a cancer, comprising administering to a subject in need thereof an effective amount of a compound of Structure (I):
or a pharmaceutically acceptable salt thereof, in combination with a PD-1 inhibitor, wherein the PD-1 inhibitor is nivolumab, and the cancer is resistant to checkpoint inhibitor therapy in the absence of the compound of Structure (I).
2. The method of claim 1 , wherein the compound of Structure I, or a pharmaceutically acceptable salt thereof, is administered in a unit dosage of about 1 mg to about 500 mg of a compound of Structure I, or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the cancer (i) is a solid tumor cancer, (ii) has progressed on an immuno-oncology agent, (iii) is melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, or non-small cell lung cancer, (iv) is lung cancer, or (v) is non-small cell lung cancer.
4. The method of claim 1 , wherein the cancer is (i) first line IMDC classification Intermediate- or Poor-risk Stage IV renal cell carcinoma, (ii) first line Stage III or IV unresectable advanced melanoma, (iii) metastatic colorectal cancer displaying MSI-H or dMMR that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan, or (iv) advanced renal cell carcinoma which has failed on antiangiogenic therapy.
5. The method of claim 1 , wherein the compound of Structure I, or a pharmaceutically acceptable salt thereof, is administered in a single daily dose, or in divided doses two, three, or four times daily.
6. The method of claim 1 , wherein the compound of Structure I, or a pharmaceutically acceptable salt thereof, is administered once daily or twice daily.
7. The method of claim 1 , wherein from 120 mg to 720 mg of the compound of Structure I, or a pharmaceutically acceptable salt thereof, is administered daily.
8. The method of claim 1 , wherein 3 mg/kg of nivolumab is administered by intravenous infusion every three weeks.
9. The method of claim 1 , wherein from 120 mg to 720 mg of the compound of Structure I, or a pharmaceutically acceptable salt thereof, is administered daily, and 3 mg/kg of nivolumab is administered by intravenous infusion every three weeks.
10. A method of treating a cancer, comprising administering to a subject in need thereof an effective amount of a compound of Structure (I):
or a pharmaceutically acceptable salt thereof, in combination with a PD-1 inhibitor and a CTLA-4 inhibitor, wherein the PD-1 inhibitor is nivolumab and the CTLA-4 inhibitor is ipilimumab, and the cancer is resistant to checkpoint inhibitor therapy in the absence of the compound of Structure (I).
11. The method of claim 10 , wherein the cancer (i) is a solid tumor cancer, (ii) has progressed on an immuno-oncology agent, (iii) is melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, or non-small cell lung cancer, (iv) is lung cancer, or (v) is non-small cell lung cancer.
12. The method of claim 10 , wherein the cancer is (i) first line IMDC classification Intermediate- or Poor-risk Stage IV renal cell carcinoma; (ii) first line Stage III or IV unresectable advanced melanoma; (iii) metastatic colorectal cancer displaying MSI-H or dMMR that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan; or (iv) advanced renal cell carcinoma which has failed on antiangiogenic therapy.
13. The method of claim 10 , wherein the compound of Structure I, or a pharmaceutically acceptable salt thereof, is administered in a single daily dose, or in divided doses two, three, or four times daily.
14. The method of claim 10 , wherein the compound of Structure I, or a pharmaceutically acceptable salt thereof, is administered once daily or twice daily.
15. The method of claim 10 , wherein from 120 mg to 720 mg of the compound of Structure I, or a pharmaceutically acceptable salt thereof, is administered daily.
16. The method of claim 10 , wherein 3 mg/kg of nivolumab is administered by intravenous infusion every three weeks for four doses, followed by 240 mg of nivolumab, administered by intravenous infusion every 2 weeks, or 480 mg of nivolumab, administered by intravenous infusion every 4 weeks.
17. The method of claim 10 , wherein 1 mg/kg ipilimumab is administered by intravenous infusion every three weeks for four doses.
18. The method of claim 10 , wherein from 120 mg to 720 mg of the compound of Structure I, or a pharmaceutically acceptable salt thereof, is administered daily; 3 mg/kg of nivolumab is administered by intravenous infusion every three weeks for four doses, followed by 240 mg of nivolumab, administered by intravenous infusion every 2 weeks, or 480 mg of nivolumab, administered by intravenous infusion every 4 weeks; and 1 mg/kg ipilimumab is administered by intravenous infusion every three weeks for four doses.
19. The method of claim 18 , wherein the administration of ipilimumab is discontinued after four weeks.