Enhanced treatment regimens using mTor inhibitors
The present invention provides for methods and pharmaceutical compositions comprising inhibitors of mTorC1 and/or mTorC2. In some aspects, the invention provides for treatment regimens resulting in enhanced treatment efficacy and better tolerability.
1. A method of treating cancer in a subject in need thereof, comprising administering an mTorC1/mTorC2 inhibitor to said subject according to an intermittent regimen which comprises at least one cycle in which the mTorC1/mTorC2 inhibitor is administered for at least 1 day, followed by an intermission in which the mTorC1/mTorC2 inhibitor is not administered for at least 1 day; wherein the cancer is renal cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, endometrial uterine cancer, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, gastric cancer, fibrosarcoma, pancreatic cancer, liver cancer, melanoma, leukemia, myeloma, nasopharyngeal cancer, prostate cancer, lung cancer, glioblastoma, bladder cancer, mesothelioma, head cancer, or neck cancer;
wherein the mTorC1/mTorC2 inhibitor has the Formula:
or a pharmaceutically acceptable salt thereof, wherein:
E 2 is H; X 1 is N; X 2 is N; W 2 is NH; k is 1; R 2 is H; and R 1 is isopropyl.
2. The method of claim 1 , wherein the intermittent regimen is effective to achieve an mTorC1/mTorC2 inhibitor plasma concentration of greater than about 100 nM for a duration longer than about 20 hours during a 7-day period of administration.
3. The method of claim 1 , wherein the intermittent regimen is effective to achieve an mTorC1/mTorC2 inhibitor plasma concentration of greater than about 100 nM for a duration of at least about 30 hours during a 7-day period of administration.
4. The method of claim 1 , wherein the intermittent regimen is effective to achieve a Cmax of greater than about 200, 250, 300, 350, 400, 450, 500, 550 or 600 nM.
5. The method of claim 1 , wherein the intermittent regimen is effective to achieve a Cmax of greater than about 300 nM.
6. The method of claim 1 , wherein the mTorC1/mTorC2 inhibitor is administered for 2, 3, 4, 5, 6 or 7 consecutive days followed by an intermission in which the mTorC1/mTorC2 inhibitor is not administered for at least 1 day.
7. The method of claim 1 , wherein the regimen comprises at least one cycle in which the mTorC1/mTorC2 inhibitor is administered for 2, 3, 4, 5, 6 or 7 consecutive days followed by an intermission in which the mTorC1/mTorC2 inhibitor is not administered for at least 3, 4, or 5 consecutive days.
8. The method of claim 1 , wherein the regimen comprises at least one cycle in which the mTorC1/mTorC2 inhibitor is administered for 1 day followed by an intermission in which the mTorC1/mTorC2 inhibitor is not administered for 6 consecutive days.
9. The method of claim 1 , wherein the regimen comprises at least one 7-day cycle in which the mTorC1/mTorC2 inhibitor is administered for 3 consecutive days followed by an intermission of 4 consecutive days.
10. The method of claim 1 , wherein the regimen comprises at least one 7-day cycle in which the mTorC1/mTorC2 inhibitor is administered for 5 consecutive days followed by an intermission of 2 consecutive days.
11. The method of claim 1 , wherein the wherein the regimen comprises at least one 7-day cycle in which the mTorC1/mTorC2 inhibitor is administered at least 3 times on alternate days within the 7 days.
12. The method of claim 1 , wherein the mTorC1/mTorC2 inhibitor is administered parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, intramuscularly, liposomally, via local delivery by catheter or stent, subcutaneously, intraadiposally, or intrathecally.
13. The method of claim 1 , wherein the mTorC1/mTorC2 inhibitor is administered orally.
14. The method of claim 1 , wherein the cancer is renal cancer.
15. The method of claim 1 , wherein cancer is renal cell carcinoma.
16. The method of claim 1 , wherein the cancer is ovarian cancer.
17. The method of claim 1 , wherein the cancer is breast cancer.
18. The method of claim 1 , wherein the cancer is uterine sarcoma.
19. The method of claim 1 , wherein the cancer is endometrial uterine cancer.
20. The method of claim 1 , wherein the cancer is cervical cancer.
21. The method of claim 1 , wherein the cancer is gastric cancer.