Methods for the treatment of cancer using 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
Provided are methods of treating cancer in a human subject. The method includes selecting a subject in need of treatment of cancer; administering to the subject a therapeutically effective amount of gedatolisib at least once a week for a period of three weeks; discontinuing administration of gedatolisib for a period of one week; and resuming administration of gedatolisib at least once a week following the period of discontinuation. The administration for at least a period of three weeks and discontinued administration for at least a period of one week constitutes a cycle, where the cycle is repeated for at least two cycles.
1. A method of treating ER+/HER2− breast cancer in a human subject who is being or has been treated with a hormonal therapy, said method comprising:
administering to the human subject (i) gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, at a dosage of 180 mg/week, once a week for a period of three weeks; and (ii) a therapeutic dosage of a CDK 4/6 inhibitor for a period of three weeks;
discontinuing administration of gedatolisib, or pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4/6 inhibitor for a period of one week; and
resuming administration of (i) gedatolisib, or pharmaceutically acceptable salt, solvate, or ester thereof, at a dosage of 180 mg/week once a week and (ii) the CDK 4/6 inhibitor at a therapeutic dosage following the period of discontinuation,
wherein the administration for a period of three weeks and discontinued administration for a period of one week constitutes a cycle, wherein the cycle is repeated for at least two cycles; and
wherein the administration of the CDK 4/6 inhibitor occurs during concurrent weeks as the administration of gedatolisib, or pharmaceutically acceptable salt, solvate, or ester thereof.
2. The method of claim 1 , wherein resumed administration of (i) gedatolisib, or pharmaceutically acceptable salt, solvate, or ester thereof, occurs at a dosage of 180 mg/week once a week for a period of three weeks; and (ii) the CDK 4/6 inhibitor occurs at a therapeutic dosage for a period of three weeks.
3. The method of claim 1 , wherein the cycle of administration occurs for at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, or at least 9 cycles.
4. The method of claim 1 , wherein the CDK 4/6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, riviciclib, and combinations thereof.
5. The method of claim 1 , wherein the CDK 4/6 inhibitor is palbociclib.
6. The method of claim 5 , wherein the palbociclib is administered at a dose of 125 mg per day.
7. The method of claim 1 , further comprising administering hormonal treatment to the human subject.
8. The method of claim 7 , wherein hormonal treatment comprises administering the estrogen receptor antagonist fulvestrant.
9. The method of claim 8 , wherein the fulvestrant is administered at a dose of 500 mg every two weeks.
10. The method of claim 8 , wherein the fulvestrant is administered at a dose of 500 mg every four weeks.
11. The method of claim 1 , wherein the human subject is a pre-menopausal or post-menopausal female patient.
12. The method of claim 1 , wherein the human subject has failed a prior treatment for cancer in a period of less than twelve months.
13. The method of claim 1 , wherein the human subject has failed a prior treatment for cancer in a period of less than six months.
14. The method of claim 1 , wherein the human subject has failed two or more prior treatments for cancer.
15. The method of claim 12 , wherein the failed prior treatment is an endocrine treatment for cancer.
16. The method of claim 7 , wherein hormonal treatment comprises administering an aromatase inhibitor.
17. The method of claim 16 , wherein the aromatase inhibitor is letrozole.
18. The method of claim 17 , wherein letrozole is administered at a dosage of 2.5 mg daily.
19. A method of treating ER+/HER2− breast cancer in a human subject who is being or has been treated with a hormonal therapy, said method comprising:
administering to the human subject: (i) gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, at a dosage of 180 mg/week once a week for a period of three weeks; and (ii) a CDK 4/6 inhibitor at a therapeutic dosage for a period of three weeks, wherein the CDK 4/6 inhibitor is selected from the from the group consisting of palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, riviciclib;
discontinuing administration of gedatolisib, or pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4/6 inhibitor for a period of one week; and
resuming administration of (i) gedatolisib, or pharmaceutically acceptable salt, solvate, or ester thereof, at a dosage of 180 mg/week once a week and (ii) the CDK 4/6 inhibitor at a therapeutic dosage following the period of discontinuation,
wherein the administration for a period of three weeks and discontinued administration for a period of one week constitutes a cycle,
wherein the cycle is repeated for at least two cycles; and
wherein the administration of the CDK 4/6 inhibitor occurs during concurrent weeks as the administration of gedatolisib, or pharmaceutically acceptable salt, solvate, or ester thereof.
20. The method of claim 19 , wherein the CDK 4/6 inhibitor is palbociclib.
21. The method of claim 20 , wherein palbociclib is administered at a dose of 125 mg per day.
22. The method of claim 19 , wherein the hormonal therapy comprises treatment with letrozole or fulvestrant.
23. The method of claim 19 , wherein the cycle of administration occurs for at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, or at least 9 cycles.
24. A method of treating ER+/HER2− breast cancer in a human subject, the method comprising:
administering to the human subject: (i) gedatolisib, or a pharmaceutically acceptable salt, solvate, or ester thereof, at a dosage of 180 mg/week once a week for a period of three weeks; (ii) a CDK 4/6 inhibitor at a therapeutic dosage for a period of three weeks, wherein the CDK 4/6 inhibitor is selected from the from the group consisting of palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, riviciclib; and (iii) a hormonal therapy selected from fulvestrant and letrozole;
discontinuing administration of gedatolisib, or pharmaceutically acceptable salt, solvate, or ester thereof, and the CDK 4/6 inhibitor for a period of one week; and
resuming administration of (i) gedatolisib, or pharmaceutically acceptable salt, solvate, or ester thereof, at a dosage of 180 mg/week once a week and (ii) the CDK 4/6 inhibitor at a therapeutic dosage following the period of discontinuation,
wherein the administration for a period of three weeks and discontinued administration for a period of one week constitutes a cycle,
wherein the cycle is repeated for at least two cycles; and
wherein the administration of the CDK 4/6 inhibitor occurs during concurrent weeks as the administration of gedatolisib, or pharmaceutically acceptable salt, solvate, or ester thereof.
25. The method of claim 24 , wherein the CDK 4/6 inhibitor is palbociclib.
26. The method of claim 25 , wherein palbociclib is administered at a dose of 125 mg per day.
27. The method of claim 24 , wherein fulvestrant is administered at a dose of 500 mg every two weeks.
28. The method of claim 24 , wherein letrozole is administered at a dosage of 2.5 mg daily.
29. The method of claim 24 , wherein the cycle of administration occurs for at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, or at least 9 cycles.