Methods of treating hepatic-only metastatic uveal melanoma

Abstract

Provided herein is a method of treating metastatic uveal melanoma (MUM) in a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor with a PKC inhibitor and a c-MET inhibitor.

Description

This article describes a method for treating patients with metastatic uveal melanoma (MUM) who have liver tumors but essentially no extrahepatic tumors using PKC inhibitors and c-MET inhibitors. Abstract

Claims

CLAIMS1. A method of treating metastatic uveal melanoma (MUM) in a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor, the method comprising administering a therapeutically effective amount of a PKC inhibitor and administering a therapeutically effective amount of a cMet inhibitor to the patient.

2. A method of treating metastatic uveal melanoma (MUM) in a patient, the method comprising: a) selecting a patient having a hepatic tumor and an essential absence of an extra-hepatic tumor; and b) administering a therapeutically effective amount of a PKC inhibitor and administering a therapeutically effective amount of a cMet inhibitor to the patient.

3. The method of claim 1 or 2, wherein the patient is selected by assessing a screening test.

4. A method of treating metastatic uveal melanoma (MUM) in a patient, the method comprising: a) selecting a patient having a hepatic tumor and essential absence of an extra-hepatic tumor, wherein the patient selection is determined by assessing a screening test; and b) administering a therapeutically effective amount of a PKC inhibitor and a therapeutically effective amount of a cMet inhibitor to the patient.

5. The method of any one of claims 1 to 4, wherein the PKC inhibitor is Compound 1 :Compound 1 or a pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1 to 5, wherein the cMet inhibitor is Compound 2:or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1 to 6, wherein the patient does not have an extrahepatic tumor.

8. The method of any one of claims 1 to 7, wherein the treatment reduces a size of the hepatic tumor by at least 10%.

9. The method of any one of claims 1 to 8, wherein the patient has a progression free survival of greater than or equal to 3, 4, 5, 6, 7, 8, or 9, months.

10. The method of any one of claims 1 to 9, wherein the patient has a progression free survival of greater than or equal to 10 or 11 months.

11. The method of any one of claims 1 to 10, wherein the treatment has a disease control rate of at least 60%, 70%, 80%, 85%, 90%, 92%, or 95%.

12. The method of any one of claims 1 to 11, wherein the treatment has a disease control rate of at least 98%.

13. The method of any one of claims 1 to 12, wherein the treatment has a disease control rate of at least 99%.

14. The method of any one of claims 5 to 13, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered in a total daily dosage of about 400 mg to about 600 mg.

15. The method of any one of claims 5 to 14, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg two times per day (BID).

16. The method of any one of claims 5 to 14, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg two times per day (BID).

17. The method of any one of claims 5 to 16, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered daily.

18. The method of any one of claims 6 to 17, wherein Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered in a total daily dosage of about 400 mg to about 500 mg.

19. The method of any one of claims 6 to 18, wherein Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg two times per day (BID).

20. The method of any one of claims 6 to 15 and 17 to 19, whereinCompound 1 , or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg BID every day of at least one 7-day dosing cycle; andCompound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of at least one 7-day dosing cycle.

21. The method of any one of claims 6 to 14 and 16 to 19, whereinCompound 1 , or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of at least one 7-day dosing cycle; andCompound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of at least one 7-day dosing cycle.

22. The method of claim 21, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, are each administered for at least eight (8) 7-day dosing cycles.

23. The method of any one of claims 6 to 15 and 17 to 20, wherein the treatment is according to a dosing schedule comprising(i) a first treatment cycle of at least one 7-day dosing cycle, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone at a dose of 300 mg BID every day of the first treatment cycle, followed by(ii) a second treatment cycle of at least one 7-day dosing cycle, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 300 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg BID every day of the second treatment cycle.

24. The method of any one of claims 6 to 15 and 17 to 20, wherein the treatment is according to a dosing schedule comprising(i) a first treatment cycle of at least one 7-day dosing cycle, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone at a dose of about 300 mg BID every day of the first treatment cycle, followed by(ii) a second treatment cycle of at least three (3) 7-day dosing cycles, wherein Compound 1 , or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of the second treatment cycle.

25. The method of any one of claims 6 to 14, 16 to 19, and 21, wherein the treatment is according to a dosing schedule comprising(i) a first treatment cycle of at least one 7-day dosing cycle, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone at a dose of 200 mg BID every day of the first treatment cycle, followed by(ii) a second treatment cycle of at least one 7-day dosing cycle, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg BID every day of the second treatment cycle.

26. The method of any one of claims 6 to 14, 16 to 19, and 21, wherein the treatment is according to a dosing schedule comprising(i) a first treatment cycle of at least one 7-day dosing cycle, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered alone at a dose of about 200 mg BID every day of the first treatment cycle, followed by(ii) a second treatment cycle of at least three (3) 7-day dosing cycles, wherein Compound 1 , or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg BID every day of the second treatment cycle.

27. The method of any one of claims 23 to 26, wherein the second treatment cycle comprises at least seven (7) 7-day dosing cycles, at least eleven (11) 7-day dosing cycles, at least fifteen (15) 7-day dosing cycles, at least nineteen (19) 7-day dosing cycles, at least twenty-three (23) 7-day dosing cycles, or at least twenty-seven (27) 7-day dosing cycles.28.The method of any one of claims 1 to 27, wherein the metastatic uveal melanoma is a solid tumor.

29. The method of claim 28, wherein the solid tumor harbors a GNAQ or GNA11 mutation.

30. The method of any one of claims 6 to 29, wherein Compound 1, or an equivalent dose of a pharmaceutically acceptable salt thereof, and Compound 2, or an equivalent dose of a pharmaceutically acceptable salt thereof, are administered separately.

31. The method of any one of claims 3 to 30, wherein the screening test is selected from CT scan, MRI, PET scan, ultrasound, and X-ray, or a combination thereof.

32. The method of any one of embodiments 8 to 31, wherein reduction in the size of the hepatic tumor is measured using RECIST 1.1 criteria.

33. The method of any one of claims 1 to 32, wherein the patient is in recognized need of such treatment.

34. The method of any one of claims 1 to 33, wherein the PKC inhibitor, or a pharmaceutically acceptable salt thereof, and the cMet inhibitor, or a pharmaceutically acceptable salt thereof, are each administered orally.