Low dose combination therapy for treatment of myeloproliferative neoplasms

1. A method of inhibiting or ameliorating a myeloproliferative neoplasm in a human patient in need thereof, comprising administering to said human patient a dose from about 2 mg/day to about 100 mg/day N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, and about 10 mg/day to about 50 mg/day of ruxolitinib, or a pharmaceutically acceptable salt thereof; wherein the myeloproliferative neoplasm is selected from polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibosis, chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), chronic neutrophilic leukemia (CNL), and chronic eosinophilic leukemia.

2. The method of claim 1 , wherein the ruxolitinib, or a pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.

3. The method of claim 1 , wherein the N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is selected from the phosphoric acid salt, dihydrochloric acid salt, hydrochloric acid salt, maleic acid salt, adipic acid salt, hydrobromic acid salt, (R)-(−)-mandelic acid salt, salicylic acid salt, benzoic acid salt, benzenesulfonic acid salt, L-pyroglutamic acid salt, methanesulfonic acid salt, (1S)-(+)-10-camphorsulfonic acid salt, fumaric acid salt, sulfuric acid salt, L-tartaric acid salt, and D-tartaric acid salt of N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide.

4. The method of claim 1 , wherein the N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is the phosphoric acid salt of N-{(7R)-4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide.

5. The method of claim 1 , wherein the dose of N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is from about 8 mg/day to about 80 mg/day.

6. The method of claim 1 , wherein the dose of N-{(7R)-4-[(3R,4R,5S)-3-amino-4hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is from about 8 mg/day to about 60 mg/day.

7. The method of claim 1 , wherein the dose of N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is from about 8 mg/day to about 50 mg/day.

8. The method of claim 1 , wherein the dose of N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is from about 8 mg/day to about 40 mg/day.

9. The method of claim 1 , wherein the dose of N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is from about 8 mg/day to about 20 mg/day.

10. The method of claim 1 , wherein the dose of N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is from about 2 mg BID to about 50 mg BID.

11. The method of claim 1 , wherein the dose of N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is from about 4 mg BID to about 40 mg BID.

12. The method of claim 1 , wherein the dose of N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is from about 4 mg BID to about 30 mg BID.

13. The method of claim 1 , wherein the dose of N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is from about 4 mg BID to about 25 mg BID.

14. The method of claim 1 , wherein the dose of N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is from about 4 mg BID to about 20 mg BID.

15. The method of claim 1 , wherein the dose of N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, is from about 4 mg BID to about 10 mg BID.

16. The method of claim 1 , wherein the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof, is about 10 mg/day to about 30 mg/day.

17. The method of claim 1 , wherein the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof, is about 10 mg/day.

18. The method of claim 1 , wherein the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof, is about 20 mg/day.

19. The method of claim 1 , wherein the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof, is about 30 mg/day.

20. The method of claim 1 , wherein the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof, is about 5 mg BID to about 25 mg BID.

21. The method of claim 1 , wherein the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof, is about 5 mg BID to about 15 mg BID.

22. The method of claim 1 , wherein the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof, is about 5 mg BID.

23. The method of claim 1 , wherein the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof, is about 10 mg BID.

24. The method of claim 1 , wherein the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof, is about 15 mg BID.

25. The method of claim 1 , wherein the myeloproliferative neoplasm is selected from polycythemia vera (PV).

26. The method of claim 1 , wherein the myeloproliferative neoplasm is selected from essential thrombocythemia (ET).

27. The method of claim 1 , wherein the myeloproliferative neoplasm is selected from primary myelofibrosis.

28. The method of claim 1 , wherein the ruxolitinib, or pharmaceutically acceptable salt thereof, and the N-{(7R)-4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof, are administered orally.