PIM KINASE INHIBITORS FOR TREATMENT OF MYELOPROLIFERATIVE NEOPLASMS AND FIBROSIS ASSOCIATED WITH CANCER
Methods for treatment of myeloproliferative neoplasms and/or fibrosis associated with cancer are provided. The disclosed methods comprise administering a PIM kinase inhibitor, and optionally a JAK kinase inhibitor or other therapeutic agent, to a mammal in need thereof.
1 . A method for treating a myeloproliferative neoplasm in a mammal in need thereof, the method comprising administering to the mammal:
from about 250 mg to about 2.5 g per day of a compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof; and
an effective amount of ruxolitinib, or a pharmaceutically acceptable salt thereof.
2 . The method of claim 1 , comprising administering to the mammal from about 300 mg to about 1.5 g per day or from about 450 mg to about 1.5 g per day of the compound of structural formula 1, or a pharmaceutically acceptable salt thereof.
3 . The method of claim 1 , comprising administering to the mammal about 360 mg/day, about 480 mg/day, about 720 mg/day, about 960 mg/day, or about 1,080 mg/day of the compound of structural formula 1, or a pharmaceutically acceptable salt thereof.
4 . The method of any one of claims 1 - 3 , wherein the myeloproliferative neoplasm is myelofibrosis.
5 . The method of claim 4 , wherein the myelofibrosis is intermediate-risk myelofibrosis or high-risk myelofibrosis.
6 . The method of claim 4 , wherein the myelofibrosis is primary myelofibrosis.
7 . The method of claim 4 , wherein the myelofibrosis is secondary myelofibrosis.
8 . The method of claim 1 , wherein treating the myeloproliferative neoplasm results in the mammal being measurable residual disease (MRD)-negative.
9 . The method of claim 1 , wherein treating the myeloproliferative neoplasm results in complete remission in the mammal.
10 . The method of claim 1 , wherein the compound of structural formula 1, or a pharmaceutically acceptable salt thereof, is administered orally.
11 . The method of claim 10 , wherein the compound of structural formula 1, or a pharmaceutically acceptable salt thereof, is administered once daily.
12 . The method of claim 10 ,
wherein the compound of structural formula 1, or a pharmaceutically acceptable salt thereof, is administered twice daily.
13 . The method of claim 1 , wherein the compound of structural formula 1, or a pharmaceutically acceptable salt thereof, is administered for from about seven days to about one year.
14 . The method of claim 13 , wherein the compound of structural formula 1, or a pharmaceutically acceptable salt thereof, is administered for 28 days.
15 . The method of claim 13 , wherein the compound of structural formula 1, or a pharmaceutically acceptable salt thereof, is administered for one year.
16 . The method of claim 2 , wherein
the effective amount of ruxolitinib, or a pharmaceutically acceptable salt thereof, is from about 5 mg/day to about 100 mg/day.
17 . The method of claim 16 , wherein the effective amount of ruxolitinib, or a pharmaceutically acceptable salt thereof, is about 2.5 mg/day to about 60 mg/day, from about 5 mg/day to about 60 mg/day, or from about 10 mg/day to about 50 mg/day.
18 . The method of claim 17 , wherein the ruxolitinib, or a pharmaceutically acceptable salt thereof, is administered orally.
19 . The method of claim 17 , wherein the ruxolitinib, or a pharmaceutically acceptable salt thereof, is administered twice daily.
20 . The method of claim 17 , wherein the ruxolitinib, or a pharmaceutically acceptable salt thereof, is administered for from about seven days to about one year.
21 . The method of claim 1 , wherein the myeloproliferative neoplasm has been previously treated with ruxolitinib in the absence of the compound of structural formula 1, or a pharmaceutically acceptable salt thereof.
22 . The method of claim 1 , wherein the myeloproliferative neoplasm is a ruxolitinib-resistant myeloproliferative neoplasm.