INHIBITORS OF THE FIBROBLAST GROWTH FACTOR RECEPTOR 4 IN COMBINATION WITH CYCLIN-DEPENDENT KINASE INHIBITORS
Described herein are selective inhibitors of FGFR4, pharmaceutical compositions including such compounds, and combinations with other therapeutic agents, such as CDK inhibitors (e.g., CDK4/6 inhibitors), and methods of using such combinations.
1 . A method for treating a cancer characterized by amplified FGF19 in a patient in need thereof comprising administering a therapeutically effective amount of at least one fibroblast growth factor receptor 4 (FGFR4) inhibitor in combination with at least one cyclin-dependent kinase (CDK) inhibitor to the patient, wherein:
the at least one CDK inhibitor is chosen from CDK4/6 inhibitors; and
the at least one FGFR4 inhibitor is chosen from N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide (Compound 1), N-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-3-methylphenyl)acrylamide (Compound 2), and pharmaceutically acceptable salts thereof.
2 . (canceled)
3 . The method of claim 1 , wherein the at least one CDK inhibitor is chosen from palbociclib, 7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone, N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine, GZ38-1, and pharmaceutically acceptable salts thereof.
4 . The method of claim 1 , wherein the at least one CDK inhibitor is chosen from palbociclib and pharmaceutically acceptable salts thereof.
5 - 7 . (canceled)
8 . The method of claim 1 , wherein the cancer is further characterized by fibroblast growth factor 19 (FGF19) overexpression.
9 . (canceled)
10 . The method of claim 8 , wherein the cancer is further characterized by wild-type retinoblastoma protein and wild type klotho beta.
11 - 13 . (canceled)
14 . The method of claim 1 , wherein the cancer is further characterized by FGFR4 overexpression.
15 . The method of claim 1 , wherein the cancer is chosen from breast cancer, ovarian cancer, lung cancer, liver cancer, a sarcoma, esophagus cancer, large intestine cancer, colon cancer, head and neck cancer, and hyperlipidemia.
16 . The method of claim 15 , wherein the cancer is liver cancer.
17 . The method of claim 16 , wherein the cancer is hepatocellular carcinoma or hepatoblastoma.
18 . The method of claim 17 , wherein the cancer is fibrolamellar hepatocellular carcinoma.
19 . The method of claim 17 , wherein the cancer is unresectable hepatocellular carcinoma.
20 . The method of claim 15 , wherein the cancer is breast cancer.
21 . The method of claim 20 , wherein the cancer is metastatic breast cancer.
22 . The method of claim 21 , wherein the cancer is receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer.
23 . The method of claim 1 , wherein the patient is a human.
24 . (canceled)
25 . (canceled)
26 . The method of claim 1 , wherein Compound 1 or a pharmaceutically acceptable salt is orally administered to the patient once or twice daily.
27 . The method of claim 26 , wherein 100 mg to 300 mg of Compound 1 or an equivalent amount of a pharmaceutically acceptable salt of Compound 1 is administered twice daily.
28 - 40 . (canceled)
41 . The method of claim 4 , wherein 50 mg to 150 mg of palbociclib is orally administered to the patient once daily.
42 - 44 . (canceled)
45 . The method of claim 4 , wherein palbociclib is administered to the patient for twenty-one consecutive days, followed by seven days in which no palbociclib is administered to the patient.
46 . The method of claim 45 , wherein the twenty-eight day administration schedule is repeated one or more times.
47 - 51 . (canceled)