AXL INHIBITORS FOR USE IN COMBINATION THERAPY FOR PREVENTING, TREATING OR MANAGING METASTATIC CANCER
This invention is directed to methods of preventing, treating or managing cancer, preferably metastatic cancer, in a patient. The methods comprise administering an effective amount of an Axl inhibitor in combination with the administration of an effective amount of one or more chemotherapeutic agents.
1 .- 4 . (canceled)
5 . A method for treating or managing Acute Myeloid Leukemia (AML) in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of an Axl inhibitor selected from 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, as an isolated stereoisomer or mixture thereof or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof, and a therapeutically effective amount of cytarabine.
6 . The method of claim 5 , wherein said Axl inhibitor is selected from the group consisting of:
a. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;
b. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;
c. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine; and
d. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(8)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.
7 . The method of claim 5 , wherein the Axl inhibitor and the therapeutically effective amount of cytarabine are administered concurrently.
8 . The method of claim 5 , wherein the Axl inhibitor and the therapeutically effective amount of cytarabine are administered sequentially.
9 . The method of claim 5 , wherein the Axl inhibitor is administered in a dosing regimen between 0.001 mg/kg to 100 mg/kg for the duration of the treatment.
10 . The method of claim 5 , wherein the Axl inhibitor is administered in a dosing regimen between 1.0 mg/kg to 100 mg/kg for the duration of the treatment.
11 . The method of claim 5 , wherein the Axl inhibitor is administered orally.
12 . The method of claim 5 , wherein the therapeutically effective amount of cytarabine is delivered by sub-cutaneous infusion.
13 . A method for treating or managing Acute Myeloid Leukemia (AML) in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of an Axl inhibitor selected from 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, as an isolated stereoisomer or mixture thereof or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof, and a therapeutically effective amount of a chemotherapeutic agent.
14 . The method of claim 13 , wherein said chemotherapeutic agent is cytarabine.
15 . The method of claim 13 , wherein the Axl inhibitor is administered in a dosing regimen between 0.001 mg/kg to 100 mg/kg for the duration of the treatment.
16 . The method of claim 13 , wherein the Axl inhibitor is administered in a dosing regimen between 1.0 mg/kg to 100 mg/kg for the duration of the treatment.
17 . The method of claim 13 , wherein the Axl inhibitor and the therapeutically effective amount of said chemotherapeutic agent are administered concurrently.
18 . The method of claim 13 , wherein the Axl inhibitor and the therapeutically effective amount of said chemotherapeutic agent are administered sequentially.
19 . The method of claim 13 , wherein the Axl inhibitor is administered orally.
20 . The method of claim 15 , wherein the therapeutically effective amount of cytarabine is delivered by sub-cutaneous infusion.
21 . The method of claim 15 , wherein said Axl inhibitor is selected from the group consisting of:
a. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;
b. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;
c. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine; and
d. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(8)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.