Combination of a PD-1 antagonist, a VEGFR/FGFR/RET tyrosine kinase inhibitor and a CBP/beta-catenin inhibitor for treating cancer
View Patent ↗The present disclosure describes a combination therapy comprising an antagonist of Programmed Death 1 receptor (PD-1), a lenvatinib or a pharmaceutically acceptable salt thereof, and (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (E7386) or a pharmaceutically acceptable salt thereof, —and the use of the combination therapies for the treatment of a cancer.
1 . A method for treating a cancer in a human subject comprising administering to the human subject a combination therapy which comprises:
(i) an antagonist of a Programmed Death 1 protein (PD-1) which is an anti-PD-1 antibody;
(ii) lenvatinib having the structure:
or a pharmaceutically acceptable salt thereof, wherein the lenvatinib is administered daily; and
(iii) (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (E7386) having the structure:
or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of: a renal cell carcinoma (RCC), a colorectal cancer (CRC), a hepatocellular carcinoma (HCC), a melanoma, and a bladder cancer.
2 . The method of claim 1 , wherein the cancer is a RCC.
3 . The method of claim 1 , wherein the anti-PD-1 antibody is pembrolizumab or nivolumab.
4 . The method of claim 1 , wherein the anti-PD-1 antibody is pembrolizumab.
5 . The method of claim 1 , wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered daily; and pembrolizumab is administered once every three weeks.
6 . The method of claim 5 , wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 24 mg, 20 mg, 18 mg, 12 mg or 8 mg; and pembrolizumab is administered at a dose of 200 mg for an adult human subject or 2 mg/kg up to 200 mg for a pediatric human subject once every three weeks.
7 . The method of claim 1 , wherein lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate; and E7386 or a pharmaceutically acceptable salt thereof is E7386.
8 . The method of claim 1 , wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered daily; and the anti-PD-1 antibody is pembrolizumab and is administered once every six weeks.
9 . The method of claim 8 , wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 24 mg, 20 mg, 18 mg, 12 mg or 8 mg; and pembrolizumab is administered at a dose of 400 mg once every six weeks.