Combination of (a) a phosphoinositide 3-kinase inhibitor and (b) a modulator of RAS/RAF/MEK pathway

Abstract

The invention relates to a pharmaceutical combination which comprises (a) a phosphoinositide 3-kinase inhibitor compound and (b) a compound which modulates the Ras/Raf/Mek pathway for the treatment of a proliferative disease, especially a solid tumor disease; a pharmaceutical composition comprising such a combination; the use of such a combination for the preparation of a medicament for the treatment of a proliferative disease; a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of a warm-blooded animal, especially a human.

What is claimed is: 
     
         1 . A method of treating a warm-blooded animal having a proliferative disorder, comprising simultaneously, sequentially or separately administering to said animal (a) a phosphoinositide 3-kinase inhibitor compound selected from 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quiolin-1-yl)-phenyl]-propionitrile, 8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one, or 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine and (b) a compound which modulates the Ras/Raf/Mek pathway selected from (i.) a compound which modulates Raf kinase activity selected from sorafenib, Raf265, SB590885, XL281 or PLX4032, or (ii.) a compound which modulates Mek kinase activity selected from PD325901, PD-181461, ARRY142886/AZD6244, ARRY-509, XL518, JTP-74057, AS-701255, AS-701173, AZD8330, ARRY162, ARRY300, RDEA436, E6201, R04987655/R-7167, GSK1120212 or AS703026, wherein the active ingredients are present in free form or in the form of a pharmaceutically acceptable salt thereof, in a quantity which is therapeutically effective against said proliferative disease. 
     
     
         2 . A method according to  claim 1 , wherein the phosphoinositide 3-kinase inhibitor compound is 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine or a pharmaceutically acceptable salt thereof. 
     
     
         3 . A method according to  claim 1 , wherein the compound which modulates the Ras/Raf/Mek pathway is a compound which modulates Raf kinase activity selected from the group consisting of Raf265 or PLX4032 or a pharmaceutically acceptable salt thereof. 
     
     
         4 . A method according to  claim 1 , wherein the compound which modulates the Ras/Raf/Mek pathway is a compound which modulates Mek kinase activity selected from the group consisting of ARRY142886/AZD6244, ARRY-509, AZD8330, ARRY162, ARRY300, GSK1120212 or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A method according to  claim 1 , wherein the proliferative disorder is a solid tumor selected from the group consisting of breast cancer, ovarian cancer, colon cancer, gastro-intestinal cancer, cervix cancer, lung cancer, head and neck cancer, bladder cancer, prostate cancer and Kaposi's sarcoma. 
     
     
         6 . A method according to  claim 1 , wherein the proliferative disease is selected from the group consisting of melanoma, lung cancer, colorectal cancer (CRC), breast cancer, kidney cancer, renal cell carcinoma (RCC), liver cancer, acute myelogenous leukemia (AML), myelodysplastic syndromes (MDS), non-small-cell lung cancer (NSCLC), thyroid cancer, pancreatic cancer, neurofibromatosis, and hepatocellular carcinoma. 
     
     
         7 . A method according to  claim 1 , wherein the proliferative disease is selected from the group consisting of melanoma, lung cancer, colorectal cancer (CRC), breast cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer. 
     
     
         8 . A method according to  claim 1 , wherein the proliferative disease has a genetic alteration in the Ras/Raf/Mek signal transduction pathway consisting of a HRAS, KRAS, NRAS or BRAF mutation or gene amplification. 
     
     
         9 . A method of treating a warm-blooded animal having a proliferative disorder selected from the group consisting of melanoma, lung cancer, colorectal cancer (CRC), breast cancer, kidney cancer, renal cell carcinoma (RCC), liver cancer, myelodysplastic syndromes (MDS), non-small cell lung cancer (NSCLC), thyroid cancer, pancreatic cancer, neurofibromatosis, hepatocellular carcinoma, ovarian cancer, colon cancer, cancer of the gastrointestinal tract, cervix cancer, head and neck cancer, bladder cancer, and Kaposi's sarcoma, comprising administering to said animal (a) a phosphoinositide 3-kinase inhibitor compound 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine and (b) a compound which modulates Mek kinase activity selected from PD325901, PD-181461, ARRY142886/AZD6244, ARRY-509, XL518, JTP-74057, AS-701255, AS-701173, AZD8330, ARRY162, ARRY300, RDEA436, E6201, R04987655/R-7167, GSK1120212 or AS703026, wherein the active ingredients are present in free form or in the form of a pharmaceutically acceptable salt thereof, in a quantity which is therapeutically effective against said proliferative disease. 
     
     
         10 . A method according to  claim 9 , wherein the compound which modulates Mek kinase activity is ARRY142886/AZD6244, AZD8330, ARRY162, ARRY300, or GSK11202 or a pharmaceutically acceptable salt thereof.