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.

1 . A combination which comprises (a) a phosphoinositide 3-kinase inhibitor compound inhibitor and (b) a compound which modulates the Ras/Raf/Mek pathway, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use. 
     
     
         2 . A combination according to  claim 1 , wherein said combination comprises an amount of (a) a phosphoinositide 3-kinase inhibitor compound inhibitor and (b) a compound which modulates the Ras/Raf/Mek pathway in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof in a synergistic ratio. 
     
     
         3 . A combination according to  claim 1  wherein the phosphoinositide 3-kinase inhibitor compound is COMPOUND A, COMPOUND B or COMPOUND C. 
     
     
         4 . A combination according to  claim 1  wherein the compound which modulates the Ras/Raf/Mek pathway modulates Raf kinase activity. 
     
     
         5 . A combination according to  claim 1  wherein the compound which modulates the Ras/Raf/Mek pathway modulates Mek kinase activity. 
     
     
         6 . A combination according to  claim 4  wherein the compound which modulates Raf kinase activity is Sorafenib, Raf265, SB590885, XL281 or PLX4032. 
     
     
         7 . A combination according to  claim 5  wherein the compound which modulates Mek kinase activity is PD325901, PD-181461, ARRY142886/AZD6244, ARRY-509, XL518, JTP-74057, AS-701255, AS-701173, AZD8330, ARRY162, ARRY300, RDEA436, E6201, RO4987655/R-7167, GSK1120212 or AS703026. 
     
     
         8 . A pharmaceutical composition comprising a quantity which is jointly therapeutically effective against a proliferative disease of a combination according to  claim 1  and at least one pharmaceutically acceptable carrier. 
     
     
         9 . A combination as defined in  claim 1  for the treatment of a proliferative disease. 
     
     
         10 . A combination according to  claim 9  wherein the proliferative disease is a solid tumor. 
     
     
         11 . A combination according to  claim 9  wherein the proliferative disease is melanoma, lung cancer, colorectal cancer (CRC), breast cancer, kidney cancer such as e.g. renal cell carcinoma (RCC), liver cancer, acute myelogenous leukemia (AML), myelodysplastic Syndromes (MDS), non-small-cell lung cancer (NSCLC), thyroid cancer, pancreatic cancer, neurofibromatosis or hepatocellular carcinoma. 
     
     
         12 . A combined preparation, which comprises (a) one or more unit dosage forms of phosphoinositide-3 kinase inhibitor and (b) one or more unit dosage forms of a compound which modulates the Ras/Raf/Mek pathway. 
     
     
         13 . A synergistic combination for human administration comprising a PI3K inhibitor compound and a compound which modulates the Ras/Raf/Mek pathway, in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof, in a w/w combination range which corresponds to a synergistic combination range of 10:1 to 1:1 parts by weight in the BN472 tumor model or pancreatic tumor models PANC1 and MiaPaCa2. 
     
     
         14 . A synergistic combination for human administration comprising a PI3K inhibitor compound and a compound which modulates the Ras/Raf/Mek pathway, in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof, in a w/w combination range which corresponds to a synergistic combination range of 1-50 mg/kg and 1-30 mg/kg respectively, in the BN472 tumor model or pancreatic tumor models PANC1 and MiaPaCa2. 
     
     
         15 . A combination according to  claim 1  for human administration comprising a synergistic amount of a PI3K inhibitor compound at about MTD and a compound which modulates the Ras/Raf/Mek at 50%-100% of the MTD.