Combination of regorafenib and pd-1/pd-l1(2) inhibitors for treating cancer

Abstract

The present invention relates to pharmaceutical compositions and combinations comprising regorafenib or its hydrate, solvate, metabolite or pharmaceutically acceptable salt or a polymorph thereof and a PD-1/PD-L1(2) inhibitor for treating, preventing or managing diseases and conditions including hyperproliferative disorders such as cancer in humans and other mammals.

1 - 11 . (canceled) 
     
     
         12 . A method of treating malignant disorders and pre-malignant hyper-proliferative disorders in a subject in need thereof comprising administering chemotherapeutic agents, wherein said chemotherapeutic agents consist of effective amounts of
 a) Regorafenib or its hydrate, solvate, metabolite or pharmaceutically acceptable salt, or a polymorph thereof and   b) Pembrolizumab,   wherein the Regorafenib metabolite is selected from the group consisting of:   4-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide I-oxide,   4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-(hydroxymethyl)pyridine-2-carboxamide,   4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]pyridine-2-carboxamide and   4-[4-({[4-chloro-3(trifluoromethyl)phenyl] carbamoyl}amino)-3-fluorophenoxy]pyridine-2-carboxamide I-oxide.   
     
     
         13 . The method of claim  1  wherein Regorafenib is orally administered first followed by the administration of Pembrolizumab intravenously. 
     
     
         14 . A method of treating hyper-proliferative disorders in a subject in need thereof comprising administering chemotherapeutic agents, wherein said chemotherapeutic agents consist of effective amounts of
 a) Regorafenib or its hydrate, and   b) Pembrolizumab,   wherein the hyper-proliferative disorders are selected from the group consisting of cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.   
     
     
         15 . The method of claim  3  wherein the hyper-proliferative disorder is selected from the group consisting of hepatic cell cancer, colorectal cancer and gastrointestinal stromal tumors (GIST). 
     
     
         16 . The method of claim  3  wherein the hyper-proliferative disorder is hepatic cell cancer. 
     
     
         17 . The method of claim  3  wherein the hyper-proliferative disorder is colorectal cancer. 
     
     
         18 . The method of claim  3  wherein Regorafenib is orally administered first followed by the administration of Pembrolizumab intravenously. 
     
     
         19 . The method of claim  3  wherein Regorafenib is orally administered in the form of a tablet in an amount of 10 to 100 mg. 
     
     
         20 . A pharmaceutical combination comprising chemotherapeutic agents, wherein the chemotherapeutic agents consist of
 a) Regorafenib or its hydrate, solvate, metabolite, pharmaceutically acceptable salt, or a polymorph thereof and   b) Pembrolizumab,   wherein the Regorafenib metabolite is selected from the group consisting of:   4-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide I-oxide,   4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-(hydroxymethyl)pyridine-2-carboxamide,   4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]pyridine-2-carboxamide and   4-[4-({[4-chloro-3(trifluoromethyl)phenyl] carbamoyl}amino)-3-fluorophenoxy]pyridine-2-carboxamide I-oxide.   
     
     
         21 . The combination of claim  9  wherein said chemotherapeutic agents are in separate dosage forms for administration simultaneously or sequentially to a patient in need thereof. 
     
     
         22 . The combination of claim  10  wherein Regorafenib is in an oral dosage form and Pembrolizumab is in an intravenous dosage form. 
     
     
         23 . The combination of claim  11  wherein Regorafenib is in the form of a tablet in an amount of 10 to 100 mg. 
     
     
         24 . The combination of claim  9  wherein Regorafenib is in a dosage form in an amount of 10 to 100 mg. 
     
     
         25 . The combination of claim  9  which is in the form of a medicament with combined dosages for treating cancer of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid or their distant metastases. 
     
     
         26 . The combination of  claim 14  wherein the amount of Regorafenib is effective for treating hepatic cell cancer, colorectal cancer or gastrointestinal stromal tumors (GIST). 
     
     
         27 . The combination of  claim 14  wherein the amount of Regorafenib is effective for treating hepatic cell cancer. 
     
     
         28 . The combination of  claim 14  wherein the amount of Regorafenib is effective for treating colorectal cancer. 
     
     
         29 . The combination of claim  9  wherein Regorafenib is in the form of a solid dispersion and the matrix for the solid dispersion of Regorafenib is selected from the group consisting polyvinylpyrrolidone, vinylpyrrolidone/vinylacetate copolymer, polyalkylene glycol, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polymethacrylates, polyvinyl alcohol, polyvinyl acetate, vinyl alcohol/vinyl acetate copolymer, polyglycolized glycerides, xanthan gum, carrageenan, chitosan, chitin, poyldextrin, dextrin, starch and proteins.
 wherein the hyper-proliferative disorder is colorectal cancer.