Therapeutic combinations of orally administered docetaxel and a p-gp inhibitor for the treatment of cancer

Abstract

The present disclosure provides pharmaceutical combinations of orally administered docetaxel and a P-gp inhibitor. The pharmaceutical combinations are suitable for the treatment of cancer in a subject and for reducing or preventing toxicity, hypersensitivity-type infusion reactions, and other negative outcomes resulting from or associated with intravenously administered docetaxel (e.g., Taxotere® or docetaxel formulated with polysorbate 80) therapy in a subject suffering from cancer.

1 .- 127 . (canceled) 
     
     
         128 . A method for treating cancer in a subject in need thereof, comprising:
 a. oral administration of docetaxel at an amount of about 15 mg/m 2  to about 450 mg/m 2  to the subject once a day and for 1-7 times a week; and   b. oral administration of Compound A:   
       
         
           
           
               
               
           
         
         to the subject once a day and for 1-7 times a week, and 
         wherein Compound A is administered simultaneously with or prior to the docetaxel. 
       
     
     
         129 . A method for reducing hematologic toxicity and/or neurotoxicity, and/or other toxicities or symptoms in a subject suffering from cancer and undergoing docetaxel therapy, comprising:
 a. oral administration of docetaxel at an amount of about 15 mg/m 2  to about 450 mg/m 2  to the subject once a day and for 1-7 times a week; and   b. oral administration of Compound A:   
       
         
           
           
               
               
           
         
         to the subject once a day and for 1-7 times a week, 
         wherein the plasma exposure of the orally administered docetaxel, as measured by AUC (0→∞) , is equal to or greater than the plasma exposure, as measured by AUC (0→∞) , of intravenously administered docetaxel at an amount of about 30 mg/m 2  to 100 mg/m 2  over a period of about 1 to about 24 hours once every three weeks, once every two weeks, or once every week, and 
         wherein Compound A is administered simultaneously with or prior to the docetaxel. 
       
     
     
         130 . A method for reducing or preventing hypersensitivity-type infusion reactions associated with intravenously administered docetaxel therapy in a subject suffering from cancer, comprising:
 a. oral administration of docetaxel at an amount of about 15 mg/m 2  to about 450 mg/m 2  to the subject once a day and for 1-7 times a week; and   b. oral administration of Compound A:   
       
         
           
           
               
               
           
         
         to the subject once a day and for 1-7 times a week; 
         wherein the orally administered docetaxel reaches therapeutic blood or plasma levels in the subject, and 
         wherein Compound A is administered simultaneously with or prior to the docetaxel. 
       
     
     
         131 .- 139 . (canceled) 
     
     
         140 . The method of  claim 128 , wherein the docetaxel is administered as a single dose. 
     
     
         141 . The method of  claim 128 , wherein the docetaxel is administered at an amount of about 75 mg/m 2  to about 350 mg/m 2 . 
     
     
         142 . The method of  claim 128 , wherein Compound A or a pharmaceutically acceptable salt or solvate thereof is administered orally at an amount of about 15 mg to about 50 mg. 
     
     
         143 . The method of  claim 128 , wherein the cancer is breast cancer. 
     
     
         144 . The method of  claim 128 , wherein the cancer is pancreatic cancer. 
     
     
         145 . The method of  claim 128 , wherein the cancer is non-small cell lung cancer. 
     
     
         146 . The method of  claim 128 , wherein the cancer is ovarian cancer. 
     
     
         147 . The method of  claim 128 , wherein the cancer is esophageal cancer. 
     
     
         148 . The method of  claim 128 , wherein the cancer is endometrial cancer. 
     
     
         149 . The method of  claim 128 , wherein the cancer is cervical cancer. 
     
     
         150 . The method of  claim 128 , wherein the cancer is urothelial cancer. 
     
     
         151 . The method of  claim 128 , wherein the cancer is prostate cancer. 
     
     
         152 . The method of  claim 128 , wherein Compound A or a pharmaceutically acceptable salt or solvate thereof is administered before the docetaxel is administered. 
     
     
         153 . The method of  claim 128 , wherein Compound A or a pharmaceutically acceptable salt or solvate thereof and the docetaxel are administered on the same day. 
     
     
         154 . The method of  claim 128 , comprising oral administration of docetaxel once per week. 
     
     
         155 . The method of  claim 128 , comprising oral administration of docetaxel at least twice per week. 
     
     
         156 . The method of  claim 128 , comprising oral administration of docetaxel once over a three-week period.