Anti-neoplastic combinations and dosing regimens using cdk4/6 inhibitor compounds to treat rb-positive tumors

Abstract

This invention directed to methods for treating select RB-positive cancers and other Rb-positive abnormal cellular proliferative disorders using CDK4/6 inhibitors in specific dosing and combination or alternation regimes. In one aspect, treatments of select RB-positive cancers are disclosed using specific CDK4/6 inhibitors in combination or alternation with a Bruton's tyrosine kinase (BTK) inhibitor.

We claim: 
     
         1 . A method for the treatment of an Rb-positive cancer in a human in need thereof comprising administering an effective amount of Bruton's tyrosine kinase (BTK) inhibitor selected from ibrutinib and acalabrutinib in combination with a CDK 4/6 inhibitor compound of the structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the Rb-positive cancer is a solid tumor. 
     
     
         3 . The method of  claim 2 , wherein the solid tumor is selected from non-small cell lung cancer, colorectal cancer, liver cancer, ovarian cancer, glioblastoma, breast cancer. 
     
     
         4 . The method of  claim 3 , wherein the solid tumor is non-small cell lung cancer. 
     
     
         5 . The method of  claim 3 , wherein the solid tumor is colorectal cancer. 
     
     
         6 . The method of  claim 3 , wherein the solid tumor is liver cancer. 
     
     
         7 . The method of  claim 3 , wherein the solid tumor is ovarian cancer. 
     
     
         8 . The method of  claim 3 , wherein the solid tumor is glioblastoma. 
     
     
         9 . The method of  claim 3 , wherein the solid tumor is breast cancer. 
     
     
         10 . The method of  claim 9 , wherein the breast cancer is Erb-2/human epidermal growth factor receptor (HER)-2-positive breast cancer. 
     
     
         11 . The method of any of  claim 1 , wherein the Rb-positive cancer is a hematological cancer. 
     
     
         12 . The method of  claim 11 , wherein the hematological cancer is acute myeloid leukemia (AML). 
     
     
         13 . The method of  claim 11 , wherein the hematological cancer is acute lymphocytic leukemia (ALL). 
     
     
         14 . The method of  claim 11 , wherein the hematological cancer is a T-cell cancer. 
     
     
         15 . The method of any of  claim 1 , wherein the CDK 4/6 inhibitor compound is conjugated to a radioisotope. 
     
     
         16 . The method of  claim 1 , wherein the CDK 4/6 inhibitor compound is conjugated to a targeting agent. 
     
     
         17 . The method of  claim 16 , wherein the targeting agent is an antibody or antibody fragment.