Treatment Of RB-Negative Tumors Using Topoisomerase Inhibitors In Combination With Cyclin Dependent Kinase 4/6 Inhibitors

Abstract

This invention is in the area of improved therapeutic combinations for and methods of treating selected retinoblastoma (Rb)-negative cancers and Rb-negative abnormal cellular proliferative disorders using particular topoisomerase inhibitors and specific cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. In one aspect, the improved treatment of select Rb-negative cancers is disclosed using specific compounds disclosed herein in combination with a topoisomerase I inhibitor.

1 . A method for treating a host having triple negative breast cancer comprising administering an effective amount of a topoisomerase inhibitor selected from topotecan, etirinotecan pegol, belotecan, cositecan, and irinotecan and a CDK 4/6 inhibitor compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt therein. 
       
     
     
         2 . The method of  claim 1 , wherein the host is a human. 
     
     
         3 . The method of  claim 2 , wherein the CDK 4/6 inhibitor compound is Compound Q or its pharmaceutically acceptable salt. 
     
     
         4 . The method of  claim 2 , wherein the CDK 4/6 inhibitor compound is Compound T or its pharmaceutically acceptable salt. 
     
     
         5 . The method of  claim 2 , wherein the CDK 4/6 inhibitor compound is Compound U or its pharmaceutically acceptable salt. 
     
     
         6 . The method of  claim 2 , wherein the CDK 4/6 inhibitor compound is Compound GG or its pharmaceutically acceptable salt. 
     
     
         7 . The method of  claim 2 , wherein the CDK 4/6 inhibitor compound is Compound X or its pharmaceutically acceptable salt. 
     
     
         8 . The method of  claim 2 , wherein the CDK 4/6 inhibitor compound is Compound BB or its pharmaceutically acceptable salt. 
     
     
         9 . The method of  claim 2 , wherein the at least one chemotherapeutic agent is topotecan. 
     
     
         10 . The method of  claim 2 , wherein the at least one chemotherapeutic agent is irinotecan. 
     
     
         11 . The method of  claim 2 , wherein the at least one chemotherapeutic agent is etirinotecan pegol. 
     
     
         12 . The method of  claim 2 , wherein the at least one chemotherapeutic agent is belotecan. 
     
     
         13 . The method of  claim 2 , wherein the at least one chemotherapeutic agent is cositecan. 
     
     
         14 . A method for treating a host having RB-negative cervical cancer comprising administering an effective amount of a chemotherapeutic agent selected from topotecan, etirinotecan pegol, belotecan, cositecan, and irinotecan and a CDK 4/6 inhibitor compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt therein. 
       
     
     
         15 . The method of  claim 14 , wherein the host is a human. 
     
     
         16 . The method of  claim 15 , wherein the CDK 4/6 inhibitor compound is Compound Q or its pharmaceutically acceptable salt. 
     
     
         17 . The method of  claim 15 , wherein the CDK 4/6 inhibitor compound is Compound T or its pharmaceutically acceptable salt. 
     
     
         18 . The method of  claim 15 , wherein the CDK 4/6 inhibitor compound is Compound U or its pharmaceutically acceptable salt. 
     
     
         19 . The method of  claim 15 , wherein the CDK 4/6 inhibitor compound is Compound GG or its pharmaceutically acceptable salt. 
     
     
         20 . The method of  claim 15 , wherein the CDK 4/6 inhibitor compound is Compound X or its pharmaceutically acceptable salt. 
     
     
         21 . The method of  claim 15 , wherein the CDK 4/6 inhibitor compound is Compound BB or its pharmaceutically acceptable salt. 
     
     
         22 . The method of  claim 15 , wherein the at least one chemotherapeutic agent is topotecan. 
     
     
         23 . The method of  claim 15 , wherein the at least one chemotherapeutic agent is irinotecan. 
     
     
         24 . A method for treating a host having small cell lung cancer comprising administering an effective amount of a chemotherapeutic agent selected from belotecan, etirinotecan pegol, and cositecan and a CDK 4/6 inhibitor compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt therein. 
       
     
     
         25 . The method of  claim 24 , wherein the host is a human. 
     
     
         26 . The method of  claim 25 , wherein the CDK 4/6 inhibitor compound is Compound Q or its pharmaceutically acceptable salt. 
     
     
         27 . The method of  claim 25 , wherein the CDK 4/6 inhibitor compound is Compound T or its pharmaceutically acceptable salt. 
     
     
         28 . The method of  claim 25 , wherein the CDK 4/6 inhibitor compound is Compound U or its pharmaceutically acceptable salt. 
     
     
         29 . The method of  claim 25 , wherein the CDK 4/6 inhibitor compound is Compound GG or its pharmaceutically acceptable salt. 
     
     
         30 . The method of  claim 25 , wherein the CDK 4/6 inhibitor compound is Compound X or its pharmaceutically acceptable salt. 
     
     
         31 . The method of  claim 25 , wherein the CDK 4/6 inhibitor compound is Compound BB or its pharmaceutically acceptable salt. 
     
     
         32 . The method of  claim 25 , wherein the at least one chemotherapeutic agent is etirinotecan pegol. 
     
     
         33 . The method of  claim 25 , wherein the at least one chemotherapeutic agent is belotecan. 
     
     
         34 . The method of  claim 25 , wherein the at least one chemotherapeutic agent is cositecan.