Combination therapy with peptide epoxyketones

Abstract

ABSTRACT The invention provides combination therapy, wherein one or more other therapeutic agents are administered agents are administered with peptide epoxyketones or a pharmaceutically acceptable salt thereof. Another aspect of the invention relates to treating cancer with a peptide epoxyketone administered in combination with another therapeutic agent.

We claim: 
     
       1. A method for treating cancer, comprising administering to a patient, in combination, (1) a peptide epoxyketone proteasome inhibitor, or a pharmaceutically acceptable salt thereof; and (2) a therapeutic agent;
 wherein the peptide epoxyketone proteasome inhibitor has the following structure: 
 
       
         
           
           
               
               
           
         
         the therapeutic agent comprises lenalidomide in an amount of at least 10 mg and dexamethasone; 
         the cancer is relapsed or refractory multiple myeloma; and 
         the efficacy shown by administering (1) and (2) in combination is greater than the efficacy shown by administering either of (1) or (2) alonethe patient exhibits a maximum M protein change of greater than 50% (partial response, “PR”) for at least 100 days. 
       
     
     
       2. The method of  claim 1 , wherein the peptide epoxyketone proteasome inhibitor and the therapeutic agent are administered within about 5 minutes to within about 48 hours of one another. 
     
     
       3. A method for treating cancer, consisting essentially of administering to a patient, in combination, (1) a peptide epoxyketone proteasome inhibitor, or a pharmaceutically acceptable salt thereof; (2) lenalidomide in an amount of at least 10 mg, and (3) dexamethasone;
 wherein the peptide epoxyketone proteasome inhibitor has the following structure: 
 
       
         
           
           
               
               
           
         
         the cancer is relapsed or refractory multiple myeloma; and 
         the efficacy shown by administering (1) and (2) in combination is greater than the efficacy shown by administering either of (1) or (2) alonethe patient exhibits a maximum M protein change of greater than 50% (partial response, “PR”) for at least 100 days. 
       
     
     
       4. The method of  claim 3  wherein the peptide epoxyketone proteasome inhibitor and lenalidomide are administered within about 5 minutes to within about 48 hours of one another. 
     
     
       5. The method or  claim 4  wherein the peptide epoxyketone proteasome inhibitor, lenalidomide and dexamethasone are administered within about 5 minutes to within about 48 hours of one another. 
     
     
       6. The method of claim 1, wherein the lenalidomide is administered in an amount of at least 20 mg. 
     
     
       7. The method of claim 3, wherein the lenalidomide is administered in an amount of at least 20 mg. 
     
     
       8. The method of claim 1, wherein the peptide epoxyketone proteasome inhibitor is administered in an amount of at least 15 mg/m 2 . 
     
     
       9. The method of claim 3, wherein the peptide epoxyketone proteasome inhibitor is administered in an amount of at least 15 mg/m 2 . 
     
     
       10. The method of claim 1, wherein the efficacy shown by administering (1) and (2) in combination is synergistically greater than the efficacy shown by administering either of (1) or (2) alone. 
     
     
       11. The method of claim 10, wherein the peptide epoxyketone proteasome inhibitor is administered as a pharmaceutical composition including a cyclodextrin and optionally a buffer. 
     
     
       12. The method of claim 3, wherein the efficacy shown by administering (1) and (2) in combination is synergistically greater than the efficacy shown by administering either of (1) or (2) alone. 
     
     
       13. The method of claim 12, wherein the peptide epoxyketone proteasome inhibitor is administered as a pharmaceutical composition including a cyclodextrin and optionally a buffer. 
     
     
       14. The method of claim 1, wherein the patient exhibits a maximum M protein change of greater than 90% (very good partial response, “VGPR”) for at least 100 days. 
     
     
       15. The method of claim 1, wherein the patient exhibits a maximum M protein change of 100% (complete response, “CR”) for at least 100 days. 
     
     
       16. The method of claim 3, wherein the patient exhibits a maximum M protein change of greater than 90% (very good partial response, “VGPR”) for at least 100 days. 
     
     
       17. The method of claim 3, wherein the patient exhibits a maximum M protein change of 100% (complete response, “CR”) for at least 100 days.