Methods for Cancer Therapy

Abstract

for treating cancer, or preventing cancer recurrence or progression; wherein ring A, Z1 and Z2 are as defined herein.

1 . A method for delaying or preventing cancer recurrence or progression, comprising administering to a patient, who has undergone a primary cancer therapy and who is in remission, a single-agent maintenance therapy, wherein the single-agent consists of a compound of formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       on a dosing schedule comprising at least four 28-day treatment cycles,
 wherein the 28-day treatment cycle comprises four consecutive weeks in which the compound of formula (I), or pharmaceutically acceptable salt thereof, is administered once a week for the first three weeks of the treatment cycle and the compound of formula (I), or pharmaceutically acceptable salt thereof, is not administered during the fourth week; 
 wherein the primary cancer therapy comprises an autologous stem cell transplant; 
 wherein ring A is 
 
       
         
           
           
               
               
           
         
       
       and
 Z 1  and Z 2  are each independently hydroxyl; or Z 1  and Z 2  together form a cyclic boronic ester having 2-20 carbon atoms, and optionally one or more heteroatoms selected from N, S, or O. 
 
     
     
         2 . The method of  claim 1 , wherein the compound of formula (I), or pharmaceutically acceptable salt thereof, is administered orally. 
     
     
         3 . The method of  claim 1 , wherein the compound of formula (I), or pharmaceutically acceptable salt thereof, is administered on days 1, 8, and 15 of each treatment cycle. 
     
     
         4 . The method of  claim 1 , wherein the dosing schedule comprises about twenty-six treatment cycles. 
     
     
         5 . The method of  claim 4 , wherein the compound of formula (I), or pharmaceutically acceptable salt thereof, is administered at a first dose for at least four treatment cycles, and a second dose in the treatment cycles 5 through 26. 
     
     
         6 . The method of  claim 5 , wherein the first dose is about 3.0 mg and the second dose is about 4.0 mg. 
     
     
         7 . The method of  claim 5 , wherein the first dose is about 3.0 mg, and the second dose is about 3.0 mg. 
     
     
         8 . The method of  claim 5 , wherein the first dose is about 2.3 mg, and the second dose is about 3.0 mg. 
     
     
         9 . The method of  claim 5 , wherein the first dose is about 2.3 mg, and the second dose is about 2.3 mg. 
     
     
         10 . The method of  claim 5 , wherein the first dose and the second dose are the same. 
     
     
         11 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (IV) 
       
         
           
           
               
               
           
         
       
       or an ester or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method of  claim 11 , wherein said compound of formula (IV) is administered to the patient in a form of an ester, or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 12 , wherein the ester is a compound of formula (IIIa) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The method of  claim 13 , wherein the compound of formula (IIIa) is in a solid dosage form. 
     
     
         15 . The method of  claim 14 , wherein the solid dosage form is capsule. 
     
     
         16 . The method of  claim 15 , wherein the capsule contains a mixture of ixazomib citrate, microcrystalline cellulose, talc, and magnesium stearate. 
     
     
         17 . The method of  claim 1 , wherein the primary cancer therapy comprises a proteasome inhibitor based regimen, or an immunomodulating drug based regimen, or both. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the primary cancer therapy comprises a proteasome inhibitor based regimen, or an immunomodulating drug based regimen, or both, followed by autologous stem cell transplant. 
     
     
         20 . The method of  claim 1 , wherein the primary cancer therapy comprises a proteasome inhibitor based regimen, or an immunomodulating drug based regimen, or both, followed by a conditioning regimen comprising melphalan and autologous stem cell transplant. 
     
     
         21 . The method of  claim 17 ,  19  or  20 , wherein the proteasome inhibitor based regimen comprises bortezomib, ixazomib, carfilzomib, disulfiram, epigallocatechin-3-gallate, salinosporamid A, ONX0912, CEP-18770, or Epoxomicin. 
     
     
         22 . The method of  claim 21 , wherein the proteasome inhibitor based regimen comprises bortezomib. 
     
     
         23 . The method of  claim 17 ,  19  or  20 , wherein the immunomodulating drug based regimen comprises lenalidomide or pomalidomide. 
     
     
         24 . The method of  claim 23 , wherein the immunomodulating drug based regimen comprises lenalidomide. 
     
     
         25 . The method of  claim 1 , wherein the first 28-day treatment cycle begins at least 75 days after autologous stem cell transplant. 
     
     
         26 . The method of  claim 1 , wherein the first 28-day treatment cycle begins prior to 115 days after autologous stem cell transplant. 
     
     
         27 . The method of  claim 1 , wherein the cancer is multiple myeloma. 
     
     
         28 . The method of  claim 1 , wherein the cancer is multiple myeloma or refractory multiple myeloma. 
     
     
         29 . The method of  claim 1 , wherein the cancer is amyloidosis. 
     
     
         30 . The method of  claim 1 , wherein the patient is an individual diagnosed with multiple myeloma or refractory multiple myeloma. 
     
     
         31 . The method of  claim 1 , wherein the method is a maintenance therapy to prevent relapse or recurrence of multiple myeloma in the patient who has undergone a primary cancer therapy. 
     
     
         32 . The method of  claim 1 , wherein the method is a maintenance therapy to prevent progression of multiple myeloma in the patient who has undergone a primary cancer therapy. 
     
     
         33 . The method of  claim 31  or  32 , wherein the patient has achieved complete or partial clinical and hematolotic recovery following the primary cancer therapy. 
     
     
         34 . The method of  claim 1 , wherein the method is a maintenance therapy for treating a patient at risk of developing or experiencing a recurrence of a proteasome-mediated disorder. 
     
     
         35 . The method of  claim 1 , wherein the method is a maintenance therapy for treating a patient at risk of developing or experiencing a recurrence of a cancer selected from multiple myeloma. 
     
     
         36 . A method for delaying or preventing cancer recurrence or progression, comprising administering to a patient, who has undergone a primary cancer therapy and who is in remission, a single-agent maintenance therapy, wherein the single-agent consists of a compound of formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         on a dosing schedule comprising at least four 28-day treatment cycles, 
         wherein the compound of formula (I), or pharmaceutically acceptable salt thereof, is administered at a first dose for the first four treatment cycles, and a second dose for at least one treatment cycle after the first four treatment cycles, wherein the second dose is different from the first dose; 
         wherein the 28-day treatment cycle comprises four consecutive weeks in which the compound of formula (I), or pharmaceutically acceptable salt thereof, is administered once a week for the first three weeks of the treatment cycle and the compound of formula (I), or pharmaceutically acceptable salt thereof, is not administered during the fourth week; 
         wherein the primary cancer therapy comprises an autologous stem cell transplant; 
         wherein ring A is 
       
       
         
           
           
               
               
           
         
       
       and
 Z 1  and Z 2  are each independently hydroxyl; or Z 1  and Z 2  together form a cyclic boronic ester having 2-20 carbon atoms, and optionally one or more heteroatoms selected from N, S, or O. 
 
     
     
         37 . The method of  claim 36 , wherein the compound of formula (I), or pharmaceutically acceptable salt thereof, is administered orally. 
     
     
         38 . The method of  claim 36 , wherein the compound of formula (I), or pharmaceutically acceptable salt thereof, is administered on days 1, 8, and 15 of each treatment cycle. 
     
     
         39 . The method of  claim 36 , wherein the dosing schedule comprises about twenty-six treatment cycles. 
     
     
         40 . The method of  claim 39 , wherein the first dose is about 3.0 mg and the second dose is about 4.0 mg. 
     
     
         41 . The method of  claim 40 , wherein the first dose is about 2.3 mg, and the second dose is about 3.0 mg. 
     
     
         42 . The method of  claim 36 , wherein the compound of formula (I) is a compound of formula (IV) 
       
         
           
           
               
               
           
         
       
       or an ester or a pharmaceutically acceptable salt thereof. 
     
     
         43 . The method of  claim 42 , wherein said compound of formula (IV) is administered to the patient in a form of an ester, or a pharmaceutically acceptable salt thereof. 
     
     
         44 . The method of  claim 43 , wherein the ester is a compound of formula (IIIa) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The method of  claim 44 , wherein the compound of formula (IIIa) is in a solid dosage form. 
     
     
         46 . The method of  claim 45 , wherein the solid dosage form is capsule. 
     
     
         47 . The method of  claim 46 , wherein the capsule contains a mixture of ixazomib citrate, microcrystalline cellulose, talc, and magnesium stearate. 
     
     
         48 . The method of  claim 36 , wherein the primary cancer therapy comprises an autologous stem cell transplant. 
     
     
         49 . The method of  claim 36 , wherein the first 28-day treatment cycle begins at least 75 days after autologous stem cell transplant. 
     
     
         50 . The method of  claim 36 , wherein the first 28-day treatment cycle begins prior to 115 days after autologous stem cell transplant. 
     
     
         51 . The method of  claim 36 , wherein the cancer is multiple myeloma. 
     
     
         52 . The method of  claim 36 , wherein the cancer is multiple myeloma or refractory multiple myeloma. 
     
     
         53 . The method of  claim 36 , wherein the patient is an individual diagnosed with multiple myeloma or refractory multiple myeloma. 
     
     
         54 . The method of  claim 36 , wherein the method is a maintenance therapy to prevent relapse or recurrence of multiple myeloma in the patient who has undergone a primary cancer therapy. 
     
     
         55 . The method of  claim 36 , wherein the method is a maintenance therapy to prevent progression of multiple myeloma in the patient who has undergone a primary cancer therapy. 
     
     
         56 . The method of  claim 54  or  55 , wherein the patient has achieved complete or partial clinical and hematolotic recovery following the primary cancer therapy. 
     
     
         57 . The method of  claim 36 , wherein the method is a maintenance therapy for treating a patient at risk of developing or experiencing a recurrence of a proteasome-mediated disorder. 
     
     
         58 . The method of  claim 36 , wherein the method is a maintenance therapy for treating a patient at risk of developing or experiencing a recurrence of a cancer selected from multiple myeloma.