Methods of treating chronic lymphocytic leukemia using 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione

Abstract

Provided herein are methods of using 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopolog, or a pharmaceutically acceptable salt thereof, alone or in combination with obinutuzumab, for treating, preventing or managing chronic lymphocytic leukemia/small lymphocytic lymphoma.

What is claimed is: 
     
         1 . A method of treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), comprising administering to a subject in need thereof a therapeutically effective amount of Compound 3 of the formula: 
       
         
           
           
               
               
           
         
         or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A method of treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1 of the formula: 
       
         
           
           
               
               
           
         
         or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof. 
       
     
     
         3 . A method of treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), comprising administering to a subject in need thereof a therapeutically effective amount of Compound 2 of the formula: 
       
         
           
           
               
               
           
         
         or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The method of any one of  claims 1  to  3 , wherein the CLL/SLL is relapsed or refractory CLL/SLL. 
     
     
         5 . The method of  claim 4 , wherein the CLL/SLL is relapsed or refractory to at least two prior therapies. 
     
     
         6 . The method of  claim 5 , wherein at least one of the prior therapies is a Bruton's tyrosine kinase (BTK) inhibitor, a phosphoinositide 3-kinase inhibitor, or venetoclax. 
     
     
         7 . The method of  claim 6 , wherein the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or tirabrutinib. 
     
     
         8 . The method of any one of  claims 1  to  3 , wherein the CLL is newly diagnosed. 
     
     
         9 . The method of any one of  claims 1  to  8 , wherein the compound is administered orally. 
     
     
         10 . The method of any one of  claims 1  to  9 , wherein the compound is administered once daily for 5 days followed by 2 days of rest. 
     
     
         11 . The method of any one of  claims 1  to  9 , wherein the compound is administered once daily for 7 days followed by 7 days of rest. 
     
     
         12 . The method of any one of  claims 1  to  9 , wherein the compound is administered once daily for 5 days followed by 9 days of rest. 
     
     
         13 . The method of any one of  claims 1  to  9 , wherein the compound is administered once daily for 14 days followed by 14 days of rest. 
     
     
         14 . The method of any one of  claims 1  to  9 , wherein the compound is administered once daily for 21 days followed by 7 days of rest. 
     
     
         15 . The method of any one of  claims 1  to  9 , wherein the compound is administered on days 1 to 5 of a 7-day cycle, on days 1 to 3 of a 7-day cycle, on days 1 to 5 of a 14-day cycle, on days 1 to 7 of a 14-day cycle, on days 1 to 10 of a 14-day cycle, on days 1 to 7 and days 15 to 21 of a 28-day cycle, on days 1 to 21 of a 28-day cycle, or on days 1 to 14 of a 28-day cycle. 
     
     
         16 . The method of any one of  claims 1  to  13 , wherein the compound is administered in an amount of about 0.1 mg, about 0.2 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1.2 mg or about 1.6 mg per day. 
     
     
         17 . The method of any one of  claims 1  to  16 , further comprising administering to the subject a therapeutically effective amount of obinutuzumab. 
     
     
         18 . The method of  claim 17 , wherein obinutuzumab is administered intravenously. 
     
     
         19 . The method of  claim 18 , wherein obinutuzumab is administered at a dose of about 100 mg on day 1 of a first 28-day cycle, about 900 mg on day 2 of the first 28-day cycle, and about 1000 mg on each of days 8 and 15 of the first 28-day cycle and day 1 of a second to a sixth 28-day cycles. 
     
     
         20 . The method of  claim 17 , comprising (i) administering obinutuzumab at a dose of about 100 mg on day 1, about 900 mg on day 2, about 1000 mg on each of days 8 and 15 of the a first 28-day cycle (“Cycle 1”), and at a dose of about 1000 mg on day 1 of the subsequent 28-day cycle(s); and (ii) administering Compound 1 in cycles of once daily for 7 days followed by 7 days of rest, starting on day 15 of Cycle 1. 
     
     
         21 . The method of  claim 17 , comprising (i) administering obinutuzumab at a dose of about 100 mg on day 1, about 900 mg on day 2, about 1000 mg on each of days 8 and 15 of the a first 28-day cycle (“Cycle 1”), and at a dose of about 1000 mg on day 1 of the subsequent 28-day cycle(s); and (ii) administering Compound 1 in cycles of once daily for 5 days followed by 9 days of rest, starting on day 15 of Cycle 1. 
     
     
         22 . The method of  claim 17 , comprising (i) administering obinutuzumab at a dose of about 100 mg on day 1, about 900 mg on day 2, about 1000 mg on each of days 8 and 15 of the a first 28-day cycle (“Cycle 1”), and at a dose of about 1000 mg on day 1 of the subsequent 28-day cycle(s); and (ii) administering Compound 1 in cycles of once daily for 14 days followed by 14 days of rest, starting on day 15 of Cycle 1. 
     
     
         23 . The method of  claim 17 , comprising (i) administering obinutuzumab at a dose of about 100 mg on day 1, about 900 mg on day 2, about 1000 mg on each of days 8 and 15 of the a first 28-day cycle (“Cycle 1”), and at a dose of about 1000 mg on day 1 of the subsequent 28-day cycle(s); and (ii) administering Compound 1 in cycles of once daily for 21 days followed by 7 days of rest, starting on day 15 of Cycle 1. 
     
     
         24 . A compound for use in method of treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), wherein the compound is Compound 3 of the formula: 
       
         
           
           
               
               
           
         
         or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound. 
       
     
     
         25 . A compound for use in method of treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), wherein the compound is Compound 1 of the formula: 
       
         
           
           
               
               
           
         
         or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound. 
       
     
     
         26 . A compound for use in method of treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), wherein the compound is Compound 2 of the formula: 
       
         
           
           
               
               
           
         
         or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound. 
       
     
     
         27 . The compound for use of any one of  claims 24  to  26 , wherein the CLL/SLL is relapsed or refractory CLL/SLL. 
     
     
         28 . The compound for use of  claim 27 , wherein the CLL/SLL is relapsed or refractory to at least two prior therapies. 
     
     
         29 . The compound for use of  claim 28 , wherein at least one of the prior therapies is a Bruton's tyrosine kinase (BTK) inhibitor, a phosphoinositide 3-kinase inhibitor, or venetoclax. 
     
     
         30 . The compound for use of  claim 29 , wherein the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or tirabrutinib. 
     
     
         31 . The compound for use of any one of  claims 24  to  26 , wherein the CLL is newly diagnosed. 
     
     
         32 . The compound for use of any one of  claims 24  to  31 , wherein the compound is administered orally. 
     
     
         33 . The compound for use of any one of  claims 24  to  32 , wherein the compound is administered once daily for 5 days followed by 2 days of rest. 
     
     
         34 . The compound for use of any one of  claims 24  to  32 , wherein the compound is administered once daily for 7 days followed by 7 days of rest. 
     
     
         35 . The compound for use of any one of  claims 24  to  32 , wherein the compound is administered once daily for 5 days followed by 9 days of rest. 
     
     
         36 . The compound for use of any one of  claims 24  to  32 , wherein the compound is administered once daily for 14 days followed by 14 days of rest. 
     
     
         37 . The compound for use of any one of  claims 24  to  32 , wherein the compound is administered once daily for 21 days followed by 7 days of rest. 
     
     
         38 . The compound for use of any one of  claims 24  to  32 , wherein the compound is administered on days 1 to 5 of a 7-day cycle, on days 1 to 3 of a 7-day cycle, on days 1 to 5 of a 14-day cycle, on days 1 to 7 of a 14-day cycle, on days 1 to 10 of a 14-day cycle, on days 1 to 7 and days 15 to 21 of a 28-day cycle, on days 1 to 21 of a 28-day cycle, or on days 1 to 14 of a 28-day cycle. 
     
     
         39 . The compound for use of any one of  claims 24  to  35 , wherein the compound is administered in an amount of about 0.1 mg, about 0.2 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1.2 mg or about 1.6 mg per day. 
     
     
         40 . The compound for use of any one of  claims 24  to  39 , wherein the method further comprises administering to the subject a therapeutically effective amount of obinutuzumab. 
     
     
         41 . The compound for use of  claim 40 , wherein obinutuzumab is administered intravenously. 
     
     
         42 . The compound for use of  claim 41 , wherein obinutuzumab is administered at a dose of about 100 mg on day 1 of a first 28-day cycle, about 900 mg on day 2 of the first 28-day cycle, and about 1000 mg on each of days 8 and 15 of the first 28-day cycle and day 1 of a second to a sixth 28-day cycles. 
     
     
         43 . The compound for use of  claim 40 , wherein the method comprises (i) administering obinutuzumab at a dose of about 100 mg on day 1, about 900 mg on day 2, about 1000 mg on each of days 8 and 15 of the a first 28-day cycle (“Cycle 1”), and at a dose of about 1000 mg on day 1 of the subsequent 28-day cycle(s); and (ii) administering Compound 1 in cycles of once daily for 7 days followed by 7 days of rest, starting on day 15 of Cycle 1. 
     
     
         44 . The compound for use of  claim 40 , wherein the method comprises (i) administering obinutuzumab at a dose of about 100 mg on day 1, about 900 mg on day 2, about 1000 mg on each of days 8 and 15 of the a first 28-day cycle (“Cycle 1”), and at a dose of about 1000 mg on day 1 of the subsequent 28-day cycle(s); and (ii) administering Compound 1 in cycles of once daily for 5 days followed by 9 days of rest, starting on day 15 of Cycle 1. 
     
     
         45 . The compound for use of  claim 40 , wherein the method comprises (i) administering obinutuzumab at a dose of about 100 mg on day 1, about 900 mg on day 2, about 1000 mg on each of days 8 and 15 of the a first 28-day cycle (“Cycle 1”), and at a dose of about 1000 mg on day 1 of the subsequent 28-day cycle(s); and (ii) administering Compound 1 in cycles of once daily for 14 days followed by 14 days of rest, starting on day 15 of Cycle 1. 
     
     
         46 . The compound for use of  claim 40 , wherein the method comprises (i) administering obinutuzumab at a dose of about 100 mg on day 1, about 900 mg on day 2, about 1000 mg on each of days 8 and 15 of the a first 28-day cycle (“Cycle 1”), and at a dose of about 1000 mg on day 1 of the subsequent 28-day cycle(s); and (ii) administering Compound 1 in cycles of once daily for 21 days followed by 7 days of rest, starting on day 15 of Cycle 1.