Treatment of a hematologic malignancy with 2-(4-chlorophenyl)-n-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

Abstract

Provided herein are methods of treating, preventing, managing, and/or ameliorating leukemia or myelodysplastic syndrome comprising administering 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide or a stereoisomer or mixture of stereoisomers, an isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof to a patient.

What is claimed: 
     
         1 . A method for treating, preventing, managing, or ameliorating a hematological cancer comprising administering to a subject in need thereof 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, which has the following structure: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or mixture of stereoisomers, isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (Compound 1), wherein Compound 1 is administered to the subject in a dose of about 0.1 mg to about 20 mg. 
     
     
         2 . The method of  claim 1 , wherein the hematological cancer is acute myeloid leukemia. 
     
     
         3 . The method of  claim 2 , wherein the acute myeloid leukemia is refractory or relapsed acute myeloid leukemia. 
     
     
         4 . The method of  claim 1 , wherein Compound 1 is administered on days 1 to 5 of a 28 day treatment cycle. 
     
     
         5 . The method of  claim 4 , wherein the treatment cycle comprises a rest period of 23 days. 
     
     
         6 . The method of  claim 1 , wherein Compound 1 is administered on days 1 to 5 of a 42 day treatment cycle. 
     
     
         7 . The method of  claim 1 , wherein Compound 1 is administered on days 1 to 3 of a 28 day treatment cycle. 
     
     
         8 . The method of  claim 1 , wherein Compound 1 is administered on days 1 to 5 and days 15 to 19 of a 28 day treatment cycle. 
     
     
         9 . The method of  claim 4 , wherein the treatment cycle is repeated at least once. 
     
     
         10 . The method of  claim 4 , wherein the treatment cycle is repeated 2 to 4 times. 
     
     
         11 . The method of  claim 1 , wherein Compound 1 is administered in a dose of about 0.1 mg to about 10 mg. 
     
     
         12 . The method of  claim 1 , wherein Compound 1 is administered in a dose from about 0.3 mg to about 8.1 mg. 
     
     
         13 . The method of  claim 1 , wherein Compound 1 is administered in a dose of about 0.3 mg, 0.6 mg, 1.2 mg, 2.4 mg, 3.6 mg, 5.4 mg or 8.1 mg. 
     
     
         14 . The method of  claim 1 , wherein Compound 1 is administered in a dose of about 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, or 3.6 mg. 
     
     
         15 . The method of  claim 1 , wherein the subject is administered one or more of calcium, calcitriol, and/or vitamin D supplementation. 
     
     
         16 . The method of  claim 15 , wherein the subject is administered one or more of calcium, calcitriol, and vitamin D supplementation prior to administration of Compound 1. 
     
     
         17 . The method of  claim 15 , wherein the subject is administered calcium, calcitriol, and vitamin D supplementation at least 3 days prior to administration of Compound 1 on day 1 of the cycle. 
     
     
         18 . The method of  claim 1 , wherein the subject does not have a disorder disrupting normal calcium homeostasis or preventing calcium supplementation. 
     
     
         19 . The method of  claim 1  comprising administering a polymorph of (2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide). 
     
     
         20 . The method of  claim 1  comprising administering an amorphous form of (2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide). 
     
     
         21 . The method of  claim 1  comprising administering a lyophilized formulation of Compound 1, wherein the lyophilized formulation comprises Compound 1, a buffer and a bulking agent. 
     
     
         22 . The method of  claim 1 , further comprising administering a therapeutically effective amount of a second active agent or a supportive care therapy. 
     
     
         23 . The method of  claim 1 , wherein the subject is a patient 18 years or older. 
     
     
         24 . The method of  claim 1 , wherein the hematological cancer is myelodysplastic syndrome. 
     
     
         25 . The method of  claim 24 , wherein the myelodysplastic syndrome is refractory or relapsed myelodysplastic syndrome. 
     
     
         26 . The method of  claim 24 , wherein Compound 1 is administered on days 1 to 5 of a 28 day treatment cycle. 
     
     
         27 . The method of  claim 24 , wherein Compound 1 is administered on days 1 to 5 of a 42 day treatment cycle. 
     
     
         28 . The method of  claim 24 , wherein Compound 1 is administered on days 1 to 3 of a 28 day treatment cycle. 
     
     
         29 . The method of  claim 24 , wherein Compound 1 is administered on days 1 to 5 and days 15 to 19 of a 28 day treatment cycle. 
     
     
         30 . The method of  claim 26 , wherein the treatment cycle is repeated at least once. 
     
     
         31 . The method of  claim 26 , wherein the treatment cycle is repeated 2 to 4 times. 
     
     
         32 . The method of  claim 24 , wherein Compound 1 is administered in a dose of about 0.1 mg to about 10 mg. 
     
     
         33 . The method of  claim 24 , wherein Compound 1 is administered in a dose from about 0.3 mg to about 8.1 mg. 
     
     
         34 . The method of  claim 24 , wherein Compound 1 is administered in a dose of about 0.3 mg, 0.6 mg, 1.2 mg, 2.4 mg, 3.6 mg, 5.4 mg or 8.1 mg. 
     
     
         35 . The method of  claim 24 , wherein Compound 1 is administered in a dose of about 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, or 3.6 mg. 
     
     
         36 . The method of  claim 24 , wherein the subject is administered one or more of calcium, calcitriol, and/or vitamin D supplementation. 
     
     
         37 . The method of  claim 36 , wherein the subject is administered one or more of calcium, calcitriol, and vitamin D supplementation prior to administration of Compound 1. 
     
     
         38 . The method of  claim 36 , wherein the subject is administered one or more of calcium, calcitriol, and vitamin D supplementation at least 3 days prior to administration of Compound 1 on day 1 of the cycle. 
     
     
         39 . The method of  claim 24 , wherein the subject does not have a disorder disrupting normal calcium homeostasis or preventing calcium supplementation. 
     
     
         40 . The method of  claim 24  comprising administering a polymorph of (2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide). 
     
     
         41 . The method of  claim 24  comprising administering an amorphous form of (2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide). 
     
     
         42 . The method of  claim 24  comprising administering a lyophilized formulation of Compound 1, wherein the lyophilized formulation comprises Compound 1, a buffer and a bulking agent. 
     
     
         43 . The method of  claim 24 , further comprising administering a therapeutically effective amount of a second active agent or a supportive care therapy. 
     
     
         44 . The method of  claim 24 , wherein the subject is a patient 18 years or older.