Therapy for treating malignancies

Abstract

Provided are methods and compositions for treating cancers in patients carrying an IDH1 mutation using an inhibitor of a mutant IDH1 enzyme.

1 . A method of treating a malignancy characterized by the presence of a mutant allele of IDH1, comprising administering to a subject an oral dosage form comprising a therapeutically effective amount of a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor wherein the mutant IDH1 inhibitor is (S)—N—((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, or a polymorph thereof (COMPOUND 1) wherein the compound is administered with or without food and wherein if the compound is administered with food, the food is not a high-fat meal. 
       
     
     
         2 . The method of  claim 1 , wherein the oral dosage form is administered substantially contemporaneously with food. 
     
     
         3 . The method of  claim 1 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject within 10 minutes before or after ingesting food. 
     
     
         4 . The method of  claim 1 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject within 30 minutes before or after ingesting food. 
     
     
         5 . The method of  claim 1 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject within 60 minutes before or after ingesting food. 
     
     
         6 . The method of  claim 1 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject within 90 minutes before or after ingesting food. 
     
     
         7 . The method of  claim 1 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject within 120 minutes before or after ingesting food. 
     
     
         8 . The method of  claim 1  wherein the oral dosage form is administered without food. 
     
     
         9 . The method of  claim 1 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject at least 60 minutes before ingesting food. 
     
     
         10 . The method of  claim 1 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject at least 90 minutes before ingesting food. 
     
     
         11 . The method of  claim 1 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject at least 120 minutes before ingesting food. 
     
     
         12 . The method of  claim 1 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject at least 180 minutes before ingesting food. 
     
     
         13 . The method of any one of  claims 9 - 12 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject at least 60 minutes after ingesting food. 
     
     
         14 . The method of any one of  claims 9 - 12 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject at least 90 minutes after ingesting food. 
     
     
         15 . The method of any one of  claims 9 - 12 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject at least 120 minutes after ingesting food. 
     
     
         16 . The method of any one of  claims 9 - 12 , wherein the therapeutically effective amount of the oral dosage form is administered to the subject at least 180 minutes after ingesting food. 
     
     
         17 . The method of any one of  claims 1 - 16  wherein the oral dosage form is administered to a subject that has not ingested a high-fat meal for at least 30 minutes before administration of the oral dosage form. 
     
     
         18 . The method of any one of  claims 1 - 16  wherein the oral dosage form is administered to a subject that has not ingested a high-fat meal for at least 60 minutes before administration of the oral dosage form. 
     
     
         19 . The method of any one of  claims 1 - 16  wherein the oral dosage form is administered to a subject that has not ingested a high-fat meal for at least 90 minutes before administration of the oral dosage form. 
     
     
         20 . The method of any one of  claims 1 - 16  wherein the oral dosage form is administered to a subject that has not ingested a high-fat meal for at least 120 minutes before administration of the oral dosage form. 
     
     
         21 . The method of any one of  claims 1 - 16  wherein the oral dosage form is administered to a subject that has not ingested a high-fat meal for at least 180 minutes before administration of the oral dosage form. 
     
     
         22 . The method of any one of  claims 1 - 21  wherein the oral dosage form is administered to a subject that has not ingested a high-fat meal for at least 60 minutes after administration of the oral dosage form. 
     
     
         23 . The method of any one of  claims 1 - 21  wherein the oral dosage form is administered to a subject that has not ingested a high-fat meal for at least 90 minutes after administration of the oral dosage form. 
     
     
         24 . The method of any one of  claims 1 - 21  wherein the oral dosage form is administered to a subject that has not ingested a high-fat meal for at least 120 minutes after administration of the oral dosage form. 
     
     
         25 . The method of any one of  claims 1 - 21  wherein the oral dosage form is administered to a subject that has not ingested a high-fat meal for at least 180 minutes after administration of the oral dosage form. 
     
     
         26 . The method of any one of  claims 1 - 25  wherein the C max  of COMPOUND 1 is between 1500 ng/mL and 3100 ng/mL. 
     
     
         27 . The method of  claim 26 , wherein the C max  is between 1800 ng/mL and 2800 ng/mL. 
     
     
         28 . The method of any one of  claims 1 - 27  wherein the AUC 0-t  of COMPOUND 1 is between 110000 hr·ng/mL and 165000 hr·ng/mL. 
     
     
         29 . The method of  claim 28 , wherein the AUC 0-t  is between 120000 hr ng/mL and 155000 hr ng/mL. 
     
     
         30 . The method of any one of  claims 1 - 29  wherein the oral dosage form comprises a therapeutically effective amount of COMPOUND 1 as part of a solid dispersion. 
     
     
         31 . The method of  claim 30  wherein the solid dispersion comprises a partly water-soluble polymer. 
     
     
         32 . The method of  claim 30  wherein the solid dispersion comprises a water-soluble polymer. 
     
     
         33 . The method of  claim 32  wherein the polymer is a cellulose polymer. 
     
     
         34 . The method of  claim 33  wherein the polymer is selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose phthalate (HPMCP).T 
     
     
         35 . The method of  claim 34  wherein the polymer is HPMCAS. 
     
     
         36 . The method of any one of  claims 30 - 35  wherein the solid dispersion is a spray-dried dispersion. 
     
     
         37 . The method of any one of  claims 30 - 36  wherein the solid dispersion comprises between about 30 and 70% w/w COMPOUND 1. 
     
     
         38 . The method of  claim 37  wherein the solid dispersion comprises between about 40 and 60% w/w COMPOUND 1. 
     
     
         39 . The method of  claim 38  wherein the solid dispersion comprises about 50% w/w COMPOUND 1. 
     
     
         40 . The method of any one of  claims 30 - 36  wherein the solid dispersion comprises between about 15 and 35% w/w COMPOUND 1. 
     
     
         41 . The method of  claim 40  wherein the solid dispersion comprises about 25% w/w COMPOUND 1. 
     
     
         42 . The method of any one of  claims 30 - 41  wherein the dispersion is an amorphous dispersion. 
     
     
         43 . The method of any one of  claims 30 - 42  wherein the oral dosage form further comprises a surfactant. 
     
     
         44 . The method of  claim 43  wherein the surfactant is vitamin E tocopheryl polyethylene glycol succinate (Vitamin E TPGS). 
     
     
         45 . The method of any one of  claims 30 - 44  wherein the oral dosage form further comprises a filler. 
     
     
         46 . The method of  claim 45  wherein the filler is microcrystalline cellulose. 
     
     
         47 . The method of any one of  claims 30 - 46  wherein the oral dosage form further comprises a disintegrant. 
     
     
         48 . The method of  claim 47  wherein the disintegrant is croscarmellose sodium. 
     
     
         49 . The method of any one of  claims 30 - 48  wherein the oral dosage form further comprises a wetting agent. 
     
     
         50 . The method of  claim 49  wherein the wetting agent is sodium lauryl sulfate. 
     
     
         51 . The method of any one of  claims 30 - 50  wherein the oral dosage form further comprises a glidant. 
     
     
         52 . The method of  claim 51  wherein the glidant is colloidal silicon dioxide. 
     
     
         53 . The method of any one of  claims 30 - 52  wherein the oral dosage form further comprises a lubricant. 
     
     
         54 . The method of  claim 53  wherein the lubricant is magnesium stearate. 
     
     
         55 . The method of any one of  claims 30 - 54  wherein the oral dosage form comprises from between about 25% w/w to about 35% w/w of COMPOUND 1, from between about 25% w/w to about 35% w/w of hypromellose acetate succinate (HPMCAS), from between about 25% w/w to about 35% w/w of microcrystalline cellulose, from between about 5% w/w to about 7% w/w croscarmellose sodium, from between about 0.5% w/w to about 1.5% w/w sodium lauryl sulfate, about from between about 1% w/w to about 3% w/w colloidal silicon dioxide, and rom between about 0.5% w/w to about 2.5% w/w of magnesium stearate, thereby totaling 100% by weight of the oral dosage form. 
     
     
         56 . The method of any one of  claims 30 - 55  wherein the oral dosage form comprises about 30% w/w of COMPOUND 1, about 30% w/w of hypromellose acetate succinate (HPMCAS), about 29.5% w/w of microcrystalline cellulose, about 6% w/w croscarmellose sodium, about 1% w/w sodium lauryl sulfate, about 2% w/w colloidal silicon dioxide, and about 1.5% w/w of magnesium stearate. 
     
     
         57 . The method of any one of  claims 1 - 56  wherein the oral dosage form is a tablet. 
     
     
         58 . The method of any one of  claims 1 - 57 , wherein the therapeutically effective amount of COMPOUND 1 is about 500 mg. 
     
     
         59 . The method of  claim 58  wherein the therapeutically effective amount of COMPOUND 1 is administered as a single tablet comprising 500 mg COMPOUND 1. 
     
     
         60 . The method of  claim 58  wherein the therapeutically effective amount of COMPOUND 1 is administered as two tablets comprising 250 mg COMPOUND 1 each. 
     
     
         61 . The method of  claim 58  wherein the therapeutically effective amount of COMPOUND 1 is administered as four tablets comprising 125 mg COMPOUND 1 each. 
     
     
         62 . The method of  claim 58  wherein the therapeutically effective amount of COMPOUND 1 is administered as five tablets comprising 100 mg COMPOUND 1 each. 
     
     
         63 . The method of any one of  claims 1 - 62  wherein the oral dosage form is administered once a day. 
     
     
         64 . The method of any one of  claims 1 - 63 , wherein the malignancy is a hematologic malignancy. 
     
     
         65 . The method of  claim 64  wherein the hematologic malignancy is acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemias (B-ALL), or lymphoma. 
     
     
         66 . The method of  claim 65  wherein the hematologic malignancy is advanced. 
     
     
         67 . The method of  claim 65  wherein the hematologic malignancy is relapsed or refractory. 
     
     
         68 . The method of  claim 65 , wherein the malignancy is acute myelogenous leukemia (AML). 
     
     
         69 . The method of  claim 68  wherein the acute myelogenous leukemia (AML) is relapsed or refractory. 
     
     
         70 . The method of any one of  claims 1 - 63  wherein the malignancy is a solid tumor. 
     
     
         71 . The method of  claim 70  wherein the solid tumor is selected from glioma, intrahepatic cholangiocarcinomas (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, and non-small cell lung cancer (NSCLC). 
     
     
         72 . The method of  claim 71  wherein the solid tumor is intrahepatic cholangiocarcinoma. 
     
     
         73 . The method of any one of  claims 70 - 72  wherein the solid tumor is advanced. 
     
     
         74 . The method of any one of  claims 70 - 73  wherein the solid tumor is relapsed or refractory. 
     
     
         75 . The method of any one of  claims 1 - 74 , wherein the IDH1 mutation is an IDH1 R132X mutation. 
     
     
         76 . The method of  claim 74 , wherein the IDH1 mutation is an IDH1 R132H, R132C, R132L, R132V, R132S or R132GF mutation. 
     
     
         77 . An article of manufacture comprising:
 an oral dosage form comprising a therapeutically effective amount of a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor wherein the mutant IDH1 inhibitor is (S)—N—((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, having the following formula:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, or a polymorph thereof (COMPOUND 1) in a packaging material; and 
         a package insert contained within the packaging material indicating that the oral dosage form should be taken with or without food and avoiding a high-fat meal. 
       
     
     
         78 . An article of manufacture comprising:
 an oral dosage form comprising a therapeutically effective amount of a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor wherein the mutant IDH1 inhibitor is (S)—N—((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, having the following formula:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, or a polymorph thereof (COMPOUND 1) in a packaging material; and 
         a label affixed to or printed on the packaging material indicating that the oral dosage form should be taken with or without food and avoiding a high-fat meal. 
       
     
     
         79 . The article of manufacture of  claim 77  or  78 , wherein the solid dosage form is a tablet. 
     
     
         80 . The article of manufacture of any one of  claims 77 - 79 , wherein the label or package insert further indicates that the oral dosage form is administered once daily. 
     
     
         81 . The article of manufacture of any one of  claims 77 - 80 , wherein the therapeutically effective amount of COMPOUND 1 is about 500 mg, e.g., 500 mg. 
     
     
         82 . The article of manufacture of any one of  claims 77 - 81 , wherein the label or the package insert further indicates that the oral dosage form is for treating malignancies associated with an IDH1 mutation. 
     
     
         83 . The article of manufacture of any one of  claims 77 - 82 , wherein the label or the package insert further indicates that the oral dosage form is for treating acute myelogenous leukemia (AML). 
     
     
         84 . The article of manufacture of any one of  claims 77 - 82 , wherein the label or the package insert further indicates that the oral dosage form is for treating relapsed or refractory acute myelogenous leukemia (AML). 
     
     
         85 . The article of manufacture of any one of  claims 77 - 84 , wherein COMPOUND 1 is part of a solid dispersion.