THERAPY FOR TREATING MALIGNANCIES
Provided are methods and compositions for treating cancers in patients carrying an IDH1 mutation using an inhibitor of a mutant IDH1 enzyme.
1 - 85 . (canceled)
86 . A method of treating acute myeloid leukemia (AML) characterized by the presence of a mutant allele of IDH1, comprising administering to a subject in need thereof an effective amount of(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 thereof (COMPOUND 1), in combination with a therapeutically effective amount of azacitidine, wherein COMPOUND 1 is administered to a subject that has not ingested a high-fat meal.
87 . The method of claim 86 , wherein
(i) the combination of COMPOUND 1 and azacitidine is administered substantially contemporaneously with food, wherein the food is not a high-fat meal; or
(ii) wherein the combination of COMPOUND 1 and azacitidine is administered without food.
88 . The method of claim 86 , wherein
(i) the combination of COMPOUND 1 and azacitidine is administered to a subject that has not ingested a high-fat meal for at least 60 minutes before administration of the combination of COMPOUND 1 and azacitidine; and/or
(ii) the combination of COMPOUND 1 and azacitidine is administered to a subject at least 60 minutes before ingestion of any high-fat meal.
89 . The method of claim 86 , wherein COMPOUND 1 is administered at a total daily dosage of between 5 mg and 2000 mg.
90 . The method of claim 89 , wherein a total daily dose of 500 mg of COMPOUND 1 is administered to the subject.
91 . The method of claim 86 , wherein COMPOUND 1 is orally administered.
92 . The method of claim 91 , wherein COMPOUND 1 is administered as part of a solid dispersion.
93 . The method of claim 86 , wherein
(i) the C max of COMPOUND 1 is between 1500 ng/ml and 3100 ng/ml; and/or
(ii) the AUC 0-t of COMPOUND 1 is between 110000 hr-ng/ml and 165000 hr-ng/mL.
94 . The method of claim 86 , wherein the AUC 0-t of COMPOUND 1 is between 110000 hr-ng/mL and 165000 hr-ng/mL.
95 . The method of claim 86 , wherein
(i) COMPOUND 1 and azacitidine are administered concurrently; and/or
(ii) COMPOUND 1 and azacitidine are administered separately.
96 . The method of claim 86 , wherein the AML is relapsed or refractory.
97 . The method of claim 86 , wherein the IDH1 mutation is an IDH1 R132X mutation.
98 . The method of claim 97 , wherein the IDH1 mutation is an IDH1 R132H, R132C, R132L, R132V, R132S, or R132GF mutation.
99 . A method of treating acute myeloid leukemia (AML) characterized by the presence of a mutant allele of IDH1, comprising orally administering to a subject in need thereof 500 mg of(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 thereof (COMPOUND 1), in combination with a therapeutically effective amount of azacitidine, wherein COMPOUND 1 is administered to a subject that has not ingested a high-fat meal, and wherein the mutant allele of IDH1 comprises an IDH1 R132X mutation.
100 . The method of claim 99 , wherein:
(i) the combination of COMPOUND 1 and azacitidine is administered substantially contemporaneously with food, wherein the food is not a high-fat meal; or
(ii) the combination of COMPOUND 1 and azacitidine is administered without food.
101 . The method of claim 99 , wherein:
(i) the combination of COMPOUND 1 and azacitidine is administered to a subject that has not ingested a high-fat meal for at least 60 minutes before administration of the combination of COMPOUND 1 and azacitidine; and/or
(ii) the combination of COMPOUND 1 and azacitidine is administered to a subject at least 60 minutes before ingestion of any high-fat meal.
102 . The method of claim 99 , wherein:
(i) the C max of COMPOUND 1 is between 1500 ng/ml and 3100 ng/ml; and/or
(ii) the AUC 0-t of COMPOUND 1 is between 110000 hr-ng/ml and 165000 hr-ng/mL.
103 . The method of claim 99 , wherein:
(i) COMPOUND 1 and azacitidine are administered concurrently; and/or
(ii) COMPOUND 1 and azacitidine are administered separately.
104 . The method of claim 99 , wherein the AML is relapsed or refractory.
105 . The method of claim 99 , wherein the IDH1 mutation is an IDH1 R132H, R132C, R132L, R132V, R132S, or R132GF mutation.