THERAPY FOR TREATING MALIGNANCIES

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 hydroxypropylmethylcelulose 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.