METHOD FOR TREATING CANCER
The present invention relates to pharmaceutical compositions comprising inhibitor(s) of human histone methyltransferase EZH2, and methods of cancer therapy using the EZH2 inhibitor(s).
1 . A method of treating a solid tumor, B cell lymphoma, or a cancer with aberrant H3-K27 methylation, comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 337 ng*hr/ml to about 18882 ng*hr/ml after administration to the subject.
2 . The method of claim 1 , wherein said single dose ranges from about 100 mg to about 1600 mg.
3 . A method of treating an advanced solid tumor, B cell lymphoma, or a cancer with aberrant H3-K27 methylation, comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 4 ng*hr/ml to about 12 ng*hr/ml for each 1 mg of EPZ-6438.
4 . The method of any of claims 1-3 , wherein (i) said cancer is advanced, refractory or resistant cancer; or (ii) said cancer is an INI1-deficient tumor.
5 . The method of claim 4 , wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 8 ng*hr/ml to about 12 ng*hr/ml for each 1 mg of EPZ-6438.
6 . The method of claim 4 , wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 9 ng*hr/ml to about 12 ng*hr/ml for each 1 mg of EPZ-6438.
7 . The method of claim 4 , wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 9.7 ng*hr/ml to about 11.8 ng*hr/ml for each 1 mg of EPZ-6438.
8 . The method of claim 1 , wherein said therapeutically effective amount is a single 400 mg dose, wherein said single dose provides a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 1720 ng*hr/ml to about 3899 ng*hr/ml.
9 . The method of claim 1 , wherein said therapeutically effective amount is a single 800 mg dose, wherein said single dose provides a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 7798 ng*hr/ml to about 9441 ng*hr/ml.
10 . A method of treating an advanced solid tumor, B cell lymphoma, or a cancer with aberrant H3-K27 methylation, comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount provides a mean Cmax bioequivalent to a mean Cmax of from about 102 ng/ml to about 4125 ng/ml.
11 . A method of treating an advanced solid tumor, B cell lymphoma, or a cancer with aberrant H3-K27 methylation, comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount is a single dose to provide a mean Cmax bioequivalent to a mean Cmax of from about 1.2 ng/ml to about 2.6 ng/ml for each 1 mg of EPZ-6438.
12 . The method of claim 10 , comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount is a single 400 mg dose, wherein said single dose provides a mean Cmax bioequivalent to a mean Cmax of from about 476 ng/ml to about 865 ng/ml.
13 . The method of claim 10 , comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount is a single 800 mg dose, wherein said single dose provides a mean Cmax bioequivalent to a mean Cmax of from about 1730 ng/ml to about 2063 ng/ml.
14 . A method of treating a solid tumor, B cell lymphoma, or a cancer with aberrant H3-K27 methylation, comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount provides a median Tmax of from about 1 hour to about 2 hours.
15 . The method of any of preceding claims , wherein said administering comprises administering orally a dosage form to the subject, twice per day or three times per day.
16 . A method of inhibiting histone methyltransferase activity of EZH2 or a mutant thereof, comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount provides a mean AUC(0-12) of at least about 4421 ng*hr/ml after administration to the subject.
17 . The method of inhibiting histone methyltransferase activity of EZH2 or a mutant thereof, comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 1720 ng*hr/ml to about 18882 ng*hr/ml after administration to the subject.
18 . The method of claim 17 , wherein said single dose ranges from about 400 mg to about 1600 mg.
19 . The method of inhibiting histone methyltransferase activity of EZH2 or a mutant thereof, comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 4 ng*hr/ml to about 12 ng*hr/ml for each 1 mg of EPZ-6438.
20 . The method of claim 19 , wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 8 ng*hr/ml to about 12 ng*hr/ml for each 1 mg of EPZ-6438.
21 . The method of claim 19 , wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 9 ng*hr/ml to about 12 ng*hr/ml for each 1 mg of EPZ-6438.
22 . The method of claim 19 , wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 9.7 ng*hr/ml to about 11.8 ng*hr/ml for each 1 mg of EPZ-6438.
23 . The method of claim 17 , wherein said therapeutically effective amount is a single 400 mg dose, wherein said single dose provides a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 1720 ng*hr/ml to about 3899 ng*hr/ml.
24 . The method of claim 17 , wherein said therapeutically effective amount is a single 800 mg dose, wherein said single dose provides a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 7798 ng*hr/ml to about 9441 ng*hr/ml.
25 . The method of inhibiting histone methyltransferase activity of EZH2 or a mutant thereof, comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said single dose provides a mean Cmax bioequivalent to a mean Cmax of from about 102 ng/ml to about 4125 ng/ml.
26 . The method of inhibiting histone methyltransferase activity of EZH2 or a mutant thereof, comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount is a single dose to provide a mean Cmax bioequivalent to a mean Cmax of from about 1.2 ng/ml to about 2.6 ng/ml for each 1 mg of EPZ-6438.
27 . The method of claim 25 , comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount is a single 400 mg dose, wherein said single dose provides a mean Cmax bioequivalent to a mean Cmax of from about 476 ng/ml to about 865 ng/ml.
28 . The method of claim 31 , comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount is a single 800 mg dose, wherein said single dose provides a mean Cmax bioequivalent to a mean Cmax of from about 1730 ng/ml to about 2063 ng/ml.
29 . The method of inhibiting histone methyltransferase activity of EZH2 or a mutant thereof, comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount provides a median Tmax of from about 1 hour to about 2 hours.
30 . An oral dosage form for treating a solid tumor, B cell lymphoma, or a cancer with aberrant H3-K27 methylation, comprising a therapeutically effective amount of EPZ-6438, and at least one pharmaceutically acceptable carrier or excipient, wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 102 ng*hr/ml to about 18882 ng*hr/ml after administration to a human subject.
31 . The dosage form of claim 30 , wherein said cancer is advanced, refractory or resistant cancer.
32 . The dosage form of claim 31 , wherein said single dose ranges from about 100 mg to about 1600 mg.
33 . An oral dosage form for treating an advanced solid tumor or B cell lymphoma, comprising a therapeutically effective amount of EPZ-6438, and at least one pharmaceutically acceptable carrier or excipient, wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 4 ng*hr/ml to about 12 ng*hr/ml for each 1 mg of EPZ-6438.
34 . The dosage form of claim 33 , wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 8 ng*hr/ml to about 12 ng*hr/ml for each 1 mg of EPZ-6438.
35 . The dosage form of claim 33 , wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 9 ng*hr/ml to about 12 ng*hr/ml for each 1 mg of EPZ-6438.
36 . The dosage form of claim 33 , wherein said therapeutically effective amount is a single dose to provide a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 9.7 ng*hr/ml to about 11.8 ng*hr/ml after for each 1 mg of EPZ-6438.
37 . The dosage form of claim 30 , wherein said therapeutically effective amount is a single 400 mg dose, wherein said single dose provides a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 1720 ng*hr/ml to about 3899 ng*hr/ml.
38 . The dosage form of claim 30 , wherein said therapeutically effective amount is a single 800 mg dose, wherein said single dose provides a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 7798 ng*hr/ml to about 9441 ng*hr/ml.
39 . The dosage form for treating an advanced solid tumor or B cell lymphoma, comprising a therapeutically effective amount of EPZ-6438, and at least one pharmaceutically acceptable carrier or excipient, wherein said therapeutically effective amount provides a mean Cmax bioequivalent to a mean Cmax of from about 102 ng/ml to about 4125 ng/ml.
40 . The dosage form for treating an advanced solid tumor or B cell lymphoma, comprising a therapeutically effective amount of EPZ-6438, and at least one pharmaceutically acceptable carrier or excipient, wherein said therapeutically effective amount is a single dose to provides a mean Cmax bioequivalent to a mean Cmax of from about 1.2 ng/ml to about 2.6 ng/ml for each 1 mg of EPZ-6438.
41 . The dosage form of claim 39 , wherein said therapeutically effective amount is a single 400 mg dose, wherein said single dose provides a mean Cmax bioequivalent to a mean Cmax of from about 476 ng/ml to about 865 ng/ml.
42 . The dosage form of claim 39 , wherein said therapeutically effective amount is a single 800 mg dose, wherein said single dose provides a mean Cmax bioequivalent to a mean Cmax of from about 1730 ng/ml to about 2063 ng/ml.
43 . The dosage form of claim 30 , wherein said single dose provides a median Tmax of from about 1 hour to about 2 hours.
44 . The dosage form of claim 30 , being an oral unit dosage formulation comprising an amount of therapeutic agent equivalent to about 25 mg to about 400 mg of EPZ-6438 per unit dose.
45 . The dosage form of claim 44 , wherein said oral unit dosage formulation provides an dissolution rate of at least about 90%, or at least about 80%, or at least about 70% in dissolution medium (pH 1.2, 37±0.5° C.) within 60 minutes from the onset of dissolution study using the Apparatus 2 (Paddle Apparatus, paddle speed; 50 rpm) according to the procedure for immediate-release dosage form in 6.10 Dissolution test of JP16 or <711> Dissolution of USP37.
46 . The dosage form of claim 44 , wherein said oral unit dosage formulation provides an dissolution rate of at least about 90%, or at least about 80%, or at least about 70% in dissolution medium (pH 1.2, 37±0.5° C.) within 45 minutes from the onset of dissolution study using the Apparatus 2 (Paddle Apparatus, paddle speed; 50 rpm) according to the procedure for immediate-release dosage form in 6.10 Dissolution test of JP16 or <711> Dissolution of USP37.
47 . The dosage form of claim 44 , wherein said oral unit dosage formulation provides an dissolution rate of at least about 90%, or at least about 80%, or at least about 70% in dissolution medium (pH 1.2, 37±0.5° C.) within 30 minutes from the onset of dissolution study using the Apparatus 2 (Paddle Apparatus, paddle speed; 50 rpm) according to the procedure for immediate-release dosage form in 6.10 Dissolution test of JP16 or <711> Dissolution of USP37.
48 . The dosage form of claim 44 , wherein said oral unit dosage formulation provides an dissolution rate of at least about 80%, or at least about 75%, or at least about 70%, or at least about 60% in dissolution medium (pH 4.5 acetate buffer, 37±0.5° C.) within 60 minutes from the onset of dissolution study using the Apparatus 2 (Paddle Apparatus, paddle speed; 50 rpm) according to the procedure for immediate-release dosage form in 6.10 Dissolution test of JP16 or <711> Dissolution of USP37.
49 . The dosage form of claim 44 , wherein said dosage form comprises sodium starch glycolate or carmellose or a combination thereof as pharmaceutically acceptable carrier or excipient.
50 . An oral dosage form for treating an advanced solid tumor or B cell lymphoma, comprising a therapeutically effective amount of EPZ-6438, and at least one pharmaceutically acceptable carrier or excipient, wherein said therapeutically effective amount provides a mean AUC(0-12) of at least about 4421 ng*hr/ml after administration to a human subject.
51 . A method of treating an advanced solid tumor or B cell lymphoma, comprising administering orally to a subject in need thereof a dosage form with a therapeutically effective amount of EPZ-6438, wherein said therapeutically effective amount provides a mean AUC(0-12) of at least about 4421 ng*hr/ml after administration to the subject.
52 . The method or oral dosage form of any preceding claims , wherein the therapeutically effective amount is a single 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg dose.
53 . A solid pharmaceutical formulation comprising a therapeutic agent and one or more pharmaceutically acceptable excipients, wherein the therapeutic agent is N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1, l′-biphenyl]-3-carboxamide:
or its salt, or a combination thereof, and wherein the one or more pharmaceutically acceptable excipients are selected from sodium starch glycolate, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, and a combination thereof.
54 . The pharmaceutical formulation of claim 53 , wherein the concentration of the therapeutic agent in the formulation is equivalent to from about 35 wt. % to about 65 wt. % Compound 1.
55 . The pharmaceutical formulation of claim 53 , wherein the one or more pharmaceutically acceptable excipients are selected from sodium starch glycolate, carmellose, carmellose calcium, croscarmellose sodium, and a combination thereof.
56 . The pharmaceutical formulation of claim 53 , wherein the one or more pharmaceutically acceptable excipients are selected from sodium starch glycolate, carmellose, and a combination thereof.
57 . The pharmaceutical formulation of any one of claims 53-56 , wherein the one or more pharmaceutically acceptable excipients further comprise lactose, hydroxypropyl cellulose, magnesium stearate, or a combination thereof.
58 . The pharmaceutical formulation of claim 57 , wherein the formulation is in the form of a tablet.
59 . A process for making a pharmaceutical formulation of any one of claims 53-58 , the process comprising:
a) mixing a therapeutic agent, a diluent, a disintegrant and/or a lubricant to form a first mixture, wherein the therapeutic agent is selected from the group consisting of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide, a salt thereof, and a combination thereof, and optionally one or more of the steps selected from:
b) adding an aqueous, organic solvent-based solution, or an organic/aqueous mixture solution comprising a binder to the first mixture to form a second mixture;
c) granulating the second mixture to form wet granulates;
d) drying the wet granulates to form dried granulates;
e) size screening the dried granulates to obtain sized granulates
f) mixing the sized granulates with a lubricant, and a second disintegrant to form a third mixture;
g) compressing the third mixture to form tablets; and
h) applying a coating suspension to the tablets to generate film-coated tablets.
60 . A solid pharmaceutical composition comprising:
a therapeutic agent and
means for achieving immediate release of the therapeutic agent,
wherein the therapeutic agent is selected from N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1, l′-biphenyl]-3-carboxamide:
a salt thereof, and a combination thereof.
61 . The composition of claim 60 wherein the means for achieving immediate release of the therapeutic agent allows release of at least 90%, or at least 80%, or at least 70%, or at least 60% of the therapeutic agent after 60 min.
62 . The composition of claim 60 wherein the means for achieving immediate release of the therapeutic agent allows release of at least 90%, or at least 80%, or at least 70%, or at least 60% of the therapeutic agent after 45 min.
63 . The composition of claim 60 wherein the means for achieving immediate release of the therapeutic agent allows release of at least 80%, or at least 70%, or at least 60% of the therapeutic agent after 30 min.
64 . The composition of claim 60 wherein the means for achieving immediate release of the therapeutic agent allows an dissolution rate of at least about 90%, or at least about 80%, or at least about 70% in dissolution medium (pH 1.2, 37±0.5° C.) within 60 minutes from the onset of dissolution study using the Apparatus 2 (Paddle Apparatus, paddle speed; 50 rpm) according to the procedure for immediate-release dosage form in 6.10 Dissolution test of JP16 or <711> Dissolution of USP37.
65 . The composition of claim 60 wherein the means for achieving immediate release of the therapeutic agent allows an dissolution rate of at least about 90%, or at least about 80%, or at least about 70% in dissolution medium (pH 1.2, 37±0.5° C.) within 45 minutes from the onset of dissolution study using the Apparatus 2 (Paddle Apparatus, paddle speed; 50 rpm) according to the procedure for immediate-release dosage form in 6.10 Dissolution test of JP16 or <711> Dissolution of USP37.
66 . The composition of claim 60 wherein the means for achieving immediate release of the therapeutic agent allows an dissolution rate of at least about 90%, or at least about 80%, or at least about 70% in dissolution medium (pH 1.2, 37±0.5° C.) within 30 minutes from the onset of dissolution study using the Apparatus 2 (Paddle Apparatus, paddle speed; 50 rpm) according to the procedure for immediate-release dosage form in 6.10 Dissolution test of JP16 or <711> Dissolution of USP37.
67 . The composition of claim 66 , wherein the means for achieving immediate release of the therapeutic agent allows an dissolution rate of at least about 80% in dissolution medium (pH 1.2, 37±0.5° C.) within 30 minutes from the onset of dissolution study using the Apparatus 2 (Paddle Apparatus, paddle speed; 50 rpm) according to the procedure for immediate-release dosage form in 6.10 Dissolution test of JP16 or <711> Dissolution of USP37.
68 . The composition of claim 60 or 67 , wherein the means for achieving immediate release of the therapeutic agent allows an dissolution rate of at least about 80%, or at least about 75%, or at least about 70%, or at least about 60% in dissolution medium (pH 4.5 acetate buffer, 37±0.5° C.) within 60 minutes from the onset of dissolution study using the Apparatus 2 (Paddle Apparatus, paddle speed; 50 rpm) according to the procedure for immediate-release dosage form in 6.10 Dissolution test of JP16 or <711> Dissolution of USP37.
69 . The composition of claim 60 or 67 , wherein the means for achieving immediate release of the therapeutic agent allows an dissolution rate of at least about 80%, or at least about 75%, or at least about 70%, or at least about 60% in dissolution medium (pH 4.5 acetate buffer, 37±0.5° C.) within 30 minutes from the onset of dissolution study using the Apparatus 2 (Paddle Apparatus, paddle speed; 50 rpm) according to the procedure for immediate-release dosage form in 6.10 Dissolution test of JP16 or <711> Dissolution of USP37.