RU2021138145A - METHOD FOR CANCER TREATMENT USING ORAL DOSAGE FORM OF ESTROGEN RECEPTOR ALPHA INHIBITOR - Google Patents

Claims (165)

1. Dosage form for oral administration containing i) a compound represented by formula I, or a pharmaceutically acceptable salt thereof, and ii) at least one pharmaceutically acceptable excipient, where said compound of formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazole-5- yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide represented by the formula:

(E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut -1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide, and wherein said oral dosage form, when administered orally to a human once a day, is formulated to achieve a mean C _max of about 1 ng/mL to about 4 ng/mL as determined for each mg of a compound of formula I at said dosage. 2. The oral dosage form of claim 1, wherein said average C _max is from about 2 ng/mL to about 4 ng/mL for each mg of the compound of Formula I at the indicated dosage. 3. The oral dosage form of claim 2, wherein said average C _max is from about 3 ng/mL to about 4 ng/mL for each mg of the compound of Formula I at the indicated dosage. 4. Dosage form for oral administration according to claim 1, where the specified average value of C _max is in the range from 80%-125% for 3 ng/ml to 80%-125% for 3.5 ng/ml for each mg of a compound of formula I at the indicated dosage. 5. An oral dosage form according to any one of claims 1 to 4, wherein the dosage form is formulated to achieve an average t _max at said average C _max of about 2 hours to about 7 hours. 6. The oral dosage form of claim 5, wherein the dosage form is formulated to achieve an average t _max at said average C _max of about 3 hours to about 7 hours. 7. The oral dosage form of claim 6 wherein the dosage form is formulated to achieve an average t _max at said average C _max of about 3.5 hours to about 4.5 hours. 8. The oral dosage form of claim 6, wherein the dosage form is formulated to achieve an average t _max at said average C _max of about 5.5 hours to about 6.5 hours. 9. An oral dosage form according to any one of claims 1 to 6, wherein said dosage form contains a total equivalent of about 100 mg to about 600 mg of a compound of formula I. 10. An oral dosage form according to any one of claims 1 to 6, wherein said dosage form contains a total equivalent of about 450 mg of a compound of formula I. 11. Dosage form for oral administration, containing i) a compound represented by formula I, or a pharmaceutically acceptable salt thereof, and ii) at least one pharmaceutically acceptable excipient, where said compound of formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazole-5- yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide represented by the formula:

(E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut -1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide, and wherein said oral dosage form, when administered orally to a human once a day, is formulated to achieve a mean AUC of _0-24 from about 16 h ng/mL to about 44 h ng/mL for each mg of a compound of Formula I at said dosage. . 12. The oral dosage form of claim 11, wherein said mean AUC _0-24 is from about 27 h ng/mL to about 44 h ng/mL for each mg of the compound of Formula I at the indicated dosage. 13. The oral dosage form of claim 11 wherein said mean AUC _0-24 is in the range from 80%-125% for 30 h ng/ml to 80%-125% for 44 h ng/ml for each mg of a compound of formula I at the indicated dosage. 14. The oral dosage form of claim 11, wherein said dosage form contains a total equivalent of about 100 mg to about 600 mg of a compound of formula I. 15. The oral dosage form of claim 11, wherein said dosage form contains a total equivalent of about 450 mg of a compound of formula I. 16. Dosage form for oral administration, containing i) a compound represented by formula I, or a pharmaceutically acceptable salt thereof, and ii) at least one pharmaceutically acceptable excipient, where said compound of formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazole-5- yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide represented by the formula:

(E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut -1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide, and wherein said oral dosage form for oral administration to a human once a day is formulated to achieve an average t _1/2 of the compound of formula I of said dose from about 8 hours to about 22 hours. 17. The oral dosage form of claim 16, wherein said average t _1/2 is from about 8 hours to about 12 hours. 18. The oral dosage form of claim 17 wherein said mean t _1/2 is from about 9 hours to about 11 hours. 19. The oral dosage form of claim 16, wherein said dosage form contains a total equivalent of about 100 mg to about 600 mg of a compound of formula I. 20. The oral dosage form of claim 16, wherein said dosage form contains a total equivalent of about 450 mg of a compound of formula I. 21. Dosage form for oral administration, containing i) a compound represented by formula I, or a pharmaceutically acceptable salt thereof, and ii) at least one pharmaceutically acceptable excipient, where said compound of formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazole-5- yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide represented by the formula:

(E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut -1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide, and wherein said oral dosage form, when administered orally to a human once a day, is formulated to achieve a mean AUC _0-inf of about 21 h⋅ng/mL to about 67 h⋅ng/mL for each mg of a compound of Formula I at said dosage. . 22. The oral dosage form of claim 21, wherein said mean AUC _0-inf is from about 29 h⋅ng/mL to about 67 h⋅ng/mL for each mg of the compound of formula I at the indicated dosage. 23. The oral dosage form of claim 21, wherein said mean AUC _0-inf is in the range from 80%-125% for 36 h⋅ng/mL to 80%-125% for 57 h⋅ng/mL for each mg of a compound of formula I at the indicated dosage. 24. The oral dosage form of claim 21, wherein said dosage form contains a total equivalent of about 100 mg to about 600 mg of a compound of Formula I. 25. The oral dosage form of claim 21, wherein said dosage form contains a total equivalent of about 450 mg of a compound of formula I. 26. Dosage form for oral administration, containing i) a compound represented by formula I, or a pharmaceutically acceptable salt thereof, and ii) at least one pharmaceutically acceptable excipient, where said compound of formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazole-5- yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide represented by the formula:

(E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut -1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide, and wherein said oral dosage form, when administered orally to a human once a day, is formulated to achieve an average AUC _0-t of about 16 h ng/ml to about 41 h ng/ml for each mg of a compound of formula I at said dosage . 27. The oral dosage form of claim 26, wherein said average AUC _0-t is in the range 80%-125% for 27 h ng/mL to 80%-125% for 36 h ng/ml for each mg of a compound of formula I at the indicated dosage. 28. The oral dosage form of claim 26, wherein said dosage form contains a total equivalent of about 100 mg to about 600 mg of a compound of formula I. 29. The oral dosage form of claim 26, wherein said dosage form contains a total equivalent of about 450 mg of a compound of formula I. 30. An oral dosage form according to any one of claims 1, 11, 16, 21 and 26, wherein said oral dosage form is a capsule containing i) an internal phase which contains a compound of formula I or a pharmaceutically acceptable salt, lactose monohydrate, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose, colloidal anhydrous silica and magnesium stearate; And ii) an external phase which contains magnesium stearate. 31. The oral dosage form of claim 30, wherein said capsule is a hypromellose capsule. 32. An oral dosage form according to claim 31, containing the mono-HCl salt form of the compound of formula I. 33. An oral dosage form according to any one of claims 1, 11, 16, 21 and 26, wherein said oral dosage form is a tablet containing i) an internal phase which contains a compound of formula I or a pharmaceutically acceptable salt, lactose monohydrate, low-substituted hydroxypropyl cellulose, hypromellose, colloidal silicon dioxide and purified water; ii) an external phase which contains microcrystalline cellulose and magnesium stearate; And iii) a film coating containing hypromellose, talc, titanium dioxide, propylene glycol, iron oxide and purified water. 34. An oral dosage form according to claim 33, containing the mono-HCl salt form of the compound of formula I. 35. A method of treating cancer in a human, comprising administering to said subject an oral dosage form containing i) a therapeutically effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof, and ii) at least one pharmaceutically acceptable excipient, where said compound of formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazole-5- yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide represented by the formula:

(E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut -1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide, where the specified therapeutically effective amount is a single daily dose in the range from about 100 mg to 600 mg and wherein said oral dosage form has an average _Cmax of about 1 ng/ml to about 4 ng/ml in the blood plasma of said subject for each mg of a compound of formula I at said dosage. 36. The method of claim 35, wherein said average C _max is from about 2 ng/mL to about 4 ng/mL for each mg of a compound of Formula I at said dosage. 37. The method of claim 36, wherein said average C _max is from about 3 ng/mL to about 4 ng/mL for each mg of a compound of Formula I at said dosage. 38. The method according to claim 35, where the specified average value of C _max is in the range from 80%-125% for 3 ng/ml to 80%-125% for 3.5 ng/ml for each mg of a compound of formula I at the indicated dosage. 39. The method of any one of claims 35-38, wherein the dosage form has an average t _max at said average C _max of the compound of formula I from about 2 hours to about 7 hours. 40. The method of claim 39, wherein the dosage form has an average t _max at said average C _max of the compound of formula I from about 3 hours to about 7 hours. 41. The method of claim 40, wherein the dosage form has an average t _max at said average C _max of the compound of formula I from about 3.5 hours to about 4.5 hours. 42. The method of claim 40 wherein the dosage form has an average t _max at said average C _max of the compound of formula I from about 5.5 hours to about 6.5 hours. 43. A method of treating cancer in a human, comprising administering to said subject an oral dosage form containing i) a therapeutically effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof, and ii) at least one pharmaceutically acceptable excipient, where said compound of formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazole-5- yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide represented by the formula:

(E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut -1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide, and wherein said oral dosage form has an average AUC of _0-24 from about 16 h ng/mL to about 44 h ng/mL for each mg of the compound of Formula I at said dosage. 44. The method of claim 43, wherein said mean AUC _0-24 is from about 27 h ng/mL to about 44 h ng/mL for each mg of the compound of formula I at the indicated dosage. 45. The method according to item 43, where the specified average value of AUC _0-24 is in the range from 80%-125% for 30 h ng/ml to 80%-125% for 44 h ng/ml for each mg of a compound of formula I at the indicated dosage. 46. A method of treating cancer in a human, comprising administering to said subject an oral dosage form containing i) a therapeutically effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof, and ii) at least one pharmaceutically acceptable excipient, where said compound represented by formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazole -5-yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide represented by the formula:

(E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut -1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide; and wherein said oral dosage form has an average t _1/2 of about 8 hours to about 22 hours. 47. The method of claim 46 wherein said average t _1/2 is from about 8 hours to about 12 hours. 48. The method of claim 47 wherein said average t _1/2 is from about 9 hours to about 11 hours. 49. A method of treating cancer in a human, comprising administering to said subject an oral dosage form containing i) a therapeutically effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof, and ii) at least one pharmaceutically acceptable excipient, where said compound of formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazole-5- yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide represented by the formula:

(E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut -1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide; and wherein said oral dosage form has a mean AUC _0-inf of about 21 h ng/ml to about 67 h ng/ml for each mg of the compound of Formula I at said dosage. 50. The method of claim 49, wherein said mean AUC _0-inf is from about 29 h ng/mL to about 67 h ng/mL for each mg of the compound of formula I at the indicated dosage. 51. The method according to claim 49, where the specified average value of AUC _0-inf is in the range 80%-125% for 36 h ng/mL to 80%-125% for 57 h ng/ml for each mg of a compound of formula I at the indicated dosage. 52. A method of treating cancer in a human, comprising administering to said subject an oral dosage form containing i) a therapeutically effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof, and ii) at least one pharmaceutically acceptable excipient, where said compound of formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazole-5- yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide represented by the formula:

(E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut -1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide; and wherein said oral dosage form has an average AUC _0-t of about 16 h ng/mL to about 41 h ng/mL for each mg of the compound of Formula I at said dosage. 53. The method according to item 52, where the specified average value of AUC _0-t is in the range 80%-125% for 27 h ng/mL to 80%-125% for 36 h ng/ml for each mg of a compound of formula I at the indicated dosage. 54. The method of any one of claims 35, 43, 46, 49, and 52, wherein said dosage form contains a total equivalent of about 100 mg to about 600 mg of a compound of Formula I. 55. The method of claim 54, wherein said dosage form contains a total equivalent of about 200 mg to about 600 mg of a compound of Formula I. 56. The method of claim 55, wherein said dosage form contains a total equivalent of about 300 mg to about 600 mg of a compound of Formula I. 57. The method of claim 56, wherein said dosage form contains a total equivalent of about 450 mg of a compound of formula I. 58. The method of any one of claims 24, 32, 35, 38 and 41, wherein said oral dosage form is a capsule containing i) an internal phase which contains a compound of formula I or a pharmaceutically acceptable salt, lactose monohydrate, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose, colloidal anhydrous silica and magnesium stearate; And ii) an external phase which contains magnesium stearate. 59. The method of claim 47 wherein said capsule is a hypromellose capsule. 60. The method according to claim 48, containing the mono-HCl salt form of the compound of formula I. 61. The method of any one of claims 24, 32, 35, 38 and 41, wherein said oral dosage form is a tablet containing i) an internal phase which contains a compound of formula I or a pharmaceutically acceptable salt, lactose monohydrate, low-substituted hydroxypropyl cellulose, hypromellose, colloidal silicon dioxide and purified water; ii) an external phase which contains microcrystalline cellulose and magnesium stearate; And iii) a film coating containing hypromellose, talc, titanium dioxide, propylene glycol, iron oxide and purified water. 62. The method according to claim 61, containing the mono-HCl salt form of the compound of formula I. 63. The method according to any one of claims 35, 43, 46, 49 and 52, wherein said malignancy is breast cancer. 64. The method of claim 61 wherein said breast cancer is ERα positive breast cancer. 65. The method of claim 64, wherein said breast cancer expresses wild-type ERα. 66. The method of claim 64, wherein said breast cancer expresses a mutant ERα. 67. The method of any one of claims 35, 43, 46, 49 and 52, wherein said oral dosage form is administered once a day. 68. The method of claim 57, wherein said oral dosage form is administered once a day. 69. The method of any one of claims 35, 43, 46, 49, and 52, wherein said oral dosage form is administered to a person on an empty stomach. 70. The method of any one of claims 35, 43, 46, 49 and 52, wherein said oral dosage form is administered to a human in a fed state.