Method for treating cancer with an oral dosage form of an estrogen receptor-alpha inhibitor
The present invention relates to pharmaceutical compositions comprising an inhibitor of human ERα, and methods of cancer therapy using the ERα inhibitor. In particular, described herein are dosages of H3B-6545 with defined pharmacokinetic (PK) profiles that allow the inhibitor to be efficaciously and safely administered to a human subject in need thereof.
1 . An oral dosage form, wherein said oral dosage form is a capsule comprising by total weight of the capsule: 28% to 44% of a compound given by Formula I or a pharmaceutically acceptable salt thereof, wherein said Formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide represented by the structure:
12% to 19% of a lactose monohydrate, 8% to 13% of a low-substituted hydroxypropyl cellulose, 1% to 5% of a microcrystalline cellulose, 0.5% to 5% of a hydroxypropyl cellulose, 0.05% to 0.5% of a colloidal anhydrous silica, and 0.1% to 1% of a magnesium stearate,
wherein said oral dosage form is formulated to achieve a mean Cmax of about 1 ng/mL to about 4 ng/mL as measured for every mg of Formula I in said oral dosage form.
2 . The oral dosage form of claim 1 , wherein the capsule further comprises by total weight of the capsule: 18% to 44% of a hypromellose capsule shell.
3 . The oral dosage form of claim 1 comprising:
(i) an internal phase comprising:
150 to 160 mg of the compound given by Formula I or the pharmaceutically acceptable salt thereof,
67 to 68 mg of the lactose monohydrate,
45 mg of the low-substituted hydroxypropyl cellulose,
15 mg of the microcrystalline cellulose,
9 mg of the hydroxypropyl cellulose,
0.6 mg of the colloidal anhydrous silica, and
1.5 mg of the magnesium stearate; and
(ii) an external phase comprising 1.5 mg of the magnesium stearate.
4 . The oral dosage form of claim 3 , wherein the oral dosage form comprises a capsule shell, wherein the capsule shell comprises:
(i) hypromellose;
(ii) iron oxide red; and/or
(iii) titanium dioxide.
5 . The oral dosage form of claim 3 , comprising a mono-HCl salt form of the compound given by Formula I.
6 . The oral dosage form of claim 1 comprising:
i) an internal phase comprising:
50 to 60 mg of the compound given by Formula I or the pharmaceutically acceptable salt thereof,
22 to 23 mg of the lactose monohydrate,
15 mg of the low-substituted hydroxypropyl cellulose,
5 mg of the microcrystalline cellulose,
3 mg of the hydroxypropyl cellulose,
0.2 mg of the colloidal anhydrous silica, and
0.5 mg of the magnesium stearate; and
ii) an external phase comprising 0.5 mg of the magnesium stearate.
7 . The oral dosage form of claim 6 , wherein said dosage form comprises a capsule shell, wherein said capsule shell comprises hypromellose, iron oxide red, and titanium dioxide.
8 . The oral dosage form of claim 6 , comprising a mono-HCl salt form of the compound given by Formula I.
9 . The oral dosage form of claim 1 , comprising:
i) an internal phase comprising:
25 to 30 mg of the compound given by Formula I or the pharmaceutically acceptable salt thereof,
11 to 12 mg of the lactose monohydrate,
7.5 mg of the low-substituted hydroxypropyl cellulose,
2.5 mg of the microcrystalline cellulose,
1.5 mg of the hydroxypropyl cellulose,
0.1 mg of the colloidal anhydrous silica, and
0.25 mg of the magnesium stearate; and
ii) an external phase comprising 0.25 mg of the magnesium stearate.
10 . The oral dosage form of claim 9 , wherein said dosage form comprises a capsule shell, wherein said capsule shell comprises hypromellose, iron oxide red, and titanium dioxide.
11 . The oral dosage form of claim 9 , comprising a mono-HCl salt form of the compound given by Formula I.
12 . An oral dosage form comprising:
(i) an internal phase comprising:
150 to 160 mg of a compound given by Formula I or a pharmaceutically acceptable salt thereof, wherein said Formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide represented by the structure:
241 to 242 mg of a lactose monohydrate,
90 mg of a low-substituted hydroxypropyl cellulose,
18 mg of a hypromellose, and
1.2 mg of a colloidal silicon dioxide; and
(ii) an external phase comprising 12 mg of a magnesium stearate and 78 mg of a microcrystalline cellulose,
wherein said oral dosage form is formulated to achieve a mean Cmax of about 1 ng/mL to about 4 ng/mL as measured for every mg of Formula I in said oral dosage form.
13 . The oral dosage form of claim 12 , further comprising a film coating comprising hypromellose, talc, titanium dioxide, propylene glycol, ferric oxide, and purified water.
14 . The oral dosage form of claim 1 , comprising a mono-HCl salt form of the compound given by Formula I.
15 . The oral dosage form of claim 1 , wherein the dosage form is formulated to achieve a mean tmax of said mean Cmax in about 2 hours to about 7 hours.
16 . The oral dosage form of claim 1 , wherein said mean Cmax is in the range of 80% to 125% of 3 ng/mL to 80% to 125% of 3.5 ng/mL for every mg of Formula I in said dosage form.
17 . The oral dosage form of claim 12 , comprising a mono-HCl salt form of the compound given by Formula I.
18 . A method of treating cancer in a human subject comprising administering to said subject the oral dosage form of claim 1 .