Method of treating cancers with SAHA and pemetrexed
The present invention relates to a method of treating cancer in a subject in need thereof, by administering to a subject in need thereof a first amount of a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a second amount of an anti-cancer agent. The HDAC inhibitor and the anti-cancer agent may be administered to comprise therapeutically effective amounts. In various aspects, the effect of the HDAC inhibitor and the anti-cancer agent may be additive or synergistic.
1 . A method of treating a solid tumor in a subject in need thereof comprising administering to the subject: i) SAHA (suberoylanilide hydroxamic acid), represented by the structure:
or a pharmaceutically acceptable salt or hydrate thereof; and ii) L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl, or a pharmaceutically acceptable salt or hydrate thereof, wherein the SAHA and the L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl, or pharmaceutically acceptable salts or hydrates thereof, are administered in amounts effective for treating the tumor.
2 . The method of claim 1 , wherein: i) SAHA (suberoylanilide hydroxamic acid) and ii) Pemetrexed (N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl)disodium salt, heptahydrate) are administered.
3 . The method of claim 2 , wherein the SAHA is administered orally.
4 . The method of claim 2 , wherein the Pemetrexed is administered intravenously.
5 . The method of claim 4 , wherein the Pemetrexed is administered as a 10 minute infusion.
6 . The method of claim 5 , wherein the Pemetrexed is administered at a dose of about 500 mg/m 2 .
7 . The method of claim 6 , wherein the Pemetrexed is administered once daily at a dose of about 500 mg/m 2 for at least one treatment period of 1 out of 21 days.
8 . The method of claim 7 , wherein the SAHA is first administered, followed by the Pemetrexed.
9 . The method of claim 8 , wherein the Pemetrexed is administered two days after the first day of administration of SAHA.
10 . The method of claim 9 , wherein the subject is treated with one or more adjunctive agents that reduce or eliminate hypersensitivity reactions before, during, and after administration of Pemetrexed.
11 . The method of claim 10 , wherein the subject is treated with one or more of dexamethasone, folic acid, and Vitamin B 12 before, during, and after administration of Pemetrexed.
12 . The method of claim 11 , wherein the subject is treated with (i) 2-25 mg of dexamethasone orally on the day before, the day of, and the day after administration of Pemetrexed; (ii) 400-1000 μg of folic acid orally daily, during a period starting 7 days before administration of Pemetrexed, throughout at least one treatment period, and for 21 days after the last administration of Pemetrexed; and (iii) 1000 μg of Vitamin B 12 intramuscularly 1 week before the first administration of SAHA in a treatment period and, where the total treatment period comprises three or more treatment periods of 21 days, the 1000 μg of Vitamin B 12 is administered every 63 days during the total treatment period.
13 . The method of any one of claims 2 - 12 , wherein the SAHA is administered once daily at a dose of about 300 mg for at least one treatment period of 7 out of 21 days.
14 . The method of any one of claims 2 - 12 , wherein the SAHA is administered once daily at a dose of about 400 mg for at least one treatment period of 7 out of 21 days.
15 . The method of any one of claims 2 - 12 , wherein the SAHA is administered once daily at a dose of about 400 mg for at least one treatment period of 14 out of 21 days.
16 . The method of any one of claims 2 - 12 , wherein the SAHA is administered once daily at a dose of about 400 mg for at least one treatment period continuously.
17 . The method of any one of claims 2 - 12 , wherein the SAHA is administered once daily at a dose of about 500 mg for at least one treatment period of 7 out of 21 days.
18 . The method of any one of claims 2 - 12 , wherein the SAHA is administered once daily at a dose of about 600 mg for at least one treatment period of 7 out of 21 days.
19 . The method of any one of claims 2 - 12 , wherein the SAHA is administered twice daily at about 200 mg per dose for at least one treatment period of 3 out of 7 days.
20 . The method of claim 21 , wherein the SAHA is administered for at least one treatment period of 3 out of 7 days for one week, followed by a two-week rest period.
21 . The method of claim 21 , wherein the SAHA is administered for at least one treatment period of 3 out of 7 days for two weeks, followed by a one-week rest period.
22 . The method of claim 21 , wherein the SAHA is administered for at least one treatment period of 3 out of 7 days, wherein the administration is repeated weekly.
23 . The method of any one of claims 2 - 12 , wherein the SAHA is administered twice daily at about 300 mg per dose for at least one treatment period of 3 out of 7 days.
24 . The method of claim 23 , wherein the SAHA is administered for at least one treatment period of 3 out of 7 days for one week, followed by a two-week rest period.
25 . The method of claim 23 , wherein the SAHA is administered for at least one treatment period of 3 out of 7 days for two weeks, followed by a one-week rest period.
26 . The method of claim 23 , wherein the SAHA is administered for at least one treatment period of 3 out of 7 days, wherein the administration is repeated weekly.
27 . The method of any one of claims 2 - 12 , wherein the SAHA is administered at a total daily dose of up to 300 mg, and the Pemetrexed is administered at a total daily dose of up to 500 mg/m 2 .
28 . The method of any one of claims 2 - 12 , wherein the SAHA is administered at a total daily dose of up to 400 mg, and the Pemetrexed is administered at a total daily dose of up to 500 mg/m 2 .
29 . The method of any one of claims 2 - 12 , wherein the SAHA is administered at a total daily dose of up to 600 mg, and the Pemetrexed is administered at a total daily dose of up to 500 mg/m 2 .
30 . A pharmaceutical composition comprising: i) suberoylanilide hydroxamic acid (SAHA), represented by the structure:
or a pharmaceutically acceptable salt or hydrate thereof and ii) L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl, or a pharmaceutically acceptable salt or hydrate thereof, and optionally one or more pharmaceutically acceptable excipients.
31 . The pharmaceutical composition of claim 30 , wherein the composition is formulated for oral or intravenous administration.
32 . The pharmaceutical composition of claim 31 , wherein the composition is formulated for oral administration and comprises one or more pharmaceutically acceptable excipients comprising microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
33 . The pharmaceutical composition of any one of claims 30 - 32 , which comprises: i) SAHA (suberoylanilide hydroxamic acid) and ii) Pemetrexed (L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl)disodium salt, heptahydrate).