Methods of using SAHA and Bortezomib for treating cancer
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 such as suberoylanilide hydroxamic acid (SAHA), or a pharmaceutically acceptable salt or hydrate thereof, and a second amount of one or more anti-cancer agents, including Bortezomib. 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 multiple myeloma 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) (1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid (Bortezomib) or a pharmaceutically acceptable salt or hydrate thereof, wherein the SAHA and the Bortezomib are administered in amounts effective for treating the multiple myeloma.
2 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered orally.
3 . The method of claim 1 , wherein the [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid or pharmaceutically acceptable salt or hydrate thereof is administered intravenously.
4 . The method of any one of claims 1 - 3 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 400 mg for at least one treatment period of 7 out of 21 days.
5 . The method of any one of claims 1 - 3 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 400 mg for at least one treatment period of 10 out of 21 days.
6 . The method of any one of claims 1 - 3 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered twice daily at a dose of 200 mg for at least one treatment period of 14 out of 21 days.
7 . The method of any one of claims 1 - 3 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 400 mg for at least one treatment period of 14 out of 21 days.
8 . The method of any of claims 1 - 7 wherein the administration of SAHA or pharmaceutically acceptable salt or hydrate thereof is repeated for up to eight treatment periods of 21 days.
9 . The method of any one of claims 1 - 8 , wherein the [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 0.7 mg/m 2 on Days 4, 8, 11 and 15 out of 21 days.
10 . The method of any one of claims 1 - 8 , wherein the [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 0.9 mg/m 2 on Days 4, 8, 11 and 15 out of 21 days.
11 . The method of any one of claims 1 - 8 , wherein the [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 0.9 mg/m 2 on Days 1, 4, 8, and 11 out of 21 days.
12 . The method of any one of claims 1 - 8 , wherein the [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyI)amino]propyl]amino]butyl] boronic acid or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of about 1.1 mg/m 2 on Days 1, 4, 8, and 11 out of 21 days.
13 . The method of any one of claims 1 - 8 , wherein the [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of about 1.3 mg/m 2 on Days 1, 4, 8, and 11 out of 21 days.
14 . The method of any one of claims 1 - 3 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered twice daily at a dose of 200 mg, and Bortezomib or pharmaceutically acceptable salt or hydrate thereof is administered at a total daily dose of 0.7 mg/m 2 .
15 . The method of any one of claims 1 - 3 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered twice daily at a dose of 200 mg, and Bortezomib or pharmaceutically acceptable salt or hydrate thereof is administered at a total daily dose of 0.9 mg/m 2 .
16 . The method of any one of claims 1 - 3 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 400 mg, and Bortezomib or pharmaceutically acceptable salt or hydrate thereof is administered at a total daily dose of 0.9 mg/m 2 .
17 . The method of any one of claims 1 - 3 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 400 mg, and Bortezomib or pharmaceutically acceptable salt or hydrate thereof is administered at a total daily dose of 1.1 mg/m 2 .
18 . The method of any one of claims 1 - 3 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 400 mg, and Bortezomib or pharmaceutically acceptable salt or hydrate thereof is administered at a total daily dose of 1.3 mg/m 2 .
19 . The method of any one of claims 1 - 18 , wherein SAHA and Bortezomib are administered.
20 . The method of any one of claims 1 - 18 further comprising orally administering dexamethasone or a pharmaceutically acceptable salt or hydrate thereof wherein the dexamethasone or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 20 mg on Days 1-4 and 9-12 for at least one treatment period of 21 days.
21 . A pharmaceutical composition comprising: i) suberoylanilide hydroxamic acid (SAHA), esented by the structure:
or a pharmaceutically acceptable salt or hydrate thereof; and ii) [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid, or a pharmaceutically acceptable salt or hydrate thereof.
22 . The pharmaceutical composition of claim 21 which comprises SAHA and Bortezomib