METHODS OF USING SAHA AND BORTEZOMIB FOR TREATING MULTIPLE MYELOMA
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, or a pharmaceutically acceptable salt or hydrate thereof is orally administered 200 mg to 800 mg per day for at least one treatment cycle on days 4-11 of a 21 day cycle, and Bortezomib, or a pharmaceutically acceptable salt or hydrate thereof, is intravenously administered 0.7-1.3 mg/m 2 per day for at least one treatment cycle on days 1, 4, 8 and 11 of a 21 day cycle.
2 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered twice daily at a dose of 100 mg for at least one treatment period of days 4-11 out of 21 days.
3 . The method of claim 1 , 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 days 4-11 out of 21 days.
4 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered twice daily at a dose of 300 mg for at least one treatment period of days 4-11 out of 21 days.
5 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered twice daily at a dose of 400 mg for at least one treatment period of days 4-11 out of 21 days.
6 . The method of claim 1 , 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 days 4-11 out of 21 days.
7 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 500 mg for at least one treatment period of days 4-11 out of 21 days.
8 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 600 mg for at least one treatment period of days 4-11 out of 21 days.
9 . The method of claim 1 wherein the administration of SAHA or pharmaceutically acceptable salt or hydrate thereof is repeated for up to eight treatment periods of days 4-11 out of 21 days.
10 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered twice daily at a dose of 100 mg and [(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 at a total daily dose of 1.0 mg/m 2 .
11 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered twice daily at a dose of 100 mg and [(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 at a total daily dose of 1.3 mg/m 2 .
12 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered twice daily at a dose of 200 mg and [(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 at a total daily dose of 1.3 mg/m 2 .
13 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered twice daily at a dose of 300 mg and [(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 at a total daily dose of 1.3 mg/m 2 .
14 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered twice daily at a dose of 400 mg and [(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 at a total daily dose of 1.3 mg/m 2 .
15 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 400 mg and [(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 at a total daily dose of 1.3 mg/m 2 .
16 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 500 mg and [(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 at a total daily dose of 1.3 mg/m 2 .
17 . The method of claim 1 , wherein the SAHA or pharmaceutically acceptable salt or hydrate thereof is administered once daily at a dose of 600 mg and [(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 at a total daily dose of 1.3 mg/m 2 .
18 . The method of claim 1 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 for at least one treatment period of 5 out of 21 days.
19 . The method claims 1 further comprising orally administering dexamethasone once daily at a dose of 20 mg for at least one treatment period of days 4-8 out of 21 days.
20 . 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:
and
ii) (1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-(pyrazinylcarbonyl)amino]propyl]amino/butyl] boronic acid (Bortezomib), wherein the SAHA, is orally administered once daily at 400 mg per day for at least one treatment cycle on days 4-11 of a 21 day cycle, and Bortezomib, is intravenously administered at 1.3 mg/m 2 per day for at least one treatment cycle on days 1, 4, 8 and 11 of a 21 day cycle.
21 . The method claims 20 further comprising orally administering dexamethasone once daily at a dose of 20 mg for at least one treatment period of days 4-8 out of 21 days.