Methods of using SAHA and Bortezomib for treating cancer

• US 20070197473A1
• Filed: 11/03/2006
• Published: 08/23/2007
• Est. Priority Date: 11/04/2005
• Status: Abandoned Application

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Fine, Bernard, Frankel, Stanley, Randolph, Sophia, Deutsch, Paul
• Application Number:
  US11/592,528
• Publication Number:
  US 20070197473A1
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics

Abstract

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.

Claims

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/m² 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/m² 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/m² 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/m² 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/m² 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/m².

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/m².

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/m².

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/m².

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/m².

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