Method of treating multiple myeloma using 17-AAG or 17-AG or a prodrug of either in combination with a proteasome inhibitor

• US 20060252740A1
• Filed: 04/26/2006
• Published: 11/09/2006
• Est. Priority Date: 04/29/2005
• Status: Abandoned Application

• Current Assignee: Kosan Biosciences, Inc. (Bristol-Myers Squibb Company)
• Original Assignee: Kosan Biosciences, Inc. (Bristol-Myers Squibb Company)
• Inventors: Johnson, Robert G. Jr., Hannah, Alison L., Sherrill, J. Michael, Zhou, Yiqing, Cropp, Gillian F.
• Application Number:
  US11/412,299
• Publication Number:
  US 20060252740A1
• Time in Patent Office: Days
• US Class Current: 514/183
• 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 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 225/06 condensed with one six-membered ring

Abstract

A method for treating multiple myeloma in a subject by administering to the subject 17-allylamino-17-demethoxy-geldanamycin or 17-amino geldanamycin, or a pro drug of either 17-AAG or 17-AG, in combination with a proteasome inhibitor.

Claims

1. A method of treating multiple myeloma (MM) in a subject in need of such treatment, comprising the step of administering to said subject a therapeutically effective dose of 17-allylamino-17-demethoxy-geldanamycin (17-AAG) or 17-aminogeldanamycin (17-AG) or a prodrug of either 17-AAG or 17-AG, and a therapeutically effective dose of a proteasome inhibitor, and optionally repeating said step until no further therapeutic benefit is obtained.

36. The method of claim 1, wherein said proteasome inhibitor is a peptide aldehyde.

37. The method of claim 1, wherein said peptide aldehyde is a peptide boronate.

38. The method of claim 37, wherein said peptide boronate is a dipeptide boronic acid.

39. The method of claim 38, wherein said dipeptide boronic acid is bortezomib.

40. The method of claim 1, wherein said administering step results in an induction of HSP70 in peripheral blood mononuclear cells of said subject.

41. The method of claim 40, wherein said induction of HSP70 is observable one day after said administering step.

42. The method of claim 1, wherein said administering step results in an increase of apoptosis of CD138⁺ cells among the bone marrow aspirate cells of said subject.

43. The method of claim 42, wherein said increase of apoptosis of CD138⁺ cells is observable four hours after said administering step.

44. The method of claim 1, wherein said administering step results in a decrease of total AKT in bone marrow aspirate cells of said subject.

45. The method of claim 44, wherein said decrease of total AKT is observable four hours after said admnistering step.

2. A method of treating MM in a subject in need of such treatment, comprising the step of administering multiple doses of 17-AAG or 17-AG or a prodrug of either to said subject over a time period of at least 2 weeks, wherein each such dose is in the range of about 100 to about 340 mg/m² of 17-AAG, or an equivalent amount of 17-AG or a 17-AAG prodrug or 17-AG prodrug, and multiple doses of a proteasome inhibitor, wherein said proteasome inhibitor is bortezomib and each such dose is at least about 1 mg/m².

3. The method of claim 2, wherein each such dose of 17-AAG is in the range of about 150 to about 340 mg/m or an equivalent amount of 17-AG or a prodrug of 17-AAG or 17-AG.

4. The method of claim 2, wherein said dose of is administered twice weekly for at least two weeks.

5. The method of claim 4, wherein said dose is administered twice weekly for at least two weeks in a three week period.

6. The method of claim 5, wherein multiple cycles of treatment are administered to the subject, wherein each cycle of treatment comprises of said dose administered twice weekly for at least two weeks in a three week period.

35. The method of claim 2, wherein said each dose of bortezomib is of the range of about 1.0 to about 1.3 mg/m².

7. A method of treating MM in a subject in need of such treatment, comprising the step of administering a therapeutically effective dose of a proteasome inhibitor and a therapeutically effective dose of 17-AAG or a prodrug of 17-AAG that results in an AUC_total of 17-AAG per dose in the range of about 2,300 to about 19,000 ng/mL*h.

8. The method of claim 7, wherein said dose of 17-AAG is administered at a rate and frequency such that the C_max of 17-AAG does not exceed 9,600 ng/mL.

9. The method of claim 7, wherein said dose of 17-AAG is administered at a rate and frequency such that the C_max of 17-AAG is greater than 1,300 ng/mL.

10. The method of claim 9, wherein said dose of 17-AAG is administered at a rate and frequency such that the C_max of 17-AAG is greater than 1,800 ng/mL.

11. The method of claim 7, wherein said dose of 17-AAG is administered at a rate and frequency such that the C_max of 17-AAG is greater than 1,300 but does not exceed 9,600 ng/mL.

12. The method of claim 7, wherein said dose of 17-AAG is administered at a rate and frequency such that the C_max of 17-AAG is greater than 1,800 but does not exceed 9,600 ng/mL.

13. A method of treating MM in a subject in need of such treatment, comprising the step of administering to said subject a therapeutically effective dose of a proteasome inhibitor and a therapeutically effective dose of 17-AG or a prodrug of 17-AG that results in an AUC_total of 17-AG per dose in the range of about 800 to about 17,000 ng/mL*h.

14. The method of claim 13, wherein said dose of 17-AG is administered at a rate and frequency such that the C_max of 17-AAG does not exceed 1,400 ng/mL.

15. The method of claim 13, wherein said dose of 17-AG is administered at a rate and frequency such that the C_max of 17-AAG is greater than 140 ng/mL.

16. The method of claim 15, wherein said dose of 17-AG is administered at a rate and frequency such that the C_max of 17-AAG is greater than 230 ng/mL.

17. The method of claim 13, wherein said dose of 17-AG is administered at a rate and frequency such that the C_max of 17-AAG is greater than 140 but does not exceed 1,400 ng/mL.

18. The method of claim 17, wherein said dose of 17-AG is administered at a rate and frequency such that the C_max of 17-AAG is greater than 230 but does not exceed 1,400 ng/mL.

19. A method of treating MM in a subject in need of such treatment, comprising the step of administering to said subject a therapeutically effective dose of a proteasome inhibitor and a therapeutically effective dose of 17-AAG, a prodrug of 17-AAG, 17-AG, or a prodrug of 17-AG that results in a combined AUC_total of 17-AAG and 17-AG per dose in the range of about 3,500 to about 35,000 ng/mL*h.

20. The method of claim 19, wherein said dose of 17-AAG, a prodrug of 17-AAG, 17-AG, or a prodrug of 17-AG is administered at a rate and frequency such that the C_max of 17-AAG does not exceed 9,600 ng/mL or the C_max of 17-AG does not exceed 1,400 ng/mL.

21. The method of claim 19, wherein said dose of 17-AAG, a prodrug of 17-AAG, 17-AG, or a prodrug of 17-AG is administered at a rate and frequency such that the C_max of 17-AAG is greater than 1,300 ng/mL or the C_max of 17-AG is greater than 140 ng/mL.

22. The method of claim 21, wherein said dose is administered at a rate and frequency such that the C_max of 17-AAG is greater than 1,800 ng/mL or the C_max of 17-AG is greater than 230 ng/mL.

23. The method of claim 19, wherein said dose of 17-AAG, a prodrug of 17-AAG, 17-AG, or a prodrug of 17-AG is administered at a rate and frequency such that the C_max of 17-AAG is greater than 1,300 but does not exceed 9,600 ng/mL or the C_max of 17-AG is greater than 140 but does not exceed 1,400 ng/mL.

24. The method of claim 23, wherein said dose is administered at a rate and frequency such that the C_max of 17-AAG is greater than 1,800 but does not exceed 9,600 ng/mL or the C_max of 17-AG is greater than 230 ng/mL but does not exceed 1,400 ng/mL.

25. A method of treating MM in a subject in need of such treatment, comprising the step of administering to said subject a therapeutically effective dose of a proteasome inhibitor and a therapeutically effective dose of 17-AAG or a prodrug of 17-AAG that results in a Terminal T_1/2 of 17-AAG in the range of 1.6 h to 5.6 h.

26. The method of claim 25, wherein said dose of 17-AAG or a prodrug of 17-AAG results in an AUC_total of 17-AAG per dose in the range of about 2,300 to about 19,000 ng/mL*h.

27. A method of treating MM in a subject in need of such treatment, comprising the step of administering to said subject a therapeutically effective dose of a proteasome inhibitor and a therapeutically effective dose of 17-AG or a prodrug of 17-AG that results in a Terminal T_1/2 of 17-AG in the range of 3.7 h to 9.1 h.

28. The method of claim 27, wherein said dose of 17-AG or a prodrug of 17-AG results in an AUC_total of 17-AG per dose in the range of about 800 to about 17,000 ng/mL*h.

29. A method of treating MM in a subject in need of such treatment, comprising the step of administering to said subject a therapeutically effective dose of a proteasome inhibitor and a therapeutically effective dose of 17-AAG or a prodrug of 17-AAG that results in a Volume of distribution V_Z of 17-AAG in the range of 56 L to 250 L.

30. The method of claim 29, wherein said dose of 17-AAG or a prodrug of 17-AAG results in an AUC_total of 17-AG per dose in the range of about 2,300 to about 19,000 ng/mL*h.

31. A method of treating MM in a subject in need of such treatment, comprising the step of administering to said subject a therapeutically effective dose of a proteasome inhibitor and a therapeutically effective dose of 17-AAG or a prodrug of 17-AAG that results in a Clearance of 17-AAG in the range of 13 to 85 L/h.

32. The method of claim 31, wherein said dose of 17-AAG or a prodrug of 17-AAG results in an AUC_total of 17-AG per dose in the range of about 2,300 to about 19,000 ng/mL*h.

33. A method of treating MM in a subject in need of such treatment, comprising the step of administering to said subject a therapeutically effective dose of a proteasome inhibitor and a therapeutically effective dose of 17-AAG or a prodrug of 17-AAG that results in a Volume of distribution V_SS of 17-AAG in the range of 96 to 250 L.

34. The method of claim 33, wherein said dose of 17-AAG or a prodrug of 17-AAG results in an AUC_total of 17-AG per dose in the range of about 2,300 to about 19,000 ng/mL*h.