TREATMENT OF RENAL CANCER USING A COMBINATION OF AN ANTI-PD-1 ANTIBODY AND ANOTHER ANTI-CANCER AGENT

• US 20170088626A1
• Filed: 03/04/2015
• Published: 03/30/2017
• Est. Priority Date: 03/05/2014
• Status: Abandoned Application

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: JURE-KUNKEL, Maria, GAGNIER, Paul, FELTQUATE, David
• Application Number:
  US15/122,827
• Publication Number:
  US 20170088626A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• 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 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/12 of the kidneys
• 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: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

This disclosure provides a method for treating a subject afflicted with a renal cancer, which method comprises administering to the subject therapeutically effective amounts of: (a) an anti-cancer agent which is an antibody or an antigen-binding portion thereof that specifically binds to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity; and (b) another anti-cancer agent. The other anti-cancer agent may be an anti-angiogenic tyrosine kinase inhibitor or an anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) antibody. The disclosure also provides a kit for treating a subject afflicted with a renal cancer, the kit comprising a dosage of an anti-PD-1 antibody, a dosage of another anti-cancer agent which is an anti-angiogenic tyrosine kinase inhibitor or an anti-CTLA-4 antibody, and instructions for using the anti-PD-1 antibody and the other anti-cancer agent in any of the disclosed methods for treating a renal cancer.

Claims

1. A method for treating a subject afflicted with a renal cancer comprising administering to the subject a combination of therapeutically effective amounts of:

(a) an anti-cancer agent which is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity; and

(b) another anti-cancer agent.

2. The method of claim 1, wherein the renal cancer is renal cell carcinoma.

3. The method of claim 1, wherein the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1.

4. The method of claim 1, wherein the anti-PD-1 antibody or antigen-binding portion thereof is a chimeric, humanized or human monoclonal antibody or a portion thereof.

5. The method of any one of claims 1-4, wherein the anti-PD-1 antibody or antigen-binding portion thereof comprises a heavy chain constant region which is of a human IgG1 or IgG4 isotype.

6. The method of claim 1, wherein the anti-PD-1 antibody is nivolumab.

7. The method of claim 1, wherein the anti-PD-1 antibody is pembrolizumab.

8. The method of claim 1, wherein the other anti-cancer agent is an anti-angiogenic tyrosine kinase inhibitor.

9. The method of claim 8, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a dose ranging from about 0.1 to about 10.0 mg/kg body weight once about every 2, 3 or 4 weeks.

10. The method of claim 9, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a dose of 2 or 5 mg/kg body weight once every 3 weeks.

11. The method of claim 8, wherein the tyrosine kinase inhibitor is sunitinib.

12. The method of claim 11, wherein the sunitinib is administered at a dose ranging from 12.5 to 50 mg in a cycle comprising daily administration for 28 days and no administration for 14 days, and repetition of the cycle for as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.

13. The method of claim 11, wherein the sunitinib is administered at a dose ranging from 12.5 to 50 mg in a cycle comprising daily administration for 28 days and no administration for 14 days, followed by daily administration of sunitinib at about 37.5 mg for as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.

14. The method of claim 8, wherein the tyrosine kinase inhibitor is pazopanib.

15. The method of claim 14, wherein the pazopanib is administered at a dose ranging from 400 to 800 mg administered daily or every other day for as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.

16. The method of claim 1, wherein the other anti-cancer agent is an antibody or an antigen-binding portion thereof that binds specifically to Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and inhibits CTLA-4 activity.

17. The method of claim 16, wherein the anti-CTLA-4 antibody or antigen-binding portion thereof cross-competes with ipilimumab for binding to human CTLA-4.

18. The method of claim 16, wherein the anti-CTLA-4 antibody or antigen-binding portion thereof is a chimeric, humanized or human monoclonal antibody or a portion thereof.

19. The method of any one of claims 16-18, wherein the anti-CTLA-4 antibody or antigen-binding portion thereof comprises a heavy chain constant region which is of a human IgG1 isotype.

20. The method of claim 16, wherein the anti-CTLA-4 antibody is ipilimumab.

21. The method of claim 16, wherein the anti-CTLA-4 antibody is tremelimumab.

22. The method of claim 16, comprising:

(a) an induction phase, wherein the anti-PD-1 and anti-CTLA-4 antibodies or antigen-binding portions thereof are administered in combination in 2, 4, 6, 8 or 10 doses, each dose ranging from 0.1 to 10.0 mg/kg body weight administered at least once every 2, 3, or 4 weeks;

followed by

(b) a maintenance phase, wherein no anti-CTLA-4 antibody or antigen-binding portion thereof is administered and the anti-PD-1 antibody or antigen-binding portion thereof is repeatedly administered at a dose ranging from 0.1 to 10 mg/kg at least once every 2, 3 or 4 weeks.

23. The method of claim 22, wherein:

(a) the induction phase comprises 4 combination doses administered at 3-week intervals, wherein;

(i) the anti-PD-1 antibody or antigen-binding portion thereof is administered at 3 mg/kg body weight and the anti-CTLA-4 antibody or antigen-binding portion thereof is administered at 1 mg/kg body weight;

(ii) the anti-PD-1 antibody or antigen-binding portion thereof is administered at 1 mg/kg body weight and the anti-CTLA-4 antibody or antigen-binding portion thereof is administered at 3 mg/kg body weight;

or

(iii) the anti-PD-1 antibody or antigen-binding portion thereof is administered at 3 mg/kg body weight and the anti-CTLA-4 antibody or antigen-binding portion thereof is administered at 3 mg/kg body weight; and

(b) the maintenance phase comprises repeated administration of the anti-PD-1 antibody or antigen-binding portion thereof at a dose of 3 mg/kg every 2 weeks for as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.

24. The method of any claim 22, wherein the anti-PD-1 and anti-CTLA-4 antibodies are formulated for intravenous administration.

25. The method of claim 22, wherein the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof are administered sequentially to the subject during the induction phase.

26. The method of claim 25, wherein the anti-PD-1 and anti-CTLA-4 antibodies are administered within 30 minutes of each other.

27. The method of claim 25, wherein

(a) the anti-PD-1 antibody or antigen-binding portion thereof is administered before the anti-CTLA-4 antibody or antigen-binding portion thereof;

or

(b) the anti-CTLA-4 antibody or antigen-binding portion thereof is administered before the anti-PD-1 antibody or antigen-binding portion thereof.

28. The method of claim 22, wherein the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof are administered concurrently in separate compositions.

29. The method of claim 22, wherein the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof are admixed as a single composition for concurrent administration.

30. The method of claim 22, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a subtherapeutic dose.

31. The method of claim 22, wherein the anti-CTLA-4 antibody or antigen-binding portion thereof is administered at a subtherapeutic dose.

32. The method of claim 22, wherein the anti-PD-1 antibody or antigen-binding portion thereof and the anti-CTLA-4 antibody or antigen-binding portion thereof are each administered at a subtherapeutic dose.

33. The method of claim 22, wherein administration of the anti-PD-1 antibody in the maintenance phase is continued for as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.

34. A kit for treating a subject afflicted with a renal cancer, the kit comprising:

(a) a dosage ranging from 0.1 to 10 mg/kg body weight of an anti-cancer agent which is an antibody or an antigen-binding portion thereof that specifically binds to the PD-1 receptor and inhibits PD-1 activity;

(b) a dosage of another anti-cancer agent which is

(i) an anti-angiogenic tyrosine kinase inhibitor;

or

(ii) a dosage ranging from 0.1 to 10 mg/kg body weight of an antibody or an antigen-binding portion thereof that specifically binds to and inhibits CTLA-4; and

(c) instructions for using the anti-PD-1 antibody and the other anti-cancer agent in the method of any of claim 1, 8 or 16.

35. The method of any one of claims 1 to 33, wherein the administration of the anti-PD-1 antibody or antigen-binding portion thereof and the other anti-cancer agent increases T cell infiltration of the renal cancer tissue compared to an untreated subject or a subject treated with a monotherapy of the anti-PD-1 antibody or antigen-binding portion thereof or the other anti-cancer agent.

36. The method of claim 35, wherein the increased T cell infiltration is characterized by increased infiltration of CD4⁺/Ki67⁺ T cells, CD8⁺ T cells, CD8⁺/Ki67⁺ T cells, or any combination thereof.

37. The method of claim 36, wherein the increased T cell infiltration is characterized by increased infiltration of CD4⁺/Ki67⁺ T cells, CD8⁺/Ki67⁺ T cells, or both.

38. The method of any one of claims 35 to 37, wherein the T cell infiltration is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

39. The method of any one of claims 1 to 33 and 35 to 38, wherein the administration of the anti-PD-1 antibody or antigen-binding portion thereof and the other anti-cancer agent increases proliferating T cells compared to an untreated subject or a subject treated with a monotherapy of the anti-PD-1 antibody or antigen-binding portion thereof or the other anti-cancer agent.

40. The method of claim 39, wherein the proliferating T cells are CD4⁺/Ki67⁺ T cells, CD8⁺ T cells, CD8⁺/Ki67⁺ T cells, or any combination thereof.

41. The method of claim 39 or 40, wherein the frequency of proliferating T cells in increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

42. The method of any one of claims 1 to 33 and 35 to 41, wherein the administration of the anti-PD-1 antibody or antigen-binding portion thereof and the other anti-cancer agent decreases the number of monocytic myeloid-derived suppressor cells compared to an untreated subject or a subject treated with a monotherapy of the anti-PD-1 antibody or antigen-binding portion thereof or the other anti-cancer agent.

43. The method of claim 42, wherein the number of monocytic myeloid-derived suppressor cells is decreased by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

44. The method of claim 42 or 43, wherein the monocytic myeloid-derived suppressor cells are characterized by CD11b⁺/Ly6C^hi/Ly6G⁻

expression or CD11b⁺/Ly6C^low/Ly6G⁻

expression.

45. The method of any one of claims 1 to 33 and 35 to 44, wherein the administration of the anti-PD-1 antibody or antigen-binding portion thereof and the other anti-cancer agent increases the number of granulocytic myeloid cells compared to an untreated subject or a subject treated with a monotherapy of the anti-PD-1 antibody or antigen-binding portion thereof or the other anti-cancer agent.

46. The method of claim 44, wherein the number of granulocytic myeloid cells is increased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

47. The method of claim 45 or 46, wherein the granulocytic myeloid cells are characterized by CD11b⁺/Ly6C⁻

/Ly6G⁺ expression.

48. The method of any one of claims 1 to 33 and 35 to 47, wherein the administration of the anti-PD-1 antibody or antigen-binding portion thereof and the other anti-cancer agent decreases T-regulatory cells compared to an untreated subject or a subject treated with a monotherapy of the anti-PD-1 antibody or antigen-binding portion thereof or the other anti-cancer agent.

49. The method of claim 48, wherein the T-regulatory cells are characterized by CD45⁺/CD4⁺/CD25⁺/FoxP3⁺ expression.