PD-L1 Antagonist Combination Treatments

Patent metadata

Field	Value
Publication number	US-2018169232-A1
Application number	US-201615736615-A
Country	US
Kind code	A1
Filing date	Jun 15, 2016
Priority date	Jun 16, 2015
Publication date	Jun 21, 2018
Grant date	—

Abstract

The present disclosure describes combination therapies comprising an antagonist of Programmed Death Ligand 1 receptor (PD-L1) and another therapeutic agent, and the use of the combination therapies for the treatment of cancer.

First claim

1 . A method for treating a cancer in a subject comprising administering to the subject a combination therapy which comprises an antagonist of a Programmed Death Ligand 1 protein (PD-L1) and a VEGFR inhibitor, wherein the PD-L1 antagonist is an anti-PD-L1 monoclonal antibody comprising: three CDRs from a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 8, and three CDRs from a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 9, and wherein the VEGFR inhibitor is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide or a pharmaceutically acceptable salt thereof.

2 .- 3 . (canceled)

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

5 . The method of claim 4 , wherein the PD-L1 antagonist is avelumab and the VEGFR inhibitor is axitinib.

6 . The method of claim 5 , wherein the PD-L1 antagonist is administered as an initial dose of at least about 5 mg/kg, or about 10 mg/kg; and the VEGFR inhibitor is administered as an initial dose of at least 3 mg/kg or 5 mg/kg.

7 . (canceled)

8 . The method of claim 6 , wherein the PD-L1 antagonist is administered about once every two weeks; and the VEGFR inhibitor is administered twice daily.

9 .- 23 . (canceled)

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

25 . The method of claim 24 , wherein the advanced renal cell carcinoma is previously untreated advanced renal cell carcinoma.

26 . A method for treating a cancer in a subject comprising administering to the subject a combination therapy which comprises an antagonist of a Programmed Death Ligand 1 protein (PD-L1) and a second agent, wherein the second agent is an anti-4-1BB antibody, an anti-M-CSF antibody, or an anti-OX40 antibody.

27 . The method of claim 26 , wherein the PD-L1 antagonist is an anti-PD-L1 monoclonal antibody comprising three CDRs from a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 8 and three CDRs from a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 9; wherein the anti-4-1BB antibody comprises three CDRs from a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 18 and three CDRs from a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 19; wherein the anti-M-CSF antibody comprises three CDRs from a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 30 and three CDRs from a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 31; and wherein the anti-OX40 antibody comprises three CDRs from a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 38 and three CDRs from a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 39.

28 . The method of claim 27 , wherein the second agent is an anti-4-1BB antibody.

29 . (canceled)

30 . The method of claim 28 , wherein the PD-L1 antagonist is administered as a 1-hour intravenous infusion every 2 weeks at a dose of 10 mg/kg, and the anti-4-1BB antibody is administered at 100 mg as a 1-hour IV infusion once every 4 weeks on Day 1 of each cycle.

31 . The method of claim 30 , wherein when the anti-4-1BB antibody and the PD-L1 antagonist are both administered on the same day, the anti-4-1BB antibody is administered first, followed by the avelumab infusion no more than 30 minutes after the end of the anti-4-1BB antibody infusion.

32 . (canceled)

33 . The method of claim 28 , wherein the combination therapy further comprises a third agent, wherein the third agent is an anti-M-CSF antibody or an anti-OX40 antibody.

34 . The method of claim 33 , wherein the anti-M-CSF antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences shown in SEQ ID NO: 30 and SEQ ID NO: 31, respectively.

35 . The method of claim 33 , wherein the anti-OX40 antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences shown in SEQ ID NO: 38 and SEQ ID NO: 39, respectively.

36 .- 37 . (canceled)

38 . The method of claim 28 , wherein the PD-L1 antagonist is avelumab.

39 . The method of claim 38 , wherein the PD-L1 antagonist is administered as an initial dose of at least about 5 mg/kg, or about 10 mg/kg.

40 . (canceled)

41 . The method of claim 39 , wherein the PD-L1 antagonist is administered about once every two weeks; and the second agent is administered about once every two weeks.

42 . The method of claim 26 , further comprising administering a chemotherapy, radiotherapy, or chemoradiotherapy to the subject.

43 . The method of claim 42 , wherein the chemoradiotherapy comprises cisplatin and intensity modulated radiation therapy (IMIRT).

44 . The method of claim 26 , wherein the cancer is diffuse large B-cell lymphoma (DLBCL) or Squamous Cell Carcinoma of the Head and Neck (SCCHN).

45 . A method for treating a cancer in a subject comprising administering to the subject a combination therapy which comprises an antagonist of a Programmed Death Ligand 1 protein (PD-L1) and one or more CD20 antagonists.

46 . The method of claim 45 , wherein the PD-L1 antagonist is an anti-PD-L1 monoclonal antibody comprising: three CDRs from a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 8 and three CDRs from a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 9; and the CD20 antagonist is rituximab.

47 . The method of claim 46 , wherein the combination therapy further comprises bendamustine.

48 .- 50 . (canceled)

51 . The method of claim 47 , wherein the CD20 antagonist is administered on Day 1 of a 28-day cycle, the PD-L1 antagonist is administered on Day 2 and Day 16 of the 28-day cycle, or on Day 1 and Day 15 of the 28-day cycle, and the bendamustine is administered intravenously at a dose of 90 mg/m 2 on Day 2 and Day 3 of the 28-day cycle, or on Day 1 and Day 2 of the 28-day cycle.

52 . (canceled)

53 . The method of claim 51 , wherein the PD-L1 antagonist is administered at least 30 minutes, at least 60 minutes, or at least 3 hours after administration of bendamustine when dosed on the same day.

54 .- 55 . (canceled)

56 . The method of claim 46 , wherein the combination therapy further comprises an anti-4-1BB antibody.

57 . The method of claim 56 , wherein the anti-4-1BB antibody comprises three CDRs from a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 18 and three CDRs from a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 19.

58 . The method of claim 57 , wherein the CD20 antagonist is administered on Day 1 of a 28-day cycle, the PD-L1 antagonist is administered on Day 2 and Day 16 of the 28-day cycle or Day 1 and Day 15 of the 28-day cycle, and the anti-4-1BB antibody is administered on Day 2 of the 28-day cycle or Day 1 of the 28-day cycle.

59 .- 62 . (canceled)

63 . The method of claim 58 , wherein the a

Assignees

• Andrews Glen Ian
• Chen Shihao
• Di Pietro Alessandra
• Fontana David
• Goldberg Zelanna
• Lin Chia Yang
• Long Hua
• Martignoni Marcella
• NUYTEN Dimitry Serge Antotne
• Thall Aron David
• Woolfson Adrian
• Merck Patent Gmbh
• Pfizer

Inventors

• Andrews Glen Ian
• Chen Shihao
• Di Pietro Alessandra
• Fontana David
• Goldberg Zelanna
• Lin Chia-Yang
• Long Hua
• Martignoni Marcella
• Nuyten Dimitry Serge Antoine
• Thall Aron David
• Woolfson Adrian

Classifications

• A61K2039/507

  Comprising a combination of two or more separate antibodies · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4184 Primary

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• C07K16/2827

  against B7 molecules, e.g. CD80, CD86 · CPC title

• A61K39/39558 Primary

  against tumor tissues, cells, antigens · CPC title