Treating cancer with a combination of a pd-1 antagonist and dinaciclib

Patent metadata

Field	Value
Publication number	US-2016193334-A1
Application number	US-201414912771-A
Country	US
Kind code	A1
Filing date	Aug 15, 2014
Priority date	Aug 20, 2013
Publication date	Jul 7, 2016
Grant date	—

Abstract

The present disclosure describes combination therapies comprising an antagonist of Programmed Death 1 receptor (PD-1) and the CDK inhibitor dincaciclib, and the use of the combination therapies for the treatment of cancer, and in particular for treating cancers that express PD-L1.

First claim

1 . A method for treating a cancer in an individual comprising administering to the individual a combination therapy which comprises an antagonist of a Programmed Death 1 protein (PD-1) and a dinaciclib compound, wherein the dinaciclib compound is the compound of Formula

or a pharmaceutically acceptable salt of the compound of Formula I.

2 . The method of claim 1 , wherein the individual is a human and the PD-1 antagonist is
(a) a monoclonal antibody, or an antigen binding fragment thereof, which specifically binds to human PD-1 and blocks the binding of human PD-L1 to human PD-1; or (b) a monoclonal antibody, or an antigen binding fragment thereof, which specifically binds to human PD-L1 and blocks the binding of human PD-L1 to human PD-1.

3 . The method of claim 2 , wherein the PD-1 antagonist is an anti-PD-1 monoclonal antibody which comprises a heavy chain and a light chain, wherein the heavy and light chains comprise SEQ ID NO:21 and SEQ ID NO:22, respectively, or SEQ ID NO:23 and SEQ ID NO:24, respectively.

4 . The method of any of claims 1 to 3 , wherein the cancer is a solid tumor.

5 . The method of any of claims 1 to 3 , wherein the cancer is a Heme malignancy.

6 . The method of any of claims 3 to 5 , wherein the PD-1 antagonist is MK-3475 and the dinaciclib compound is the compound of Formula 1.

7 . A medicament comprising an antagonist of a Programmed Death 1 protein (PD-1) for use in combination with a dinaciclib compound for treating a cancer in an individual, wherein the dinaciclib compound is the compound of Formula I

or a pharmaceutically acceptable salt of the compound of Formula I.

8 . A medicament comprising a dinaciclib compound for use in combination with an antagonist of a Programmed Death 1 protein (PD-1) for treating a cancer in an individual, wherein the dinaciclib compound is the compound of Formula I

9 . The medicament of claim 7 or 8 , wherein the individual is a human and the PD-1 antagonist is
(a) a monoclonal antibody, or an antigen binding fragment thereof, which specifically binds to human PD-1 and blocks the binding of human PD-L1 to human PD-1; or
(b) a monoclonal antibody, or an antigen binding fragment thereof, which specifically binds to human PD-L1 and blocks the binding of human PD-L1 to human PD-1.

10 . The medicament of any of claims 7 to 9 , wherein the PD-1 antagonist is an anti-PD-1 monoclonal antibody which comprises a heavy chain and a light chain, wherein the heavy and light chains comprise SEQ ID NO:21 and SEQ ID NO:22, respectively, or SEQ ID NO:23 and SEQ ID NO:24, respectively.

11 . The medicament of any of claims 7 to 10 , wherein the cancer is a solid tumor.

12 . The medicament of any of claims 7 to 11 , wherein the cancer is a Heme malignancy.

13 . The medicament of any of claims 10 to 12 , wherein the PD-1 antagonist is MK-3475 or nivolumab.

14 . The medicament of claim 13 , wherein the MK-3475 is formulated as a liquid medicament which comprises 25 mg/ml MK-3475, 7% (w/v) sucrose, 0.02% (w/v) polysorbate 80 in 10 mM histidine buffer pH 5.5 and the dinaciclib compound is formulated as a liquid medicament comprising 5 mg/mL of the compound of Formula I in a sterile, aqueous citrate buffered solution at pH 3.0 to 4.2.

15 . The medicament of claim 8 , wherein the dinaciclib compound is formulated as a liquid medicament comprising 5 mg/mL of the compound of Formula I in a sterile, aqueous citrate buffered solution at pH 3.0 to 4.2.

16 . A kit which comprises a first container, a second container and a package insert, wherein the first container comprises at least one dose of a medicament comprising an antagonist of a Programmed Death 1 protein (PD-1), the second container comprises at least one dose of a medicament comprising a dinaciclib compound, and the package insert comprises instructions for treating an individual for cancer using the medicaments, wherein the dinaciclib compound is the compound of Formula I

17 . The kit of claim 16 , wherein the instructions state that the medicaments are intended for use in treating an individual having a cancer that tests positive for PD-L1 expression by an immunohistochemical (IHC) assay.

18 . The kit of claim 16 or 17 , wherein the individual is a human and the PD-1 antagonist is
(a) a monoclonal antibody, or an antigen binding fragment thereof, which specifically binds to human PD-1 and blocks the binding of human PD-L1 to human PD-1; or
(b) a monoclonal antibody, or an antigen binding fragment thereof, which specifically binds to human PD-L1 and blocks the binding of human PD-L1 to human PD-1.

19 . The kit of any of claims 16 - 18 , wherein the PD-1 antagonist is MK-3475.

20 . The method, use or kit of any of claims 1 to 19 , wherein the cancer is bladder cancer, breast cancer, clear cell kidney cancer, head/neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, small-cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mc1-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL).

Assignees

• Merck Sharp & Dohme

Inventors

• Strack Peter Richard
• Booher Robert
• Sriram Venkataraman
• Phillips Joseph H

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title