Combination therapy for cancer using bromodomain and extra-terminal (bet) protein inhibitors

Patent metadata

Field	Value
Publication number	US-2016279141-A1
Application number	US-201415034922-A
Country	US
Kind code	A1
Filing date	Nov 7, 2014
Priority date	Nov 8, 2013
Publication date	Sep 29, 2016
Grant date	—

Abstract

The present invention provides methods for treating cancer using combinations of bromodomain and extra-terminal (BET) protein inhibitors and certain chemotherapeutic drugs.

First claim

1 . A method of treating neoplasia comprising:
administering to a subject in need thereof JQ1 and/or its analog in combination with a kinase inhibitor selected from the group consisting of MK2206, dasatinib, AZD6244, crizotinib, CYT387, Lapatinib, flavopiridol, y-27632, erlotinib, Afatinib, Axitinib, Bosutinib, cetuximab, Fostamatinib, Gefitinib, Imatinib, Lapatinib, Lenvatinib, Mubritinib, Nilotinib, Panitumumab, Pazopanib, Ruxolitinib, Sorafenib, Sunitinib, Trastuzumab, Vandetanib, and Vemurafenib in an amount effective to treat the neoplasia.

2 . The method of claim 1 , wherein the kinase inhibitor is selected from the group consisting of crizotinib, CYT387, Lapatinib, and flavopiridol.

3 . The method of any one of claims 1 - 2 , wherein JQ1 and/or its analog is administered separately, sequentially or simultaneously with the kinase inhibitor.

4 . A method of treating neoplasia comprising:
administering to a subject in need thereof JQ1 and/or its analog in combination with an anti-apoptotic agent in an amount effective to treat the neoplasia.

5 . The method of claim 4 , wherein the anti-apoptotic agent is selected from the group consisting of ABT263, ABT199, ABT737, and obatoclax.

6 . The method of any one of claims 4 - 5 , wherein JQ1 and/or its analog is administered separately, sequentially or simultaneously with the anti-apoptotic agent.

7 . A method of treating neoplasia comprising:
administering to a subject in need thereof JQ1 and/or its analog in combination with an anti-neoplastic agent selected from the group consisting of vincristine, etoposide, 17-AAG, adrucil, velcade, SAHA, doxil, gemcitabine, AZD2281, DBZ, ifosfamide, revlimid, prednisone, rituximab, Bevacizumab, Pegaptanib, and Ranibizumab in an amount effective to treat the neoplasia.

8 . The method of claim 7 , wherein the anti-neoplastic agent is velcade or gemcitabine.

9 . The method of any one of claims 7 - 8 , wherein JQ1 and/or its analog is administered separately, sequentially or simultaneously with the anti-neoplastic agent.

10 . A method of treating neoplasia comprising:
administering to a subject in need thereof an effective amount of JQ1 and/or its analog in combination with temsirolimus or BEZ235, wherein temsirolimus or BEZ235 is administered at a dose where it alone has no anti-neoplastic effect.

11 . The method of claim 10 , wherein JQ1 and/or its analog is administered separately, sequentially or simultaneously with temsirolimus or BEZ235.

12 . The method of any one of the preceding claims, wherein the subject is a mammal.

13 . The method claim 12 , wherein the subject is a human patient.

14 . The method of any one of the preceding claims, wherein the subject has neoplasia selected from the group consisting of selected from the group consisting of lung cancer, lymphomas including diffuse large B-cell lymphoma and Burkitt's lymphoma, prostate cancer, basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain cancer, CNS cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectum cancer, connective tissue cancer, cancer of the digestive system, endometrial cancer, esophageal cancer, eye cancer, cancer of the head and neck, gastric cancer, intra-epithelial neoplasm, kidney cancer, larynx cancer, leukemia, liver cancer, lung cancer, hematologic neoplasias, melanoma, myeloma, neuroblastoma, oral cavity cancer, ovarian cancer, pancreatic cancer, retinoblastoma, rhabdomyosarcoma, rectal cancer, renal cancer, cancer of the respiratory system, sarcoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and cancers of the urinary system.

15 . The method of claim 14 , wherein the neoplasia is lung cancer.

16 . The method of claim 14 , wherein the neoplasia is diffuse large B-cell lymphoma.

17 . The method of claim 14 , wherein the neoplasia is Burkitt's lymphoma.

18 . The method of any one of the preceding claims, further comprising treating the subject with an additional anti-neoplasia therapy.

19 . The method of claim 18 , wherein the additional anti-neoplasia therapy is surgery, radiation therapy, chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, adjuvant therapy, immunotherapy or a combination thereof.

20 . The method of any one of the preceding claims, wherein the JQ1 and/or its analog is JQ1.

21 . A pharmaceutical composition comprising an effective amount of
(a) JQ1 or an analog thereof, and (b) a kinase inhibitor selected from the group consisting of MK2206, dasatinib, AZD6244, crizotinib, CYT387, Lapatinib, flavopiridol, y-27632, erlotinib, Afatinib, Axitinib, Bosutinib, cetuximab, Fostamatinib, Gefitinib, Imatinib, Lapatinib, Lenvatinib, Mubritinib, Nilotinib, Panitumumab, Pazopanib, Ruxolitinib, Sorafenib, Sunitinib, Trastuzumab, Vandetanib, and Vemurafenib.

22 . A kit comprising a package containing
(a) a container containing JQ1 or an analog thereof, and (b) a container containing a kinase inhibitor selected from the group consisting of MK2206, dasatinib, AZD6244, crizotinib, CYT387, Lapatinib, flavopiridol, y-27632, erlotinib, Afatinib, Axitinib, Bosutinib, cetuximab, Fostamatinib, Gefitinib, Imatinib, Lapatinib, Lenvatinib, Mubritinib, Nilotinib, Panitumumab, Pazopanib, Ruxolitinib, Sorafenib, Sunitinib, Trastuzumab, Vandetanib, and Vemurafenib.

Assignees

• Dana Farber Cancer Inst Inc
• Dana Farber Cancer Inst Inc

Inventors

• Bradner James E
• Mckeown Michael R
• Shipp Margaret A
• Chapuy Bjoern
• Wong Kwok-Kin
• Chen Zhao

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61K31/453

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/551 Primary

  having two nitrogen atoms, e.g. dilazep · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title