Combination therapies for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-2017182003-A1
Application number	US-201515312980-A
Country	US
Kind code	A1
Filing date	May 21, 2015
Priority date	May 23, 2014
Publication date	Jun 29, 2017
Grant date	—

Abstract

The present invention provides methods and compositions for treating cancer by administering an EP4 antagonist in combination with radiation therapy, antibody therapy and/or anti-metabolite chemotherapy.

First claim

1 . A method of treating cancer in a subject in need thereof comprising administering to said subject in a treatment-effective amount an EP4 antagonist in combination with radiation therapy.

2 . (canceled)

3 . The method of claim 1 , wherein said treating comprises an abscopal effect.

4 - 5 . (canceled)

6 . The method of claim 1 , wherein the EP4 antagonist is a compound of Formula (I):

wherein:
one of R 1a and R 1b is hydrogen, and the other is methyl; or R 1a and R 1b are taken together to form a cyclopropyl ring;
R 2 is methyl or fluoromethyl;
R 3 is methyl;
R 4 is hydrogen, halo, methyl, fluoromethyl, methoxy, or fluoromethoxy;
R 5 is hydrogen, halo, methyl, fluoromethyl, methoxy, or fluoromethoxy;
R 6 is hydrogen, halo, methyl, or methoxy;
R 7 is hydrogen, halo, methyl, or methoxy; and
X is oxygen;

or a pharmaceutically acceptable salt thereof.

7 . The method of claim 6 , wherein said compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8 . The method of claim 6 , wherein said compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.

9 . The method of claim 1 , wherein the cancer is selected from the group consisting of: breast cancers, cervical cancers, colorectal cancers, endometrial cancers, glioblastomas, head and neck cancers, kidney cancers, liver cancers, lung cancers, medulloblastomas, ovarian cancers, pancreatic cancers prostate cancers, skin cancers (e.g., melanoma) and urinary tract cancers.

10 . The method of claim 1 , wherein the cancer is metastatic cancer.

11 . A method of generating a memory immune response against a cancer in a subject in need thereof comprising administering to said subject in a treatment-effective amount an EP4 antagonist in combination with radiation therapy.

12 . (canceled)

13 . The method of claim 11 , wherein said generating the memory immune response comprises an abscopal effect.

14 - 15 . (canceled)

16 . The method of claim 11 , wherein the EP4 antagonist is a compound of Formula (I):

wherein:
one of R 1a and R 1b is hydrogen, and the other is methyl; or R 1a and R 1b are taken together to form a cyclopropyl ring;
R 2 is methyl or fluoromethyl;
R 3 is methyl;
R 4 is hydrogen, halo, methyl, fluoromethyl, methoxy, or fluoromethoxy;
R 5 is hydrogen, halo, methyl, fluoromethyl, methoxy, or fluoromethoxy;
R 6 is hydrogen, halo, methyl, or methoxy;
R 7 is hydrogen, halo, methyl, or methoxy; and
X is oxygen;

or a pharmaceutically acceptable salt thereof.

17 . The method of claim 16 , wherein said compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

18 . The method of claim 16 , wherein said compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.

19 . The method of claim 11 , wherein the cancer is selected from the group consisting of breast cancers, cervical cancers, colorectal cancers, endometrial cancers, glioblastomas, head and neck cancers, kidney cancers, liver cancers, lung cancers, medulloblastomas, ovarian cancers, pancreatic cancers prostate cancers, skin cancers (e.g., melanoma) and urinary tract cancers.

20 . The method of claim 11 , wherein the cancer is metastatic cancer.

21 . The method of claim 11 , wherein the memory immune response comprises epitope spreading.

22 . The method of claim 1 , wherein the method further comprises administering an anti-metabolite chemotherapy in combination with the EP4 antagonist and radiation therapy.

23 . The method of claim 22 , wherein the anti-metabolite is a deoxynucleoside analog.

24 . (canceled)

25 . The method of claim 23 , wherein the deoxynucleoside analog is capecitabine.

26 . A method of treating cancer in a subject in need thereof comprising administering to said subject in a treatment-effective amount an EP4 antagonist in combination with an anti-metabolite chemotherapy.

27 . The method of claim 26 , wherein the anti-metabolite is a deoxynucleoside analog.

28 - 29 . (canceled)

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Bao Xingfeng
• Albu Diana
• Woodall-Jappe Mary

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• C07K16/2827

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

• A61K2039/505

  comprising antibodies · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title