Combination of immunotherapies with mdm2 inhibitors

Patent metadata

Field	Value
Publication number	US-2025195473-A1
Application number	US-202519063313-A
Country	US
Kind code	A1
Filing date	Feb 26, 2025
Priority date	Aug 8, 2018
Publication date	Jun 19, 2025
Grant date	—

Abstract

The present invention relates to single therapy comprising an effective amount of a MDM2 inhibitor, as well as combination therapies comprising an effective amount of a modulator of the immune checkpoint molecule; and an effective amount of a MDM2 inhibitor, wherein the MDM2 inhibitor is represented by the following formula or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1 . A method of treating cancer, comprising administering to a subject in need thereof:
a) an effective amount of a modulator of an immune checkpoint molecule; and b) an effective amount of a MDM2 inhibitor, wherein the MDM2 inhibitor is represented by the following formula:

or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of

B is a C 4-7 carbocyclic ring;
R 1 is H, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR a , or NR a R b ;
n is 0, 1, or 2;
R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10 , independently, are selected from the group consisting of H, F, Cl, CH 3 , and CF 3 ;
R 6 is

R a is hydrogen or substituted or unsubstituted C 1-4 alkyl;
R b is hydrogen or substituted or unsubstituted C 1-4 alkyl;
R c and R d are substituents on one carbon atom of ring B, wherein
R c is H, C 1-3 alkyl, C 1-3 alkylene-OR a , OR a , or halo;
R d is H, C 1-3 alkyl, C 1-3 alkylene-OR a , OR a , or halo; or
R c and R d are taken together with the carbon to which they are attached to form a 4 to 6-membered Spiro substituent, optionally containing an oxygen atom; and
R e is —C(═O)OR a , —C(═O)NR a R b , or —C(═O)NHSO 2 CH 3 .

2 . The method of claim 1 , wherein the MDM2 inhibitor is selected from:

or a pharmaceutically acceptable salt thereof.

3 . The method of claim 1 , wherein the MDM2 inhibitor is

or a pharmaceutically acceptable salt thereof.

4 . The method of claim 1 , wherein the immune checkpoint molecule is PD-1, PD-L1 or CTLA-4.

5 . The method of claim 1 , wherein the modulator of the immune checkpoint molecule is toripalimab, pembrolizumab, ipilimumab, nivolumab, atezolizumab, avelumab or durvalumab.

6 . The method of claim 1 , wherein the effective amount of a MDM2 inhibitor is from about 1 mg to about 300 mg.

7 . The method of claim 1 , wherein the cancer is selected from the group consisting of adrenal cortical cancer, biliary tract cancer, advanced cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, brain/CNS tumors in adults, brain/CNS tumors in children, breast cancer, breast cancer in men, cancer in children, cancer of unknown primary, Castleman disease, cervical cancer, colon/rectum cancer, endometrial cancer, esophagus cancer, Ewing family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, head and neck cancer, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia-acute lymphocytic (ALL) in adults, leukemia-acute myeloid (AML), leukemia-chronic lymphocytic (CLL), leukemia-chronic myeloid (CML), leukemia-chronic myelomonocytic (CMML), leukemia in children, lung cancer-non-small cell, lung cancer-small cell, lung carcinoid tumor, lymphoma of the skin, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-Hodgkin lymphoma in children, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma-adult soft tissue cancer, skin cancer-basal and squamous cell, skin cancer-melanoma, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, Merkel cell carcinoma, urothelial carcinoma, Solid tumors that are microsatellite instability-high or mismatch repair-deficient, sarcoma, colon cancer, choriocarcinoma, acute myeloid leukemia, lymphoma, leukemia Wilms Tumor, melanoma, Hodgkin lymphoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, Merkel cell carcinoma, urothelial carcinoma, solid tumors that are microsatellite instability-high or mismatch repair-deficient, sarcoma, colon cancer, prostate cancer, choriocarcinoma, breast cancer, retinoblastoma, stomach carcinoma, acute myeloid leukemia, lymphoma, multiple myeloma, and leukemia.

8 . The method of claim 1 , wherein the MDM2 inhibitor is administered orally in an amount from about 30 mg to about 250 mg every other day, or about 50 mg to about 200 mg every other day.

9 . The method of claim 1 , wherein the MDM2 inhibitor is

or pharmaceutically acceptable salt thereof.

10 . The method of claim 9 , wherein the immune checkpoint molecule is PD-1.

11 . The method of claim 1 , wherein the MDM2 inhibitor is administered orally in the patient in an amount from about 50 mg to about 200 mg on day 1, 3, 5, 7, 9, 11, and 13 of the 21-day treatment cycle, optionally the modulator of an immune checkpoint molecule is administered via intravenous infusion in an amount of 100 mg to 300 mg on day 1 of the 21-day treatment cycle.

12 . The method of claim 1 , wherein the patient is suffering from advanced solid tumors.

13 . A method for treating hyper-progression in a patient receiving anti-PD-1/PD-L1 therapy for the treatment of cancer, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a MDM2 inhibitor, wherein the MDM2 inhibitor is

or a pharmaceutically acceptable salt thereof.

14 . A method of treating cancer, comprising administering to a subject in need thereof an effective amount of a MDM2 inhibitor, wherein the MDM2 inhibitor is represented by the following formula:

or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of

B is a C 4-7 carbocyclic ring;
R 1 is H, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR a , or NR a R b ;
n is 0, 1, or 2;
R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10 , independently, are selected from the group consisting of H, F, Cl, CH 3 , and CF 3 ;
R 6 is

Assignees

• Ascentage Pharma Suzhou Co Ltd

Inventors

• Yang Dajun
• Zhai Yifan
• Fang Douglas Dong
• Tang Qiuqiong

Classifications

• A61K39/395

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

• C07K16/2818

  against CD28 or CD152 · CPC title

• A61K31/407 Primary

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title