Combination Therapy Using a Chemokine Receptor 2 (CCR2) Antagonist and a PD-1 and/or PD-L1 Inhibitor
The present disclosure is drawn to the combination therapy of a Chemokine Receptor 2 (CCR2) antagonist and a PD-1 and/or PD-L1 inhibitor in the treatment of a central nervous system cancer.
1 . A method of treating a central nervous system cancer in a subject, comprising:
administering to a subject in need thereof, a therapeutically effective amount of an immune checkpoint inhibitor and a compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein
Ar is selected from the group consisting of substituted or unsubstituted C 6-10 aryl and substituted or unsubstituted 5- to 10-membered heteroaryl.
R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
Y 1 is selected from the group consisting of —CR 2a —, —N—, and —N + (O) − —;
Y 2 is selected from the group consisting of —CR 2b —, —N—, and —N + (O) − —;
Y 3 is selected from the group consisting of —CR 2c —, —N—, and —N + (O) − —;
R 2a , R 2b , and R 2c are each independently selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 3 , —O 2 R 3 , —C(O)NR 3 R 4 , —OR 3 , —OC(O)R 3 , —OC(O)NR 3 R 4 , —SR 3 , —S(O)R 3 , —S(O) 2 R 3 , —S(O) 2 NR 3 R 4 , —NO 2 , —NR 3 NR 3 R 4 , —NR 3 C(O)R 4 , —NR 3 C(O)OR 4 , —NR 3 S(O) 2 R 4 , —NR 3 C(O)NR 4 R 5 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;
R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
R 3 and R 4 , R 4 and R 5 or R 3 and R 5 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;
Y 4 is selected from the group consisting of —N— and —N + (O) − —;
L is selected from the group consisting of a bond, —O—, —S—, —S(O)—, —S(O) 2 —, —CR 6 R 7 , —NR 8 —, —C(O)—, —C(O)NR 8 —, and —NR 8 C(O)—;
R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, —CN, —OR 9 , —NR 10 R 11 , —S(O)R 9 , and —S(O) 2 R 9 ;
R 6 and R 7 may, together with the carbon atom to which they are attached, form substituted or unsubstituted C 3-8 cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclic ring;
R 9 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
R 10 and R 11 are each independently selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 2-8 alkenyl, and substituted or unsubstituted C 2-8 alkynyl;
R 10 and R 11 of NR 10 R 11 may, together with the nitrogen, form substituted or unsubstituted 3- to 10-membered heterocyclyl;
R 8 is selected from the group consisting of hydrogen, C(O)R 12 , S(O) 2 R 12 , CO 2 R 12 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl;
R 12 is selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;
Z 1 is selected from the group consisting of substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 3- to 10-membered heterocyclyl, and —NR 13 R 14 ;
R 13 and R 14 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted (C 1-4 alkyl)-(C 6-10 aryl), and substituted or unsubstituted (C 1-4 alkyl)-(5- to 10-membered heteroaryl);
R 13 and R 14 may, together with the nitrogen, form a substituted or unsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl.
2 . The method of claim 1 , wherein the compound is of formula (Ic), or a pharmaceutically acceptable salt thereof,
wherein Y 11 is —CH—, —N—, and —N + (O) − —.
3 . The method of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
4 . The method of claim 1 , wherein the immune checkpoint inhibitor is a monoclonal antibody.
5 . The method of claim 1 , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.
6 . The method of claim 1 , wherein the central nervous system cancer is glioma.
7 . The method of claim 1 , wherein the central nervous system cancer is glioblastoma.
8 . The method of claim 1 , wherein the central nervous system cancer is characterized as being CCR2 + .
9 . The method of claim 1 , wherein the administering of the compound of formula I, or a pharmaceutically acceptable salt thereof, promotes a decrease in CD45 hi /CD11b + /Ly6C hi cells in a tumor microenvironment and promotes an increase in CD45 hi /CD11b + /Ly6C hi cells in bone marrow.
10 . The method of claim 1 , wherein the administering to the patient of the immune checkpoint inhibitor and the compound of formula I or a pharmaceutically acceptable salt thereof promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject.
11 . The method of claim 10 , wherein the population of T-cells comprises a subpopulation of T-cells characterized as being CD45 + /CD3 + /CD4 + .
12 . The method of claim 10 , wherein the population of T-cells comprises a subpopulation of T-cells characterized as being CD45 + /CD3 + /CD8 + .
13 . The method of claim 10 , wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is provided as a pharmaceutical composition for oral administration.
14 . The method of claim 1 , wherein the effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is from 50 mg to 300 mg.
15 . A method of treating glioblastoma in a subject, comprising: administering to the subject in need thereof an effective amount of an immune checkpoint inhibitor and a compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
16 . The method of claim 15 , wherein the immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, biosimilars thereof, biobetters thereof, and bioequivalents thereof.
17 . The method of claim 15 , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody is selected from the group consisting of Nivolumab, Pembrolizumab, and Pidilizumab.
18 . The method of claim 15 , wherein the immune checkpoint inhibitor is a PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, CA-327, STI-1014, KY-1003, biosimilars thereof, biobetters thereof, and bioequivalents thereof.
19 . The method of claim 1 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor are administered concomitantly.
20 . The method of claim 1 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, and the PD-1 inhibitor and/or the PD-L1 inhibitor are administered in a combination formulation.
21 . The method of claim 1 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, and the PD-1 inhibitor and/or the PD-L1 inhibitor are administered sequentially.
22 . The method of claim 1 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered prior to administration of the PD-1 inhibitor and/or the PD-L1 inhibitor.
23 . The method of claim 1 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered after the administration of the PD-1 inhibitor and/or the PD-L1 inhibitor.
24 . The method of claim 1 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered orally and the PD-1 inhibitor and/or the PD-L1 inhibitor is administered intravenously.
25 . The method of claim 1 , wherein the subject is a human subject.
26 . A pharmaceutical combination for treating glioblastoma in a patient, comprising:
a PD-1 and/or PD-L1 inhibitor; and
a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein
Ar is selected from the group consisting of substituted or unsubstituted C 6-10 aryl and substituted or unsubstituted 5- to 10-membered heteroaryl.
R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
Y 1 is selected from the group consisting of —CR 2a —, —N—, and —N + (O) − —;
Y 2 is selected from the group consisting of —CR 2b —, —N—, and —N + (O) − —;
Y 3 is selected from the group consisting of —CR 2c —, —N—, and —N + (O) − —;
R 2a , R 2b , and R 2c are each independently selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 3 , —CO 2 R 3 , —C(O)NR 3 R 4 , —OR 3 , —OC(O)R 3 , —OC(O)NR 3 R 4 , —SR 3 , —S(O)R 3 , —S(O) 2 R 3 , —S(O) 2 NR 3 R 4 , —NO 2 , —NR 3 NR 3 R 4 , —NR 3 C(O)R 4 , —NR 3 C(O)OR 4 , —NR 3 S(O) 2 R 4 , —NR 3 C(O)NR 4 R 5 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;
R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
R 3 and R 4 , R 4 and R 5 or R 3 and R 5 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;
Y 4 is selected from the group consisting of —N— and —N + (O) − —;
L is selected from the group consisting of a bond, —O—, —S—, —S(O)—, —S(O) 2 —, —CR 6 R 7 —, —NR 8 , —C(O)—, —C(O)NR 8 —, and —NR 8 C(O)—;
R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, —CN, —OR 9 , —NR 10 R 11 , —S(O)R 9 , and —S(O) 2 R 9 ;
R 6 and R 7 may, together with the carbon atom to which they are attached, form substituted or unsubstituted C 3-8 cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclic ring;
R 9 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
R 10 and R 11 are each independently selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 2-8 alkenyl, and substituted or unsubstituted C 2-8 alkynyl;
R 10 and R 11 of —NR 10 R 11 may, together with the nitrogen, form substituted or unsubstituted 3- to 10-membered heterocyclyl;
R 8 is selected from the group consisting of hydrogen, C(O)R 12 , S(O) 2 R 12 , CO 2 R 12 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl;
R 12 is selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;
Z 1 is selected from the group consisting of substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 3- to 10-membered heterocyclyl, and —NR 13 R 14 ;
R 13 and R 14 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted (C 1-4 alkyl)-(C 6-10 aryl), and substituted or unsubstituted (C 1-4 alkyl)-(5- to 10-membered heteroaryl);
R 13 and R 14 may, together with the nitrogen, form a substituted or unsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl.
27 . The pharmaceutical combination of claim 26 , wherein the compound is selected from:
and pharmaceutically acceptable salts thereof.
28 . The pharmaceutical combination of claim 26 , wherein the compound of formula I is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
29 . The pharmaceutical combination of claim 26 , wherein the combination comprises a fixed dose combination or separate doses.
30 . The pharmaceutical combination of claim 26 , wherein the pharmaceutical composition is formulated for intravenous administration.