ADMINISTRATION OF HYPOXIA ACTIVATED PRODRUGS IN COMBINATION WITH IMMUNE MODULATORY AGENTS FOR TREATING CANCER
Cancer can be treated by administration of TH-302 in combination with an immunomodulator.
1 . A method of treating cancer, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a hypoxia-activated prodrug (HAP) in combination with a therapeutically effective amount of an immunomodulator selected from inhibitors of PD-1, PD-L1, PD-L2, and agonists of 4-1BB.
2 . A method of treating cancer, comprising the steps of: (i) identifying patients with cancer who are or would be unresponsive to immunotherapy alone; and (ii) administering a therapeutically effective amount of a hypoxia-activated prodrug (HAP) in combination with a therapeutically effective amount of an immunomodulator selected from inhibitors of PD-1, PD-L1, PD-L2, and agonists of 4-1BB only to patients who are identified as who are or would be unresponsive to immunotherapy alone.
3 . The method of claim 1 , wherein said patient is human.
4 . The method of claim 3 , wherein said compound is TH-302.
5 . The method of claim 1 , wherein said immunomodulator is selected from the group consisting of an immunoadhesin, a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, a PD-L2 antibody, and a 4-1BB antibody.
6 . The method of claim 5 , wherein said immunomodulator is selected from the group consisting of AMP-224, YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, MDX-1105, pidilizumab, AMP 514, tremelimumab, ipilimumab, pembrolizumab, and nivolumab.
7 . The method of claim 6 , wherein said immunomodulator is ipilimumab.
8 . The method of claim 6 , wherein said immunomodulator is pembrolizumab.
9 . The method of claim 6 , wherein said immunomodulator is nivolumab.
10 . The method of claim 4 , wherein the TH-302 is administered in a dose of less than about 320 mg/m 2 .
11 . The method of claim 4 , wherein the TH-302 is administered for one or more dosage cycles, each cycle comprising an infusion of TH-302 in the range of about 320 mg/m 2 or 400 mg/m 2 to about 480 mg/m 2 .
12 . The method of claim 10 , wherein the TH-302 is administered over an infusion period of about 1 to about 6 hours.
13 . The method of claim 12 , wherein the TH-302 is administered once on days 1, 8, 29 and 36 of a 5 week cycle.
14 . The method of claim 13 , wherein the immunomodulator is ipilimumab and administered for one or more dosage cycles, each cycle comprising an infusion of ipilimumab in a unit dose of about 3 mg/kg over an infusion period of about 1 to 2 hours once every three weeks of a 12 week cycle.
15 . The method of claim 3 , wherein the immunomodulator is administered on a different day than the administration of TH-302.
16 . The method of claim 14 , wherein the immunomodulator is administered on the same day as the administration of TH-302.
17 . The method of claim 16 , wherein the TH-302 is administered prior to the administration of the immunomodulator if administered on the same day.
18 . The method of claim 16 , wherein the TH-302 is administered after the administration of the immunomodulator if administered on the same day.
19 . A pharmaceutical combination comprising: a) a dose of TH-302, formulated for infusion in the range of less than about 320 mg/m 2 ; and b) a dose of an immunomodulator selected from inhibitors of PD-1, PD-L1, PD-L2, and agonists of 4-1BB.
20 . A pharmaceutical combination comprising: a) a dose of TH-302, formulated for infusion in the range of about 320 mg/m 2 to about 480 mg/m 2 ; and b) a dose of ipilimumab formulated for infusion of about 3 mg/kg.
21 . The pharmaceutical combination of claim 19 , packaged together.
22 . The method of claim 1 , wherein the cancer is selected from the group consisting of prostate cancer, pancreatic cancer, melanoma and head and neck cancer.
23 . The method of claim 22 , wherein the head and neck cancer is Human Papillomavirus (HPV) negative head and neck cancer.
24 . The pharmaceutical combination of claim 19 , in a packaged form, wherein the packaged pharmaceutical combination includes instructions for use of the combination in treating a cancer selected from the group consisting of prostate cancer, pancreatic cancer, melanoma and head and neck cancer.
25 . The pharmaceutical combination of claim 19 , wherein said immunomodulator is selected from the group consisting of an immunoadhesin, a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, a PD-L2 antibody, and a 4-1BB antibody.
26 . The pharmaceutical combination of claim 25 , wherein said immunomodulator is selected from the group consisting of AMP-224, YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, MDX-1105, pidilizumab, AMP 514, tremelimumab, ipilimumab, pembrolizumab, and nivolumab.