ADMINISTRATION OF HYPOXIA ACTIVATED PRODRUGS AND ANTIANGIOGENIC AGENTS FOR THE TREATMENT OF CANCER
Administration of a hypoxia activated prodrug in combination with an antiangiogenic agent is useful for treating cancer.
1 . A method of treating a cancer patient in need of such treatment, said method comprising administering an antiangiogenic agent and administering a hypoxia activated prodrug to said patient.
2 . The method of claim 1 , wherein the first administration of the hypoxia activated prodrug occurs only after administration of the antiangiogenic agent has resulted in an increased hypoxic fraction of the cancer.
3 . The method of claim 2 , wherein the first administration of the hypoxia activated prodrug is at least 7 days after the first administration of the antiangiogenic agent.
4 . The method of claim 1 , wherein the hypoxia activated prodrug is selected from the group consisting of TH-281, TH-302, and TH-308.
5 . The method of claim 1 , wherein the antiangiogenic agent is selected from the group consisting of an anti-VEGF antibody, a VEGF-trap, an anti-VEGFR antibody, a VEGFR inhibitor, thalidomide, a DI 14-Notch inhibitor, an anti-tubulin vascular disrupting agent (VDA), an angiopoietin-Tie2 inhibitor, a nitric oxide synthase (NOS) inhibitor, a cationic poly amino acid dendrimer, rapamycin, everolimus, temserolimus, a low molecular weight heparin, a SPARC (osteonectin) peptide, bevacizumab, ranibizumab, ramucirumab, aflibercept, interleukin 17 (IL-17), DC101, sunitinib, sorafenib, pazopanib, AMG706, cediranib, vandetanib, vargatef, brivanib, XL-184, axitinib, tivozanib, thalidomide, lanalidomide, DMXAA, nadroparin, 2,5-dimethyl-celecoxib, cyclophosphamide, HBC, and tasquinimod.
6 . The method of claim 4 , wherein the antiangiogenic agent is selected from the group consisting of bevacizumab, pazopanib, sorafenib, and sunitinib.
7 . The method of claim 6 , wherein the antiangiogenic agent is bevacizumab, and the hypoxia activated prodrug is TH-302.
8 . The method of claim 7 , wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, glioblastoma, non-squamous non-small cell lung cancer, and renal cell carcinoma.
9 . The method of claim 6 , wherein the antiangiogenic agent is pazopanib, and the hypoxia activated prodrug is TH-302.
10 . The method of claim 9 , wherein the cancer is selected from the group consisting of pancreatic cancer, renal cell carcinoma, and sarcoma.
11 . The method of claim 6 , wherein the antiangiogenic agent is sorafenib, and the hypoxia activated prodrug is TH-302.
12 . The method of claim 11 , wherein the cancer is selected from the group consisting of hepatic cell carcinoma and renal cell carcinoma.
13 . The method of claim 6 , wherein the antiangiogenic agent is sunitinib, and the hypoxia activated prodrug is TH-302.
14 . The method of claim 13 , wherein the cancer is selected from the group consisting of gastrointestinal stromal tumor, renal cell carcinoma, and pancreatic neuroendocrine tumor.
15 . The method of claim 1 , wherein the hypoxic fraction of the cancer is measured prior to or after first administration of the antiangiogenic agent.