Treatment of cancer using hypoxia activated prodrugs

Abstract

Cancer can be treated by administration of a hypoxia-activated prodrug, such as TH-302, alone or in combination with other anticancer agents and/or radiation therapy. In combination therapy, the hypoxia-activated prodrug and another anticancer agent or radiation therapy may be administered within the same 24-hour period, and administration of the hypoxia-activated prodrug may be completed prior to beginning administration of the other anticancer agent or radiation therapy.

1 .- 8 . (canceled) 
     
     
         9 . A method of treating cancer comprising administering a therapeutically effective dose of TH-302 and a therapeutically effective dose of an anticancer drug that is not a hypoxia activated prodrug to a patient in need of cancer therapy, wherein
 (a) the patient is in need of treatment for NSCLC, prostate cancer, neuroendocrine cancer, anal cancer, urachal cancer, urethral cancer, breast cancer, melanoma, or renal cell carcinoma and the anticancer drug that is not a hypoxia activated prodrug is docetaxel; or   (b) the patient is in need of treatment for bile duct cancer, ovarian cancer, esophageal cancer, NSCLC, ampullary cancer, neuroendocrine cancer, soft tissue sarcoma, or thyroid cancer and the anticancer drug that is not a hypoxia activated prodrug is gemcitabine; or   (c) the patient is in need of treatment for esophageal cancer, pancreatic cancer, NSCLC, neuroendocrine cancer, soft tissue sarcoma, colorectal cancer, hepatocellular carcinoma (HCC), renal cancer, or parotid cancer and the anticancer drug that is not a hypoxia activated prodrug is pemetrexed.   
     
     
         10 . A method of treating cancer comprising administering TH-302 as a single agent, wherein said TH-302 is administered intravenously in an amount in the range of 200 mg/m 2  to 700 mg/m 2  to a patient in need of cancer therapy. 
     
     
         11 . The method of  claim 10  wherein the cancer is a small cell lung cancer. 
     
     
         12 . The method of  claim 10  wherein the cancer is melanoma. 
     
     
         13 .- 14 . (canceled) 
     
     
         15 . A method of treating cancer, said method comprising administering to a patient in need of cancer therapy two anticancer drugs, one a hypoxia activated prodrug (HAP) and the other an anticancer drug that is not a HAP (non-HAP), wherein both drugs are administered within a 24 hour period, the HAP is administered first, and administration of the non-HAP is commenced at least about 30 minutes and no more than 8 hours after administration of the HAP is stopped. 
     
     
         16 . The method of  claim 15 , wherein the non-HAP is administered at least about 2 hours and no more than 4 hours after administration of the HAP is stopped. 
     
     
         17 . The method of  claim 15 , wherein the HAP is selected from TH-302, TH-281, PR104 and AQ4N. 
     
     
         18 . The method of  claim 15 , wherein the non-HAP is selected from the group consisting of doxorubicin, gemcitabine, pemetrexed, a platinum-containing drug, and a taxane. 
     
     
         19 . A pharmaceutical formulation comprising TH-302 as an active ingredient in an amount of about 50 mg/ml to about 300 mg/ml, a nonionic surfactant in an amount effective to act as a stabilizer, and an alcohol as a carrier. 
     
     
         20 .- 22 . (canceled) 
     
     
         23 . The pharmaceutical formulation according to  claim 19 , further comprising at least one amide carrier.