Study of Hypoxia-Activated Prodrug TH-302 to Treat Advanced Leukemias

Tumor hypoxia has been associated with resistance to chemotherapy and radiotherapy (Brown et al, 2004; Boyle 2006). TH-302, a hypoxia activated prodrug (HAP), exploits the hypoxic nature of tumors while having little or no effect on normal tissue. TH-302 belongs to a class of alkylating agents called oxazaphosphorines which have major experimental and clinical activity (Brock 1989). Since TH-302 is selectively targeted to the hypoxic microenvironment, this agent may represent an improvement over other agents in this class. Preclinical data support the hypothesis that TH-302 targets hypoxic regions of tumors and also is able to kill other tumor cells in normoxic regions as a result of cytotoxin diffusion, leading to significant effects on tumor growth. Preclinical data has shown that TH-302 has anti-tumor activity in multiple myeloma cells in vivo and in vitro. Additional preclinical data demonstrated the marked expansion of the hypoxic bone marrow areas in diseased mice with ALL. These results suggest that this agent may be useful in treating advanced leukemias. The drug is stable in plasma and liver, does not appear to be at risk for drug-drug interactions, and has mild, reversible toxicities. In this dose-escalation study, patients with advanced leukemias will receive infusions of TH-302 to determine the maximum tolerated dose.