Targeting tumor hypoxia with TH-302 and complementary chemotherapy (2008)

AACR Centennial Conference: Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA

A5 

The tumor microenvironment contains geographic regions that are well perfused (normal oxygen) and others that are poorly perfused (hypoxic). Acute (perfusion-limited) and chronic (diffusion-limited) hypoxia occur. Chronically hypoxic regions contain slowly proliferating quiescent cells that are resistant to chemotherapy and radiotherapy and are prone to mutation. Targeted treatments for hypoxic regions may improve outcomes. TH-302 is a hypoxia-activated prodrug comprised of a nitroimidazole hypoxic trigger conjugated to a cytotoxic moiety (bromo-isophosphoramide mustard; Br-IPM) and undergoes activation in severe (<1% O2) hypoxia. TH-302 is not activated by cytochrome P450s, DT diaphorase or moderate hypoxia. As designed, the prodrug TH-302 diffuses from the vasculature into the hypoxic regions. Upon activation there is also evidence that the released Br-IPM can diffuse from the hypoxic region within the tumor resulting in a bystander cytotoxic effect. As such, TH-302 may have single agent activity. However, combination therapy with a chemotherapeutic that known activity in well perfused regions of the tumor may complement the hypoxia targeting of TH-302. In vivo translational studies were designed to select effective combinations that complemented the activity and tolerance of standard chemotherapies. Complementary combinations of TH-302 with docetaxel or gemcitabine were evaluated in vivo in orthotopic and metastatic human tumor xenograft models. TH-302 demonstrated single agent activity, however, combination therapy was associated with complete responses and increased survival in orthotopic models of pancreatic cancer (MIAPaCa-2) and prostate cancer (PC-3) and in models of established bone (PC-3) and lung metastases (H460). Complementary combinations of TH-302 and 5FU, irinotecan, cisplatin, paclitaxel, or pemetrexed were also evaluated in human tumor xenografts. Combination therapy tumor growth inhibition was superior compared with TH-302 or chemotherapy alone. The dose and schedules from the translational studies were used to plan the clinical development of TH-302 as complementary chemotherapy in human subjects including accelerated titration schemes for Phase 1 monotherapy and multiple combinations in a complete Phase 1/2. Effective integration of translational preclinical studies with innovative trial designs allows for efficient assessment of multiple complementary regimens for multiple potential indications. TH-302 is an inactive prodrug with no intrinsic cytotoxicity or significant normal tissue activation. In Phase 1 trial, weekly doses of TH-302 monotherapy were escalated over 30-fold to 240 mg/m2 without any drug related grade 2 or greater toxicities. TH-302 will next be combined with standard chemotherapies to determine safety, tolerance and initial activity of combinations of TH-302 with docetaxel, gemcitabine, or pemetrexed. Evolving understanding of the geographic complexity of the tumor microenvironment suggests that rationally devised complementary combinations of anti-neoplastic agents may be necessary to improve treatment outcomes. Combination drug development is more complex and slower than single agent development. Translational studies in conjunction with innovative clinical trial designs allow for greater efficiency and more rapid development in the assessment of these combinations.