Conditions: Soft Tissue Sarcoma
Keywords: TH-302 Advanced Soft Tissue Sarcoma Doxorubicin Phase 1/2
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 107
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether TH-302 in combination with Doxorubicin is safe and effective in the treatment of Advanced Soft Tissue Sarcoma.

Detailed description:
A broad range of tumors have been shown to contain significant numbers of hypoxic cells and hypoxia has been shown to be associated with a poor prognosis and an increase in resistance to chemotherapy and radiotherapy (Brizel 1997, Vaupel 2007, Shannon 2003).

It is likely that an agent that could effectively target hypoxic regions in tumors would improve efficacy when combined with standard chemotherapy or radiotherapy. TH-302 is activated at lower oxygen concentrations than other bioreductive prodrugs (Duan 2008) and tirapazamine, a hypoxic cytotoxin that has been extensively studied in both preclinical and clinical studies. This should result in an improved therapeutic ratio (tumor vs normal tissue toxicity) as compared with other bioreductive agents. Because TH-302 is expected to be minimally toxic to aerobic cancer cells, optimal efficacy would be expected when TH-302 is combined with treatments that are most effective under aerobic conditions such as radiotherapy and cytotoxic chemotherapy. Preclinical data have shown at least additive efficacy when TH-302 is combined with chemotherapy. In order to minimize the risk of additive toxicity, TH-302 is not being evaluated in combination with alkylating agents. The study will enroll subjects with advanced soft tissue sarcoma. These tumors have evidence supporting the presence of hypoxia based on pO2 histography, F-MISO and gene expression profiling (Vaupel 2007, Francis 2007, Rajendran 2003).

Arms:
arm 1: 75 mg/m2 of Doxorubicin administered by bolus injection starting on Day 1 of a 21-day cycle.

Interventions: intervention 1: TH-302
Intervention descriptions: intervention 1: TH-302 will be administered by IV infusion over 30-60 minutes on Days 1 and 8 of a 21-day cycle.

Dose escalation dose levels:

Dose level -1 (if needed): 180 mg/m2 Starting dose: 240 mg/m2

Protocol document: