Threshold Pharmaceuticals, Inc. has initiated a clinical trial of TH-302 in combination with various chemotherapeutic agents in patients with advanced solid tumours. TH-302 is a proprietary Hypoxia-Activated Prodrug (HAP) that specifically targets tumour hypoxia.

"Targeting tumour hypoxia is an exciting area of cancer research, and may offer great promise to patients with a wide variety of cancers," said Dr. Jeffrey Infante, M.D., Sarah Cannon Research Institute, and a clinical investigator for the trial. "We are excited to continue investigations with TH-302 and about the potential benefit that it might confer to people living with cancer."

TH-302 is an anticancer agent discovered by Threshold. TH-302 is converted selectively to the drug's active form, dibromo isophosphoramide mustard, a potent DNA alkylator, within hypoxic tumour cells. TH-302 targets levels of hypoxia that are common in tumours but are rare in normal tissues - this is how selective targeting of the tumour occurs. After conversion to the active form of the drug, the more resistant hypoxic cells are exposed to high concentrations of released cytotoxic agent, which can also diffuse into the surrounding oxygenated regions of a tumour cell. TH-302 may be less likely to produce the systemic toxicity caused by most cytotoxic chemotherapies.

The clinical trial design will include three separate treatment arms that will each examine TH-302 in combination with one of the following chemotherapeutic agents: gemcitabine, docetaxel or pemetrexed. Approximately 54 patients with advanced solid tumours are planned to enrol in the Phase 1/2, open-label, dose-escalation portion of the clinical trial. The initial dose of TH-302 will be 240mg/m2 which is the highest dose with no study drug-related grade 2 or greater toxicity in the currently ongoing Phase 1 trial of TH-302. Up to six patients per dose level will participate in the dose escalation phase of the trial.

Once the maximum tolerated dose (MTD) has been reached, the phase 2 portion of the trial will enrol an additional 12 patients at the MTD within each treatment arm as follows: gemcitabine in advanced pancreatic cancer patients, docetaxel in patients with castrate-resistant prostrate cancer (CRPC) and pemetrexed in patients with non-small cell lung cancer.

TH-302 will be administered as a 30-minute intravenous infusion weekly for three weeks followed by one week off therapy in the gemcitabine arm, and weekly for two weeks followed by one week off therapy in the docetaxel and pemetrexed arms. Patients for whom no effective therapy is available or for whom monotherapy with one of the chemotherapy regimens is considered standard therapy, are eligible for the trial. Patients who successfully complete one treatment cycle without evidence of significant treatment-related toxicity or progressive disease will continue to receive treatment for up to six cycles (eight cycles for prostrate cancer).

The primary objectives of the study are to determine the MTD and dose-limiting toxicities of TH-302 when used in combination with gemcitabine or docetaxel or pemetrexed in patients with advanced solid tumours and to assess the safety of TH-302 in these combination regimens. The primary objective of the dose expansion phase of the trial is to make a preliminary assessment of the efficacy of TH-302 based on tumour response rate and progression-free survival. Secondary objectives include establishing the pharmacokinetics and making a preliminary assessment of efficacy based on serum tumour markers of TH-302 when used in combination with gemcitabine, docetaxel or pemetrexed.

Threshold is a biotechnology company focused on the discovery and development of small molecule therapeutics for the treatment of cancer. By selectively targeting abnormally-proliferating tumour cells, the Company's drug candidates are designed potentially to be more effective and less toxic to healthy tissues than conventional treatments.