REDWOOD CITY, Calif., Aug. 12, 2008 (PRIME NEWSWIRE) -- Threshold Pharmaceuticals, Inc. (Nasdaq:THLD), today announced that it has initiated a clinical trial of TH-302 in combination with various chemotherapeutic agents in patients with advanced solid tumors. TH-302 is a proprietary Hypoxia-Activated Prodrug (HAP) that specifically targets tumor hypoxia.
"Targeting tumor 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."
Clinical Trial Design
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 tumors are planned to enroll 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 enroll 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 tumors 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 tumor response rate and progression-free survival. Secondary objectives include establishing the pharmacokinetics and making a preliminary assessment of efficacy based on serum tumor markers of TH-302 when used in combination with gemcitabine, docetaxel or pemetrexed.
Clinical Rationale
In cancer, as a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. This condition is called Tumor Hypoxia. Several studies have shown that higher levels of tumor hypoxia correlate with poor treatment outcomes for a variety of solid tumors. It is believed that hypoxia may severely limit the curability of tumors. This lack of oxygen in cancer cells compared to normal cells is exploited by Threshold's Hypoxia-Activated Prodrug (HAP) platform. TH-302 may provide an opportunity to treat slowly dividing tumor cells within hypoxic regions that generally evade traditional chemotherapeutic agents and ultimately contribute to relapse. In preclinical models, TH-302 demonstrated single agent activity, however, combination therapy was associated with higher complete response rates, longer survival and greater tumor growth inhibition in multiple preclinical models utilizing various tumor types and tumor implantation methods.
About TH-302
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 tumor cells. TH-302 targets levels of hypoxia that are common in tumors but are rare in normal tissues -- this is how selective targeting of the tumor 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 tumor cell. TH-302 may be less likely to produce the systemic toxicity caused by most cytotoxic chemotherapies.
About Threshold Pharmaceuticals
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 tumor cells, the Company's drug candidates are designed potentially to be more effective and less toxic to healthy tissues than conventional treatments. For additional information, please visit our website (www.thresholdpharm.com).
Forward-Looking Statements
Except for statements of historical fact, the statements in this press release are forward-looking statements, including statements regarding Threshold's product candidates, clinical trial plans, and potential therapeutic uses and benefits of our product candidates. These statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. Potential risks and uncertainties include, but are not limited to, Threshold's ability to commence, enroll or complete its anticipated clinical trials, the time and expense required to conduct such clinical trials and analyze data, issues arising in the regulatory or manufacturing process and the results of such clinical trials (including product safety issues and efficacy results). Further information regarding these and other risks is included under the heading "Risk Factors" in Threshold's Quarterly Report on Form 10-Q, which was filed with the Securities Exchange Commission on August 7, 2008 and is available from the SEC's website (www.sec.gov) and on our website (www.thresholdpharm.com) under the heading "Investors." We do not intend to update any forward-looking statement made in this news release.