Threshold Pharmaceuticals' Phase III Drills Down on Sarcoma
BioWorld Today Contributing Writer
Threshold Pharmaceuticals Inc. is wasting no time launching a Phase III randomized trial of its sarcoma drug, TH-302, following a successful end-of-Phase-II meeting with the FDA, resulting in a special protocol assessment.
The Redwood City, Calif.-based company will enroll 450 patients with metastatic or unresectable soft tissue sarcoma to receive TH-302 in combination with doxorubicin.
Threshold has contended that a combination of TH-302, a selective hypoxia-targeting prodrug, with doxorubicin will attack sarcoma by targeting both vascular components and hypoxic components of the tumor.
"We're addressing unmet medical need currently not addressed by any other therapeutic," Threshold Senior Vice President of Clinical Operations and Biostatistics Stewart Kroll told BioWorld Today.
The end-of-Phase-II meeting confirmed Threshold's clinical trial plan, with just a few tweaks and adjustments. The FDA approved of the company's choice of overall survival as an endpoint, requesting only the addition of some pharmacokinetic and biomarker studies to confirm the clinical endpoint.
"We weren't surprised when they agreed with our study plan," Kroll said. The company had chosen to pursue overall survival because they knew that was the most bulletproof endpoint for oncology studies and that the current FDA favors it heavily.
The trial will enroll 450 patients at clinical sites in the U.S. and overseas. It will be an open-label, randomized study comparing a regimen of TH-302 plus doxorubicin with doxorubicin alone. An independent data monitoring committee will carry out an interim futility analysis based on progression-free survival halfway through enrollment. Another interim analysis based on overall survival is planned for the end of enrollment. Enrollment is expected to be complete by the end of 2013.
The Phase III sarcoma trial isn't the only iron that Threshold has in the fire. The company has launched a number of clinical trials recently, due to having achieved positive early results with a number of indications and drug combinations.
In June, it completed patient enrollment in its Phase II study in pancreatic cancer in combination with gemcitabine in patients with first-line disease with a primary endpoint of progression-free survival. It also began a Phase I/II trial of TH-302 plus Sutent (sunitinib, Pfizer Inc.) for patients with advanced renal cell carcinoma, gastrointestinal stromal tumors or pancreatic neuroendocrine tumors.
July saw the initiation of a small trial of TH-302 in combination with Avastin (bevacizumab, Roche AG) for recurrent high-grade astrocytoma, including glioblastoma. The study design calls for 28 patients whose disease has progressed after combined modality treatment with radiation and temozolomide chemotherapy, as well as therapy with Avastin. It will have a primary endpoint of progression-free survival.
Threshold said that there have been no new approved agents in first-line soft tissue sarcoma in the last 20 years, except for imatinib mesylate. Sarcomas affect connective tissue and are usually treated with surgery, chemotherapy and radiation, with doxorubicin and ifosfamide being the favored agents.
In a previous Phase I/II trial in soft tissue sarcoma in 60 patients, there was one complete response (2 percent), 18 partial responses (30 percent) and 32 stable disease (53 percent). Patients had a median progression-free survival of 6.4 months and median overall survival was 16.1 months.
Threshold would like to confirm those results with its Phase III trial. It is running the trial in combination with the Sarcoma Alliance for Research through Collaboration. Kroll said that SARC is providing support through its clinical trial expertise.
Threshold's focus on tumor hypoxia is based on the theory that the disordered vasculature within a tumor results in hypoxic microenvironments, which contain cells that are inaccessible to typical cancer therapeutics. Those cells can be resistant to treatment and may also accumulate genetic errors at a faster rate than other tumor cells. TH-302 is designed to target hypoxic cells.
Published: October 3, 2011
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