Threshold Pharmaceuticals, Inc. announced that Threshold, in collaboration with Sarcoma Alliance for Research through Collaboration (SARC), have initiated a phase III randomized clinical trial of TH-302 in patients with soft tissue sarcoma. This international pivotal trial will enroll patients with metastatic or locally advanced unresectable soft tissue sarcoma who have not previously received chemotherapy outside the adjuvant or neoadjuvant setting. The trial is designed to evaluate the efficacy and safety of TH-302 in combination with doxorubicin, compared to doxorubicin alone.

Following an end of phase II meeting with the FDA, the phase III protocol has been agreed upon under a Special Protocol Assessment (SPA). As part of that assessment, the FDA agreed that the design and planned analysis of the study adequately addresses the objectives necessary to support a regulatory submission for approval with enrollment expected to be completed by the end of 2013.

“Combining TH-302, a selective hypoxia-targeting prodrug, with doxorubicin, an agent with known activity in sarcoma, has a strong scientific rationale. TH-302 represents a novel concept in anti-cancer treatment. It was designed to deliver a cytotoxic agent to areas of a tumour that are often inaccessible to standard chemotherapies. We therefore expect that doxorubicin and TH-302 will complement one another by targeting the vascular components and hypoxic components, respectively, of a patient's sarcoma,” said William D Tap, MD, Section Chief of Sarcoma Oncology at Memorial Sloan-Kettering Institute and principal investigator for this trial. “I'm excited to be a part of this collaboration between SARC and Threshold and I am looking forward to participating in this pivotal phase III trial with the hope of establishing TH-302 as a new treatment for patients with sarcoma.”

“The proposed study is designed to confirm the encouraging results that we have previously reported in the phase I/II study of soft tissue sarcoma patients treated with TH-302 in combination with doxorubicin,” said Sant P Chawla, MD, Sarcoma Oncology Centre and principal investigator for the initial phase I/II study. “The treatment of soft tissue sarcoma is a therapeutic challenge. Besides the approval of imatinib mesylate which was limited to gastrointestinal stromal tumours, there have been no new approved agents in first-line soft tissue sarcoma over the last 20 years. We look forward to working with Threshold and SARC.”

TH-302 has been tested in over 550 patients with cancer including over 100 patients to date treated in a phase I/II trial in patients with soft tissue sarcoma. As presented at the American Society of Clinical Oncology meeting in June 2011, 60 patients from the phase II component of the study had at least one evaluable post-treatment tumour assessment. There was one complete response (2%), 18 partial responses (30%) and 32 stable disease (53%). Median progression free survival was 6.4 months (95% confidence interval: 5.6 to 8.1 months). Median overall survival was 16.1 months (95% CI: 10.4 months to upper limit not yet reached). Just under half (47%) of patients continued to receive TH-302 alone after completing the full doxorubicin regimen of 6 cycles. Myelosuppression was dose limiting with 15 per cent grade 4 neutropenia and 13% grade 4 thrombocytopenia. Collectively, these data contribute to the rationale for initiating the registration study.

The phase III trial will be a 450 patient, randomized, open-label, multi-centre trial comparing two treatment regimens for patients with metastatic and/or advanced unresectable soft tissue sarcoma who have not received prior systemic therapy. This trial is designed to demonstrate the clinical benefit of TH-302 in combination with doxorubicin compared to doxorubicin alone based on a primary efficacy endpoint of overall survival. The trial includes an interim futility analysis based on progression-free survival expected to occur about half-way into enrollment and an interim analysis based on overall survival expected to occur at the end of enrollment. Both interim analyses will be conducted by an independent data monitoring committee. Patients will be randomized to receive TH-302 (300 mg/m2 on days 1 and 8 of a 21 day cycle) in combination with doxorubicin (75 mg/m2 on day 1 of the 21 day cycle) or doxorubicin alone.

Sarcomas are a group of aggressive cancers of connective tissue of the body for which there are currently limited treatment options. Soft tissue sarcomas are treated with surgery, chemotherapy and radiation. Usually a combination of these modalities offers the best chance to treat the disease successfully. Doxorubicin and ifosfamide are the most commonly used chemotherapeutic agents in patients with advanced soft tissue sarcoma, but response rates are generally low and toxicity can be significant. The American Cancer Society estimates that 10,520 people were diagnosed with a soft tissue sarcoma in the United States in 2010, and approximately 3,920 people died from the disease.

A Special Protocol Assessment is a written agreement with the FDA on the design and planned analysis for a clinical trial. It is intended to form the basis for a marketing application and may only be changed through a written agreement between the sponsor and the FDA, or if the FDA becomes aware of new public health concerns.

Threshold is a biotechnology company focused on the discovery and development of drugs targeting Tumour Hypoxia, the low oxygen condition found in microenvironments of most tumours.

SARC is a not for profit consortium representing physician clinician/scientists who have common interest in developing new and effective treatments for patients diagnosed with sarcoma.