Threshold Pharmaceuticals, Inc., a biotechnology company, has achieved target enrollment of 620 patients with advanced soft tissue sarcoma in its pivotal phase III trial of TH-302, an investigational hypoxia-targeted drug. This enrollment triggers a milestone payment of $12.5 million from Merck KGaA, Darmstadt, Germany.

Threshold has a global license and co-development agreement with Merck for TH-302, which includes an option for Threshold to co-commercialize in the US.

"We are pleased to achieve this enrollment milestone in this pivotal trial of TH-302 for the treatment of patients with advanced soft tissue sarcoma," said Barry Selick, Ph.D., chief executive officer of Threshold. "We hope that TH-302 will ultimately be shown to be both safe and efficacious in this patient population for which there is an urgent unmet medical need."

Threshold is conducting this international, randomized, pivotal phase III trial in partnership with the Sarcoma Alliance for Research through Collaboration (SARC). The trial is enrolling patients with metastatic or locally advanced unresectable soft tissue sarcoma and is designed to evaluate the efficacy and safety of TH-302 in combination with doxorubicin, compared to doxorubicin alone.

Though Threshold will remain blinded to the data from its ongoing phase III trial, an Independent Data Monitoring Committee (IDMC), which monitors patient safety on an ongoing basis, will conduct an interim efficacy and safety analysis after 235 deaths are reported. The timing of the interim analysis, which is event-based and therefore dependent on the length of survival of patients, is currently projected to be conducted in mid-2014. The interim efficacy analysis is designed to allow for the early termination of the study based on achieving a pre-specified improvement in overall survival and the recommendation of the IDMC. If the IDMC recommends that the study continue as planned, Threshold will remain blinded to the data until the company conducts the primary analysis of overall survival after 434 deaths are reported. Unless the IDMC recommends that the study end early, top-line results of the primary efficacy analysis are currently projected to be reported in the first half of 2015.

Sarcomas are a group of aggressive cancers of connective tissues 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. An estimated 36,000 new cases of soft tissue sarcomas will be diagnosed in 2013 in the US and Europe.

TH-302 is an investigational hypoxia-targeted drug that is designed to be activated under tumor hypoxic conditions, a hallmark of many cancers. Areas of low oxygen levels (hypoxia) in solid tumors are due to insufficient blood supply as a result of aberrant vasculature. Similarly, the bone marrow of patients with hematological malignancies has also been shown, in some cases, to be severely hypoxic.

TH-302 is currently under evaluation in two phase III trials: one in combination with doxorubicin versus doxorubicin alone in patients with soft tissue sarcoma, and the other in combination with gemcitabine versus gemcitabine and placebo in patients with advanced pancreatic cancer (MAESTRO). Both phase III trials are being conducted under Special Protocol Agreements with the US Food and Drug Administration (FDA). The FDA and the European Commission have granted TH-302 Orphan Drug Designation for the treatment of soft tissue sarcoma and pancreatic cancer. TH-302 is also being investigated in hematological malignancies and in combination with other therapies in a variety of solid tumors.

Threshold is focused on the discovery and development of drugs targeting tumor hypoxia, the low oxygen condition found in microenvironments of most solid tumors as well as the bone marrows of some hematologic malignancies.