Threshold Pharmaceuticals, announced that the US Food and Drug Administration (US FDA) granted Fast Track designation for TH-302, an investigational anticancer drug, for the treatment of previously untreated patients with metastatic or locally advanced unresectable soft tissue sarcoma (STS).

The FDA established the Fast Track designation process to facilitate the development and expedite the review of drugs intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. An important feature of Fast Track is that the FDA may consider a "rolling review" of completed sections of the New Drug Application (NDA) before the complete application is submitted.

"We are pleased that FDA has granted Fast Track status for TH-302 for the treatment of previously untreated patients with metastatic or locally advanced unresectable soft tissue sarcoma," said Barry Selick, Ph.D., chief executive officer of Threshold. "Our ongoing phase 3 trial of TH-302 in these patients is being conducted under a Special Protocol Assessment with the FDA. If successful, the Fast Track designation may provide an added benefit of facilitating the NDA review process. Currently, we anticipate the primary analysis of overall survival of the phase 3 trial to be conducted in the first quarter of 2016.

Threshold is conducting this international, randomised pivotal phase 3 clinical trial in partnership with the Sarcoma Alliance for Research through Collaboration (SARC) and under a Special Protocol Assessment (SPA) agreement with the US FDA. The trial is designed to investigate the efficacy and safety of TH-302 in combination with doxorubicin, compared with doxorubicin alone, in previously untreated patients with metastatic or locally advanced unresectable STS. The primary endpoint of the trial is overall survival. Secondary endpoints include progression-free survival, overall response rate, pharmacokinetics and safety. Patients were randomized to either doxorubicin alone or to receive TH-302 300 mg/m2 administered intravenously on Days 1 and 8 with doxorubicin 75 mg/m2 on Day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302 according to the same dosing schedule, 300 mg/m2 Days 1 and 8 of each 21-day cycle. The trial enrolled a total of 640 patients across 81 study sites in Europe, Israel, North America and the Russian Federation.

Sarcomas are a group of aggressive cancers of connective tissues of the body for which currently there are limited treatment options. STS is treated with surgery, chemotherapy and radiation. A combination of these modalities usually offers the best option for treating the disease successfully. Doxorubicin and ifosfamide are the most commonly used chemotherapeutic agents in patients with advanced STS, but response rates are generally low and toxicity can be significant. The American Cancer Society has estimated that in 2014 about 12,020 new cases of STS will be diagnosed (6,550 cases in males and 5,470 in females), and 4,740 Americans (2,550 males and 2,190 females) are expected to die from STS.

TH-302, an investigational hypoxia-activated prodrug, is designed to be activated under severe 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 3 trials: one in combination with doxorubicin versus doxorubicin alone in patients with locally advanced unresectable or metastatic STS, and the other in combination with gemcitabine versus gemcitabine plus placebo in patients with advanced pancreatic cancer (the MAESTRO trial). Both phase 3 trials are being conducted under SPA agreements with the FDA. The FDA and the European Commission have granted TH-302 Orphan Drug Designation for the treatment of STS and pancreatic cancer. TH-302 is also being investigated in earlier-stage clinical trials of other solid tumors and hematological malignancies.

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