SOUTH SAN FRANCISCO, CA--(Marketwired - Mar 27, 2014) - Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced that Threshold's partner Merck KGaA, Darmstadt, Germany, through its biopharmaceutical division, has initiated a Phase 1 dose escalation study assessing the safety, tolerability and anti-tumor activity of the investigational hypoxia-targeted drug TH-302 in combination with gemcitabine and nab-paclitaxel (Abraxane®) in patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma.
"Pancreatic cancer patients are in need of meaningful therapeutic improvements and multi-drug combinations have proven to be an effective approach in some tumor types," said Tillman Pearce, M.D., Chief Medical Officer of Threshold. "This new dose escalation study is evaluating an investigational triple therapy approach with TH-302 plus gemcitabine and nab-paclitaxel, two compounds that have been approved for the treatment of pancreatic cancer, in an effort to continue the pursuit of developing potentially meaningful therapeutic improvements to existing therapies in one of the most difficult to treat cancers."
Supportive rationale for the study was derived from preclinical animal xenograft models of pancreatic cancer, in which greater anti-tumor activity was associated with the "triplet" combination (TH-302 plus gemcitabine plus nab-paclitaxel) compared with that of the "doublet" combination (gemcitabine plus nab-paclitaxel) without apparent increases in hematological toxicity or peripheral neuropathy.1
"The evaluation of potential new TH-302 combination therapies is an important component of the overall development program for TH-302 in pancreatic cancer," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "We are pleased that Merck in Darmstadt, Germany has initiated this additional trial designed to evaluate an investigational triplet therapeutic regimen for patients with pancreatic cancer while continuing to enroll the Phase 3 MAESTRO study."
About the Phase 1 Study of TH-302 in Combination with Gemcitabine and Nab-paclitaxel
The primary objectives of the Phase 1 trial are to evaluate the safety and tolerability of TH-302 in combination with gemcitabine plus nab-paclitaxel in patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma, to identify potential dose-limiting toxicities and to determine the maximum tolerated dose and the recommended Phase 2 doses. Secondary objectives include evaluating anti-tumor activity and levels of CA19-9, exploring the effect of the combination on tumor metabolic activity using [18F]-fluorodeoxyglucose (FDG) PET scans and investigating pharmacokinetics. The open-label multi-center study is expected to enroll up to 48 patients.
About the Phase 3 MAESTRO Study of TH-302 in Combination with Gemcitabine
MAESTRO is a randomized, placebo-controlled, international, multi-center, double-blind Phase 3 trial of TH-302 plus gemcitabine compared with placebo plus gemcitabine and is expected to enroll 660 patients. The primary efficacy endpoint is overall survival; the secondary endpoints include efficacy measured by progression-free survival, overall response rate and disease control rate, as well as assessments of safety and tolerability, pharmacokinetics and biomarkers. MAESTRO was initiated following a 214-patient randomized controlled Phase 2b trial of TH-302 plus gemcitabine in which the primary endpoint of improving progression-free survival was achieved.
About Pancreatic Cancer
It is estimated that approximately 337,000 cases of pancreatic cancer are diagnosed worldwide every year, accounting for 2.4% of all cancers. Pancreatic cancer is the twelfth most common cancer worldwide. Almost 67% of cases are diagnosed in people aged 65 and over; it is uncommon in people under the age of 45. Pancreatic cancer has a low survival rate regardless of stage of disease, with almost 94% of patients dying from their disease within 5 years. It is estimated that there are around 330,000 deaths from pancreatic cancer worldwide each year.
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 3 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 3 trials are being conducted under Special Protocol Agreements with the U.S. 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 has a global license and co-development agreement for TH-302 with Merck KGaA, Darmstadt, Germany, which includes an option for Threshold to co-commercialize in the U.S.
About Threshold Pharmaceuticals
Threshold Pharmaceuticals, Inc. is a biotechnology company 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. This approach offers broad potential to treat a variety of cancers. By selectively targeting tumor cells, we are building a pipeline of drugs that hold promise to be more effective and less toxic to healthy tissues than conventional anticancer drugs. For additional information, please visit our website (www.thresholdpharm.com).
Except for statements of historical fact, the statements in this press release are forward-looking statements, including statements regarding the potential therapeutic uses and benefits of its product candidates, including TH-302, and statements regarding the TH-302 clinical development program, including the expected enrollment and conduct of ongoing clinical trials and the timing thereof. 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, the ability of Threshold and Merck KGaA, Darmstadt, Germany, to enroll or complete TH-302 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), the risk that preclinical studies in animal models of disease may not accurately predict the result of human clinical trials of TH-302, and risks related to Threshold's dependence on its collaborative relationship with Merck KGaA, Darmstadt, Germany, including its dependence on decisions by Merck KGaA, Darmstadt, Germany regarding the amount and timing of resource expenditures for the development of TH-302. Further information regarding these and other risks is included under the heading "Risk Factors" in Threshold's Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission on March 6, 2014 and is available from the SEC's website (www.sec.gov) and on our website (www.thresholdpharm.com) under the heading "Investors." We undertake no duty to update any forward-looking statement made in this news release.
1. Sun J et al. 2013 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (Abstract #C287).