Darmstadt, Germany, January 25, 2013 – Merck today announced the initiation of the global Phase III MAESTRO study, assessing the efficacy and safety of investigational hypoxia-targeted drug TH-302 in combination with gemcitabine in patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma. The study is being carried out pursuant to a global licensing and co-development agreement for TH-302 between Merck and Threshold Pharmaceuticals Inc., which includes an option for Threshold to co-commercialize in the U.S. MAESTRO stands for TH-302 in the treatment of MetastAtic or unrESectable pancreaTic adenocaRcinOma.

MAESTRO is a randomized, placebo-controlled, international, multi-center, double-blind Phase III 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 (PFS), overall response rate and disease control rate, as well as assessments of safety and tolerability, pharmacokinetics and biomarkers. The study is being conducted under a Special Protocol Assessment (SPA) with U.S. Food and Drug Administration (FDA). An SPA is a review conducted by FDA on a clinical trial that will form the primary basis of an efficacy claim in a marketing application. FDA provided written agreement that the design and planned analysis of this study could adequately address objectives in support of a regulatory submission. However, the determination for drug approval by FDA is made after a complete review of a marketing application and is based on the entire data in the application. The study design was discussed with FDA also at an end of Phase 2 meeting and the European Medicines Agency (EMA) during a scientific advice procedure.
“Patients with advanced pancreatic cancer currently have a poor prognosis and limited treatment options,” said the Coordinating Investigator of the study, Prof. Eric Van Cutsem, Digestive Oncology Unit, University Hospitals, Leuven, Belgium. “Tumor hypoxia is thought to be a factor that makes pancreatic cancer particularly difficult to treat. Investigating compounds thought to be activated under tumor hypoxic conditions offers the potential to expand treatment options for this patient group in the future.”

TH-302 is an investigational hypoxia-targeted drug that 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.

“The Phase III MAESTRO study initiation is an important milestone, highlighting the progress of the TH-302 program,” said Dr. Annalisa Jenkins, Executive Vice President, Head of Global Drug Development and Medical for Merck Serono. “Together with Threshold Pharmaceuticals, we are focused on targeting difficult to treat cancers, with MAESTRO in pancreatic cancer representing the second Phase III study in this program, in addition to the Phase III study in soft tissue sarcoma.”

The Phase III trial for TH-302 was initiated following results from a randomized, controlled Phase IIb trial of TH-302 in patients with pancreatic cancer. At the ESMO 2012 Congress (European Society for Medical Oncology) updated results were presented confirming a significant improvement (p=0.008) in PFS associated with 41% reduction of risk for disease progression or death for patients treated with TH-302 340 mg/m2. This represented a 2.4-month increase in median PFS for patients receiving TH-302 340 mg/m2. The 12-month overall survival rates were also in favor of the TH-302 340 mg/m2 treatment group compared with the control arm (38% vs 26% (p=0.13)). The most common adverse events were fatigue, nausea and peripheral edema, and were similar across groups. Skin and mucosal toxicities, predominantly Grade 1 and 2, and myelosuppression were the most common adverse events related to TH-302, and did not result in increases in treatment discontinuation. Adverse events leading to discontinuation of study treatment as well as serious adverse events were balanced across all treatment arms. Severe (grade 3/4) myelosuppression was more frequent compared to gemcitabine alone. All other severe adverse events were generally below 10%.1

It is estimated that approximately 277,000 cases of pancreatic cancer are diagnosed worldwide every year, accounting for 2.2% of all cancers.2 Pancreatic cancer is the eighth most common cancer in Europe and the eleventh most common in the United States.2 Almost 67% of cases are diagnosed in people aged 65 and over; it is uncommon in people under the age of 40.3 Pancreatic cancer has a low survival rate regardless of stage of disease, with almost 95% of patients dying from their disease within 5 years.3 It is estimated that there are around 266,000 deaths from pancreatic cancer worldwide each year.2

References

1. Borad M, et al. Annals Oncol 2012;23(Supplement 9):ix27
2. Ferlay J, et al. Int J Cancer 2010;127(12):2893-917
3. http://seer.cancer.gov/statfacts/html/pancreas.html (Accessed: November 2012).

About TH-302
TH-302 is an investigational hypoxia-targeted drug that 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 III trials: one in combination with doxorubicin versus doxorubicin alone in patients with soft tissue sarcoma (STS), and the other in combination with gemcitabine versus gemcitabine and placebo in patients with advanced pancreatic cancer. Both Phase III trials are being conducted under a Special Protocol Assessment with the U.S. Food and Drug Administration (FDA). FDA and the European Commission have granted TH-302 Orphan Drug Designation for the treatment of STS. TH-302 is also being investigated in hematological malignancies and combination trials in solid tumors.

Merck signed a global license and co-development agreement for TH-302 with Threshold Pharmaceuticals Inc. in February 2012, which includes an option for Threshold to co-commercialize in the U.S.