Threshold Pharmaceuticals' partner Merck KGaA, through its biopharmaceutical division, has started a Phase I dose escalation trial of its investigational hypoxia-targeted drug TH-302 to treat pancreatic cancer.
The study is designed to evaluate the safety, tolerability and anti-tumour activity of TH-302 in combination with gemcitabine and nab-paclitaxel (Abraxane) in patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma.
Threshold chief medical officer Tillman Pearce said pancreatic cancer patients are in need of meaningful therapeutic improvements and multi-drug combinations have proven to be an effective approach in some tumour types.
"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," Pearce said.
The company added that supportive rationale for the trial was derived from preclinical animal xenograft models of pancreatic cancer, in which greater anti-tumour 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 haematological toxicity or peripheral neuropathy.
Threshold chief executive officer Barry Selick said the evaluation of potential new TH-302 combination therapies is an important component of the overall development program for TH-302 in pancreatic cancer.
"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 enrol the Phase III MAESTRO study," Selick said.
Primary objectives of the trial are to identify potential dose-limiting toxicities and to determine the maximum tolerated dose and the recommended Phase 2 doses.
The trial's secondary objectives include assessing anti-tumour activity and levels of CA19-9, exploring the effect of the combination on tumour metabolic activity using [18F] fluorodeoxyglucose (FDG) PET scans and investigating pharmacokinetics.
A total of 48 patients are expected to be enrolled in the open-label multi-centre Phase I dose escalation trial.
According to the company, 660 patients will be enrolled in the randomised, placebo-controlled, international, multi-centre, double-blind Phase III MAESTRO trial of TH-302 plus gemcitabine, compared with placebo plus gemcitabine.
The MAESTRO trial's primary efficacy endpoint is overall survival, while 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.
This was started following a 214-patient randomised controlled Phase IIb trial of TH-302 plus gemcitabine in which the primary endpoint of improving progression-free survival was achieved.
TH-302 is currently being assessed in two Phase III trials, with 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).