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Threshold Pharmaceuticals, Inc.

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July 1, 2014

Threshold Pharmaceuticals Initiates 440-Patient, Randomized, Double-Blind, Placebo-Controlled Trial of TH-302 in Combination With Pemetrexed in Advanced Non-Squamous Non-Small Cell Lung Cancer

SOUTH SAN FRANCISCO, CA -- (Marketwired) -- 07/01/14 -- Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced initiation of a 440-patient, randomized, double-blind, placebo-controlled trial of its investigational hypoxia-activated prodrug, TH-302, in combination with pemetrexed in advanced non-squamous non-small cell lung cancer (NSCLC). The international Phase 2 trial is designed to compare the combination of TH-302 and pemetrexed versus the combination of pemetrexed and placebo as second-line therapy in this patient population. A TH-302 dose of 400 mg/m2 will be utilized in combination with full-dose pemetrexed. Overall survival is the primary endpoint; secondary endpoints include safety and assessment of anti-tumor activity as determined by progression-free survival and objective response rate.

"The initiation of this trial is yet another example of our commitment, and that of our partner Merck KGaA based in Darmstadt, Germany, to develop TH-302 for the potential treatment of a broad range of cancers," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "Independent studies have demonstrated the presence of hypoxia in tumors from patients with NSCLC.1 Early clinical research conducted by Threshold also supports further evaluation of TH-302 in combination with pemetrexed as a potential second-line treatment for patients with non-squamous NSCLC, many of whom still face a poor prognosis because of limited treatment options."

"While over the past decade the ability to detect and treat specific mutations in NSCLC has proven beneficial to some patients with recurrent disease who harbor those mutations, there is still a significant need for the development of new safe and effective medicines that improve survival outcomes," said Jonathan Goldman, MD, Director of Clinical Trials in Thoracic Oncology, UCLA Hematology & Oncology, and principal investigator of the ongoing trial. "TH-302 is a hypoxia-activated prodrug that has shown encouraging anti-tumor activity across a wide range of cancers in investigational trials, and we are excited about evaluating TH-302 in combination with pemetrexed as potential second-line treatment for patients with non-squamous NSCLC."

In a completed Phase 1/2 study that evaluated TH-302 in combination with full-dose pemetrexed in 18 patients with relapsed/refractory non-squamous NSCLC, median progression-free survival was 7.0 months and median overall survival was 14.9 months. Of 15 patients evaluable for response, 6 (40%) achieved a partial response including 4 confirmed responses, 6 (40%) achieved stable disease, and 3 (20%) had progressive disease. The most common adverse events following combination therapy of TH-302 and pemetrexed were fatigue, anemia, stomatitis and nausea.
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Source: press release, 7/01/14. http://investor.thresholdpharm.com/releasedetail.cfm?ReleaseID=857290

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A Randomized Phase 2, Double-blind, Placebo-controlled, Multi-center Study Comparing Pemetrexed in Combination With TH-302 vs. Pemetrexed in Combination With Placebo as Second-line Chemotherapy for Advanced Non-Squamous, Non-Small Cell Lung Cancer
Estimated Enrollment: 440
Study Start Date: March 2014
Estimated Study Completion Date: October 2016
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
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Source: clinical trials.gov. http://clinicaltrials.gov/ct2/show/NCT02093962?term=TH-302&rank=7

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
TH-302 NSCLCOncologyNon-Small Cell Lung Cancer (NSCLC)Alkylating agent (prodrug)DNA

Mechanism of action: TH-302 is a hypoxia-activated prodrug consisting of a 2-nitroimidazole phosphoramidate conjugate with potential antineoplastic activity. The 2-nitroimidazole moiety of hypoxia-activated prodrug TH-302 acts as a hypoxic trigger, releasing the DNA-alkylating dibromo isophosphoramide mustard moiety within hypoxic regions of tumors. Normoxic tissues may be spared due to the hypoxia-specific activity of this agent, potentially reducing systemic toxicity.

Phase of Development: II

Event Type: Data: Phase II trial results

Dates: 2016-07-01 - 2016-10-31

Results:

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Threshold Pharmaceuticals and Merck KGaA, Darmstadt, Germany Agree to Key Terms for the Licensing Back of All Rights to Evofosfamide to Threshold
SOUTH SAN FRANCISCO, CA -- (Marketwired) -- 01/11/16 -- Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced an update on its evofosfamide program including that Threshold and Merck KGaA, Darmstadt, Germany have agreed upon key terms for the licensing back of all rights to evofosfamide to Threshold. The companies have a global license and co-development agreement for evofosfamide, an investigational hypoxia-activated prodrug for the treatment of cancer, which was discovered and initially developed by Threshold.

The decision to return rights to evofosfamide to Threshold follows the unblinding of two Phase 3 clinical trials of evofosfamide (TH-CR-406 and MAESTRO) and a previously unplanned, subsequent interim futility analysis of a Phase 2 clinical trial of evofosfamide in patients with non-squamous non-small cell lung cancer (n-s NSCLC). As previously announced, both Phase 3 trials failed to meet the primary endpoint of demonstrating a statistically significant improvement in overall survival. The results of the MAESTRO trial will be presented at the American Society of Clinical Oncology 2016 Gastrointestinal Cancers Symposium during an oral presentation session scheduled to begin at 2:00 p.m. Pacific Time on Friday, January 22, 2016 (Abstract #193).

Following the topline results from the two Phase 3 clinical trials, Threshold and Merck KGaA, Darmstadt, Germany decided to unblind the Phase 2 clinical trial in n-s NSCLC and conduct an interim futility analysis. The Phase 2 trial was designed to enroll 440 patients with advanced n-s NSCLC. A total of 265 patients were enrolled and 112 events (deaths) were reported at the time of the interim analysis. An independent Data Safety Monitoring Board conducted the analysis and concluded that the trial is unlikely to reach its primary endpoint of improving overall survival with statistical significance. As a result, further enrollment in this trial will be closed. Additional findings from the interim analysis indicated that evofosfamide plus pemetrexed demonstrated longer progression-free survival (PFS) associated with a reduction in the risk of progression or death by approximately 30%. No new safety findings were reported. Data for this trial will be finalized and results presented at a future medical meeting.

"We are pleased to have agreed to key terms for the licensing back of all rights to evofosfamide to Threshold and we will share our plans for the future development of evofosfamide once our ongoing analyses of the data from the recently unblinded clinical trials are complete," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "In parallel, we continue to focus on prosecuting two Phase 2 clinical trials of tarloxotinib, our hypoxia-activated EGFR tyrosine kinase inhibitor, and to assess other strategic options for the company."
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Source: press release, 1/11/16. http://investor.thresholdpharm.com/releasedetail.cfm?ReleaseID=949643

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