Date: 2016-09-29
Type of information: Interim results
phase: 3
Announcement: interim results
Company: Merck Serono, a Merck KGaA company (Germany) Threshold Pharmaceuticals (USA - CA)
Product: evofosfamide (TH-302)
Action
mechanism: TH-302 is a hypoxia-activated prodrug consisting of a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard. The product has been discovered by Threshold scientists. It is designed as a prodrug that is selectively activated under the extreme hypoxic conditions commonly found in tumors, but not typically in healthy tissues. Within regions of tumor hypoxia, TH-302 is converted to its active form, bromo isophoramide mustard (Br-IPM). Variants of IPM are clinically validated potent DNA alkylating agents, which kill tumor cells by causing DNA to crosslink thereby rendering cells unable to replicate their DNA and divide. Once activated in hypoxic tissues, Br-IPM can also diffuse into surrounding oxygenated regions of the tumor and kill cells there via a “bystander effect”.
In February 2012, Merck KGaA signed a global agreement to co-develop and commercialize TH-302 with Threshold. Under the terms of the agreement, Merck KGaA received co-development rights, exclusive global commercialization rights with Threshold retaining an option to co-commercialize the therapeutic in the United States.
Disease: patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma
Therapeutic area: Cancer - Oncology
Country: USA, Germany
Trial
details: MAESTRO (TH-302 in the treatment of MetastAtic or unrESectable pancreaTic adenocaRcinOma)) is a randomized, placebo-controlled, international, multi-center, double-blind Phase 3 trial of TH-302 plus gemcitabine compared with placebo plus gemcitabin in subjects with locally advanced unresectable or metastatic pancreatic adenocarcinoma The study is expected to enroll 660 patients. Randomized subjects will receive TH-302 plus gemcitabine or gemcitabine plus placebo in 4-week cycles until there is evidence of progressive disease, intolerable toxicity, or the subject discontinues from the trial for other reasons (for example, withdrawal of consent). The data cut-off for statistical analyses of the primary and secondary endpoints will be reached when 508 events (deaths) will be reported. No planned interim analyses will be conducted. An Independent Safety Monitoring Board (ISMB) will provide periodic evaluations of the unblinded safety data to ensure subject safety and the validity and scientific merit of the study.
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. (NCT01746979)
Latest
news: * On September 29, 2016, Threshold Pharmaceuticals outlined its plans to focus company resources on the evofosfamide program. Last December, the Company announced the outcomes of two Phase 3 studies (MAESTRO and TH-CR-406/SARC021) of evofosfamide stating that neither study met its primary endpoint. However, the Phase 3 trial (MAESTRO) data demonstrated meaningful improvement in overall survival in a subgroup of 116 patients from Japan, in which the risk of death was reduced by 48 percent for patients on the treatment arm compared to patients on the control arm. In addition, translational data evaluating the role of hypoxia in mediating treatment resistance to cancer immunotherapy conducted at The University of Texas MD Anderson Cancer Center suggests that evofosfamide may play a role in improving the efficacy of "checkpoint antibodies" such as ipilumimab. Threshold Pharmaceuticals now plans to initiate a Phase I clinical trial with four disease specific expansions of evofosfamide in combination with immune checkpoint antibodies in collaboration with researchers and clinicians at The University of Texas MD Anderson Cancer Center . The company will also pursue discussions with Japanese regulatory authorities regarding potential registration pathways for evofosfamide for treatment of pancreatic cancer. * On December 7, 2015, Threshold Pharmaceuticals announced the outcomes of two Phase 3 cancer studies (MAESTRO and TH-CR-406/SARC021) of evofosfamide which is being evaluated for first-line treatment of advanced pancreatic adenocarcinoma and advanced soft tissue sarcoma, in combination with chemotherapy. The Phase 3 studies are being conducted under Threshold's collaboration with Merck KGaA. In the Phase 3 MAESTRO study, patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma treated with evofosfamide in combination with gemcitabine did not demonstrate a statistically significant improvement in overall survival (OS) compared with gemcitabine plus placebo (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.71 - 1.01; p=0.0589). * On November 3, 2014, Threshold Pharmaceuticals announced that Threshold's partner Merck KGaA, Darmstadt, Germany , through its biopharmaceutical division, has completed target enrollment of 660 patients in the global Phase 3 MAESTRO (MetastAtic or unrESectable pancreaTic adenocarcinoma) study assessing the efficacy and safety of TH-302 in combination with gemcitabine in patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma. Threshold Pharmaceuticals anticipates conducting the primary analysis of overall survival for Phase 3 trial in patients with advanced soft tissue sarcoma in the first quarter of 2016 and having top-line data for MAESTRO in 2016. * On January 25, 2013, Merck KGaA, through its division Merck Serono, has initiated the global Phase 3 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 initiation of the Phase 3 MAESTRO study resulted in Threshold earning a $30 million milestone payment from Merck KGaA pursuant to the terms of its agreement with Merck KGaA. Threshold has a global license and co-development agreement with Merck for TH-302, which includes an option for Threshold to co-commercialize in the U.S.
Patient safety was monitored in MAESTRO and TH-CR-406/SARC021 by independent data monitoring committees throughout the conduct of each study. No new clinically significant safety findings were observed.
Detailed results from both studies will be submitted for presentation at upcoming international scientific meetings and for publication in peer-reviewed journals. Threshold will not be pursing further development of evofosfamide in soft tissue sarcoma and pancreatic cancer. Merck KGaA also announced that it is not planning to file for approval of evofosfamide in advanced soft tissue sarcoma and advanced pancreatic adenocarcinoma. The decision was made in light of the results from two Phase III studies of evofosfamide in combination with chemotherapy in these two types of cancer. Merck KGaA will now be redeploying its resources into high-profile future products, such as avelumab and all other priority programs in oncology, immuno-oncology and immunology.
Details of the two Phase III studies will be shared with the scientific community once the data have been further analyzed.
The Phase 3 MAESTRO study for TH-302 was initiated following results from a randomized, controlled Phase 2b 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%.
