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: advanced soft tissue sarcoma
Therapeutic area: Cancer - Oncology
Country:
Trial
details: TH-CR-406/SARC021 is a randomized, open-label, global, multicenter Phase 3 study, that was designed to assess the efficacy and safety of evofosfamide (300 mg/m2) in combination with doxorubicin (75 mg/m2) compared with doxorubicin alone, in patients with locally advanced unresectable or metastatic soft tissue sarcoma previously untreated with chemotherapy. A total of 640 patients were randomized in the study. The primary endpoint of the study is OS. Secondary endpoints include progression-free survival (PFS), response rate, safety and pharmacokinetics
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 TH-CR-406/SARC021 study being conducted in collaboration with the Sarcoma Alliance for Research through Collaboration (SARC), patients with locally advanced unresectable or metastatic soft tissue sarcoma treated with evofosfamide in combination with doxorubicin did not demonstrate a statistically significant improvement in OS compared with doxorubicin alone (HR: 1.06; 95% CI: 0.88 - 1.29). 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 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.* On December 30, 2013, Threshold Pharmaceuticals has announced that the target enrollment of 620 patients with advanced soft tissue sarcoma has been achieved in the company's pivotal Phase 3 trial of TH-302, its investigational hypoxia-targeted drug. The enrollment achievement triggers a milestone payment of $12.5 million USD from Merck KGaA. Threshold is conducting this international, randomized, pivotal Phase 3 trial in partnership with the Sarcoma Alliance for Research through Collaboration (SARC). The trial is enrolling patients with metastatic or locally advanced unresectable soft tissue sarcoma and is designed to evaluate the efficacy and safety of TH-302 in combination with doxorubicin, compared to doxorubicin alone.Though Threshold will remain blinded to the data from its ongoing Phase 3 trial, an Independent Data Monitoring Committee (IDMC), which monitors patient safety on an ongoing basis, will conduct an interim efficacy and safety analysis after 235 deaths are reported. The timing of the interim analysis, which is event-based and therefore dependent on the length of survival of patients, is currently projected to be conducted in mid-2014. The interim efficacy analysis is designed to allow for the early termination of the study based on achieving a pre-specified improvement in overall survival and the recommendation of the IDMC. If the IDMC recommends that the study continue as planned, Threshold will remain blinded to the data until the company conducts the primary analysis of overall survival after 434 deaths are reported. Unless the IDMC recommends that the study end early, top-line results of the primary efficacy analysis are currently projected to be reported in the first half of 2015.
