Date: 2016-08-30
Type of information: Completion of patient enrollment
phase: 1b/2
Announcement: completion of patient enrollment
Company: OncoMed Pharmaceuticals (USA - CA) GSK (UK)
Product: tarextumab (anti-Notch2/3, OMP-59R5)
Action
mechanism: monoclonal antibody. Tarextumab (anti-Notch2/3, OMP-59R5) is a fully human monoclonal antibody that targets the Notch2 and Notch3 receptors. Preclinical studies have suggested that tarextumab exhibits two mechanisms of action: (1) by downregulating Notch pathway signaling, tarextumab appears to have anti-CSC effects, and (2) tarextumab affects pericytes, impacting stromal and tumor microenvironment. Tarextumab is part of OncoMed's collaboration with GSK. GSK has an option to obtain an exclusive license to tarextumab during certain time periods through completion of the proof-of-concept Phase 2 trials.
Disease: small cell lung cancer
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: The "PINNACLE" study (A Phase 1b/2 Study of OMP-59R5 in Combination with Etoposide and Platinum Therapy in Subjects with Untreated Extensive Stage Small Cell Lung Cancer) is testing tarextumab in combination with etoposide and cisplatin and etoposide and carboplatin in first-line extensive stage small cell lung cancer patients. The study is being conducted at about 40 sites in the U.S. and is expected to enroll approximately 130 patients. Results from the Phase 2 PINNACLE trial are anticipated in 2017. (NCT01859741 )
Latest
news: * On August 30, 2016, OncoMed Pharmaceuticals announced the completion of patient enrollment in the Phase 2 "PINNACLE" clinical trial of tarextumab (anti-Notch2/3, OMP-59R5) for the treatment of small cell lung cancer (SCLC). The PINNACLE study enrolled 145 patients with extensive-stage SCLC who had not received prior treatment. Topline data from the Phase 2 trial are expected to be reported at the end of 2016 or in early 2017. * On September 9, 2015, OncoMed Pharmaceuticals reported new biomarker and updated clinical data for the company's Phase 2 anti-Notch2/3 therapeutic candidate, tarextumab (OMP-59R5). These data show the potential of Notch3 overexpression as a prognostic factor in small cell lung cancer and update OncoMed's Phase 1b results for tarextumab in combination with standard-of-care chemotherapy for the first-line treatment of patients with extensive-stage disease. Anne Chiang, M.D., Ph.D., of the Yale School of Medicine, will present these data in a mini-oral presentation this afternoon at the 16th World Lung Conference on Lung Cancer. * On September 29, 2014, OncoMed Pharmaceuticals, a clinical-stage company developing novel therapeutics that target cancer stem cells (CSCs), or tumor-initiating cells, presented data on safety and anti-tumor activity from the ALPINE and PINNACLE Phase 1b clinical studies of tarextumab (anti-Notch2/3, OMP-59R5) at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid, Spain. OncoMed's Phase 1b PINNACLE study of tarextumab enrolled 20 small cell lung cancer patients. Tarextumab was well tolerated; diarrhea, fatigue, decreased appetite and nausea were the most common treatment-related toxicities, and these events were mostly Grade 1 or 2 and easily managed with supportive care. Of sixteen patients evaluable for efficacy, thirteen achieved partial responses (81.3%). As of the data cut off of August 29, 2014, seven patients remain on treatment. Data from the Phase 1b study of tarextumab in SCLC were presented by Dr. M. Catherine Pietanza, MD, Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, today in a poster titled: "Phase 1b Trial of anti-Notch2/3 Antibody OMP-59R5 in Combination with Etoposide and Cisplatin (EP) in Patients (pts) with Untreated Extensive-Stage Small-Cell Lung Cancer (ED-SCLC): the PINNACLE Study" (#1473P).
Patients enrolled in the PINNACLE trial were randomized into two study arms and received either 15mg/kg of tarextumab every three weeks in combination with six cycles of etoposide and platinum therapy followed by tarextumab maintenance to progression or six cycles of standard chemotherapy and a placebo. The primary endpoint of the trial is progression-free survival. Secondary endpoints include overall survival and overall response rate, pharmacokinetics, safety and biomarker analyses. Overall survival, progression-free survival and overall response rates will be assessed against elevated tumor expression of certain Notch pathway genes. The protocol for the Phase 2 trial was amended in May 2016 to enable the assessment of efficacy outcomes using Notch pathway genes Hes1, Hes6, Hey1 and Hey2 as a secondary endpoint.
The PINNACLE trial was conducted at 36 sites in the United States. Enrollment in the randomized, double-blinded, multi-center clinical study began in December 2014 and was completed three months ahead of schedule.
In the Phase 1b trial, all 26 patients evaluable for tumor response saw a reduction in target lesion size as measured by RECIST criteria, with an overall response rate of 77% and a 100% clinical benefit rate. Subjects receiving doses of tarextumab at or above 12 mg/kg plus chemotherapy achieved a median progression-free survival of 5.2 months and a median overall survival of 16 months. Results from OncoMed's Phase 1b trial of tarextumab were most recently presented at the 2016 ASCO Annual Meeting.
A retrospective tumor microarray analysis that looked at Notch3 overexpression in 31 small cell lung cancer samples with available follow-up survival data showed that high levels of Notch3 protein expression appears to correlate with worse survival outcomes in patients with extensive-stage small cell lung cancer, elucidating for the first time that Notch3 may be an important prognostic factor in this solid tumor indication. Based on this analysis, prevalence of Notch3 overexpression in small cell lung cancer was estimated at 64 percent. This prevalence data is consistent with previously reported OncoMed biomarker data in small cell lung cancer.
Overall survival data presented from OncoMed's Phase 1b study of tarextumab in combination with etoposide and platinum therapy for 23 patients with previously untreated extensive-stage small cell lung cancer show a correlation between dose and efficacy. Patients who received higher doses ( > 10 mg/kg) of tarextumab every three weeks plus chemotherapy demonstrated improved overall survival compared those who received lower doses. This durability of response was observed regardless of Notch3 gene expression status. Patients whose tumors tested biomarker positive for Notch3 expression and received higher doses of tarextumab with chemotherapy achieved the most benefit and a median overall survival for these patients has not yet been reached. These data expand on the findings of a dose-dependent relationship between tumor responses and survival among patients whose tumors were high in Notch3 expression that were reported at the 2015 ASCO Annual Meeting in June.
