Date: 2016-01-25
Type of information: DSMB assessment
phase: 2
Announcement: DSMB assessment
Company: OncoMed Pharmaceuticals (USA - CA) Morphosys (Germany)
Product: tarextumab (anti-Notch 2/3, OMP-59R5)
Action
mechanism: monoclonal antibody. Tarextumab (OMP-59R5) is a fully human monoclonal antibody that targets the Notch2 and Notch3 receptors. This HuCAL-derived therapeutic antibody has been developed with the german biotech Morphosys. Initially discovered by screening a phage display library against the Notch2 receptor, the antibody binds to a conserved epitope on Notch2 and Notch3. Preclinical studies have demonstrated that OMP-59R5 exhibits two mechanisms of action: (1) by downregulating Notch pathway signaling, OMP-59R5 appears to have anti-CSC effects, and (2) OMP-59R5 affects pericytes, impacting stromal and tumor microenvironment. The program is also currently in a single-agent Phase Ia trial in advanced solid tumor patients. Data for this trial were presented at the American Society of Clinical Oncology, or ASCO, conference in June 2012. In December 2007, OncoMed and GSK entered into a strategic alliance to develop cancer stem cell antibody therapeutics targeting the Notch signaling pathway. In July 2011, OncoMed amended the terms of its research and development agreement with GSK, and the collaboration is now focused entirely on the development of two product candidates, tarextumab (anti-Notch2/3, OMP-59R5) and anti-Notch1 (OMP-52M51). Under this collaboration, OncoMed is eligible to receive from GSK with respect to tarextumab, aggregate payments of up to $344.5 million, in addition to percentage royalties in the low double digits to high teens on net product sales, and with respect to anti-Notch1, aggregate payments of up to $349.5 million, in addition to percentage royalties in the low double digits to high teens on net product sales. 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-cancer stem cell effects, and (2) tarextumab affects pericytes, impacting stromal and tumor microenvironment. Tarextumab is currently being studied in two randomized Phase 2 clinical trials. The "ALPINE" study (Antibody therapy in first-Line Pancreatic cancer Investigating anti-Notch Efficacy and safety) is assessing tarextumab with Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound) plus gemcitabine in first-line advanced pancreatic cancer patients. 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. 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: pancreatic cancer
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: The Phase 2 ALPINE trial is a randomized, double-blinded, multicenter clinical trial designed to evaluate the efficacy of tarextumab in combination with Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound) plus gemcitabine in patients with previously untreated Stage IV pancreatic cancer. The ALPINE study completed enrollment of 177 patients in August 2015. The trial was designed to compare the overall survival of patients receiving tarextumab 15 mg/kg every two weeks versus placebo in combination with Abraxane plus gemcitabine. Secondary and exploratory endpoints, including progression-free survival and overall response rate, pharmacokinetics, safety and other biomarkers, are to be evaluated. Overall survival, progression-free survival and overall response rates will be assessed using a predictive biomarker for high tumor Notch3 expression. Increased Notch3 expression is estimated to occur in approximately 70 percent of pancreatic tumors and is associated with poor patient outcomes.
Latest
news: * On January 25, 2016, OncoMed Pharmaceuticals announced an update on the Phase 2 ALPINE clinical trial following a pre-planned January 23 interim efficacy assessment of the clinical trial by an independent data safety monitoring board (DSMB). The DSMB assessed data from 172 patients treated as of a January 6, 2016 data cutoff date. From a safety standpoint, the DSMB recommended that the study proceed to completion without modification. No unexpected safety findings emerged from its review. However, the DSMB informed OncoMed of several findings regarding futility of the trial, notably: * On August 31, 2015, OncoMed Pharmaceuticals, a clinical-stage company developing novel anti-cancer stem cell and immuno-oncology therapeutics, announced that it has completed patient enrollment in its Phase 2 "ALPINE" clinical trial of tarextumab (anti-Notch2/3, OMP-59R5) for the treatment of pancreatic cancer more than eight months ahead of schedule. The ALPINE study enrolled 177 patients with advanced pancreatic cancer who had not received prior treatment. Enrollment in the randomized, double-blinded, multi-center clinical study began in July 2014. The protocol for the randomized Phase 2 ALPINE trial was amended in February 2015 to designate overall survival as the primary endpoint (rather than progression-free survival), and the target enrollment increased from 124 to at least 160 patients. These changes occurred based on the anti-cancer stem cell mechanism of action of tarextumab and following the review of final data from the Phase 1b portion of the ALPINE trial in 40 patients with first-line metastatic pancreatic cancer, where 24 patients received the tarextumab-Abaxane-gemcitabine combination. Analyses of the Phase 1b subjects receiving the three drug combination revealed a median overall survival of 14.6 months in patients whose tumor samples had elevated levels of Notch3 gene expression and 11.6 months in all patients regardless of Notch3 biomarker status. By comparison, the historical overall survival using the standard-of-care in this patient population is 8.5 months2. Results from OncoMed's Phase 1b trial of tarextumab were presented at the 2015 Gastrointestinal Cancer Symposium. * On July 16, 2014, OncoMed Pharmaceuticals announced that patient dosing has begun in the randomized, placebo-controlled Phase 2 portion of the company's "ALPINE" (Antibody therapy in first-Line Pancreatic cancer Investigating anti-Notch Efficacy and safety) clinical trial of its anti-Notch 2/3 cancer stem cell antibody, tarextumab (OMP-59R5), being studied for the treatment of pancreatic cancer. Tarextumab is being tested in combination with Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound) plus gemcitabine in patients with previously untreated stage IV pancreatic cancer. OncoMed has completed enrollment in the Phase 1b safety portion of the ALPINE clinical study, which was intended to establish a maximum-tolerated dose for tarextumab in combination with Abraxane® plus gemcitabine. As reported in January at the 2014 Gastrointestinal Cancers Symposium, tarextumab has been generally well tolerated when administered with standard of care. An overall disease control rate (partial responses + stable disease) of 63% (17 of 27) was observed among patients receiving the three-drug combination. * On October 5, 2012, MorphoSys has announced that its collaboration partner OncoMed Pharmaceuticals has advanced the HuCAL antibody OMP-59R5 into the next stage of clinical development. OMP-59R5, which is part of OncoMed's Notch pathway collaboration with GlaxoSmithKline, is now being evaluated in a Phase 1b/2 trial in the US in first-line advanced pancreatic cancer patients. This Phase 1b/2 clinical program is OncoMed's first Phase 2 trial. In December 2007, OncoMed and GSK entered into a broad strategic alliance to discover and develop novel product candidates targeting cancer stem cells via Notch pathway signaling modulation. GSK retains an option through the end of certain Phase 2 clinical trials to obtain an exclusive license to OMP-59R5.
A statistically significant worsening of response rate and progression-free survival (PFS) in the treatment arm in the overall intent-to-treat population, as well as a negative trend in each Notch biomarker subgroup
A strong trend to lack of benefit in the treatment arm for overall survival (OS), regardless of Notch biomarker levels, suggesting a low probability of achieving a statistically significant OS benefit based on analyses reviewed by the DSMB. Based on this information, OncoMed is in the process of unblinding the trial to carefully assess the current results and determine appropriate next steps for this fully enrolled trial. Eighteen patients remain on study drug treatment (tarextumab or placebo) between 172 and 527 days.
"The findings communicated by the DSMB suggest a low likelihood of a statistically significant benefit in overall survival in the tarextumab ALPINE pancreatic cancer trial," said Paul J. Hastings, Chairman and CEO. "Our aim is to quickly unblind the trial and work with our clinical sites and investigators to verify, analyze, interpret, and fully understand the data, including Notch biomarker subgroup trends, and determine next steps."
