Date: 2016-10-10
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2016 Congress
Company: Bayer Healthcare (Germany) Oncomed Pharmaceuticals (USA)
Product: vantictumab (anti-Fzd7, OMP-18R5)
Action
mechanism: monoclonal antibody/Wnt pathways inhibitor. OMP-18R5 is a monoclonal antibody that binds selected receptors in the Wnt signaling pathway and is the first antibody to specifically block these targets to enter human studies. Vantictumab is part of OncoMed's collaboration with Bayer. Bayer can elect to exercise its options on vantictumab through completion of Phase 1b trials.
Disease: pancreatic cancer
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: This open-label Phase 1b dose-escalation study assess the safety, tolerability, and PK of vantictumab when combined with nab-paclitaxel and gemcitabine. ( NCT02005315 ) The Phase 1 clinical trial of OMP-18R5 is a single-agent study designed to evaluate the safety of escalating doses of OMP-18R5 in patients with advanced solid tumors. The study will also assess pharmacokinetics, biomarkers and initial evidence of efficacy. The Phase 1 trial is being conducted at leading U.S. cancer drug development centers. Preclinical studies have shown that OMP-18R5 decreases the frequency of tumor-initiating cells across a variety of tumor types.
Latest
news: * On October 10, 2016, OncoMed Pharmaceuticals announced the presentation of interim clinical data from its ongoing Phase 1b trials of vantictumab (anti-Fzd, OMP-18R5) at the European Society of Medical Oncology (ESMO) 2016 Congress. * On August 28, 2014, OncoMed Pharmaceuticals announced that the FDA has removed the partial clinical hold on enrollment in the company's vantictumab (anti-Fzd7, OMP-18R5) Phase 1 clinical trials. Enrollment and dosing of new patients is expected to resume within the next few weeks as the study sites' institutional review boards (IRBs) receive and approve the revised trial protocols. The partial clinical hold occurred on July 1, 2014 following the company's voluntary halt to its Wnt pathway programs due to observed on-target mild-to-moderate bone-related adverse events. The FDA removed the partial clinical hold to permit the enrollment of vantictumab clinical trials following its review of a substantial clinical safety and efficacy data package and revised study protocols submitted by the company. The amendments for the Phase 1b combination trials include modified dosing regimens, risk mitigation measures, such as increased monitoring and bone protection strategies, and modified enrollment criteria. * On June 13, 2014, OncoMed Pharmaceuticals announced that the company has voluntarily halted patient enrollment and dosing in its ongoing Phase 1 clinical trials of its two Wnt pathway inhibitor programs, vantictumab (anti-Fzd7, OMP-18R5) and Fzd8-Fc (OMP-54F28). OncoMed has been informed by the participating clinical sites of recent on-target mild-to-moderate bone-related adverse events for the two programs. To date, bone-related adverse events have been observed in 8 of 63 (13%) patients treated with vantictumab and 2 of 41 (5%) patients treated with Fzd8-Fc. After careful analysis of the recent mild-to-moderate adverse event incidents, OncoMed has halted enrollment and dosing in the Phase 1 studies for both programs as a precautionary measure. OncoMed, in conjunction with its academic bone expert advisors and study investigators, continues to analyze the clinical data in order to submit amended protocols to the FDA and subsequently to the clinical study sites. The amendments for the Phase 1b combination trials will include 1) modified dosing regimens, such as lower and less frequent dosing, 2) updated risk mitigation measures, such as increased monitoring and bone protection strategies, and 3) modified enrollment criteria. Enrollment and dosing of new patients is expected to resume once amendments go through the process of review by the FDA and approval by the study sites' institutional review boards (IRBs). In parallel, the company intends to continue existing or modified dosing of those patients in the completed single-agent Phase 1a clinical trials for both vantictumab and Fzd8-Fc who have remained on treatment with the investigational agent for extended periods of time without disease progression and without significant drug-related adverse events. OncoMed has notified the FDA of these actions. * On April 28, 2011, OncoMed Pharmaceuticals has announced that the FDA has accepted an IND filing for OMP-18R5, which allows OncoMed to commence Phase1 clinical testing. OMP-18R5 is part of OncoMed’s collaboration with Bayer HealthCare Pharmaceuticals and its advancement to the clinic triggers a $20M milestone payment from Bayer to OncoMed. In June 2010, OncoMed and Bayer entered into a broad strategic alliance valued at up to $387.5M per program to develop cancer stem cell antibody and protein therapeutics targeting the Wnt signaling pathway. Bayer has the option to license OncoMed’s biologics in the Wnt pathway at any point through the completion of Phase 1 studies. This announce also triggered a milestone payment from OncoMed Pharmaceuticals to Morphosys. OMP-18R5, which targets the Wnt signaling pathway, is a HuCAL-derived, fully human antibody. In June 2006, MorphoSys and OncoMed Pharmaceuticals have concluded a license agreement on the use of MorphoSys's HuCAL technology in the research and development of human therapeutic antibodies for the treatment of various cancers, including breast, lung, colon and prostate cancer, by targeting cancer stem cells. In June 2008, the collaboration was extended until the end of May 2010. The contract included an option for OncoMed to develop up to five HuCAL-derived therapeutic antibodies.
Vantictumab is a first-in-class Wnt pathways inhibitor that is each being tested in combination with Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound) plus gemcitabine in patients with previously untreated metastatic pancreatic cancer. The trial is designed as a dose-escalation study to primarily assess safety and tolerability. Secondary objectives include a preliminary assessment of efficacy and exploratory objectives include the identification of pharmacodynamic and predictive biomarkers.
Interim Phase 1b Data in Pancreatic Cancer: The vantictumab Phase 1b clinical trial has enrolled a total of 24 patients in four dose cohorts. As of the data cut-off of August 1, 2016 for results reported at ESMO, median follow up for subjects was 5.9 months (range: 0.77-28.5 months).
Safety: Interim safety results showed that the combination of vantictumab with chemotherapy was well tolerated. The most common vantictumab-related toxicities were fatigue, nausea and dysgeusia. No Grade 4 or 5 vantictumab-related toxicities were observed. Further, vantictumab did not appear to enhance chemotherapy-related toxicities.
Following the incidence of bone fractures in the Phase 1a clinical studies of Wnt inhibitors, OncoMed implemented an enhanced bone safety plan that includes monitoring of blood bone markers and bone density, and the administration of zoledronic acid bone protection in at-risk patients. Seventeen of 24 patients received bone protective therapy and no fragility fractures have been observed. A maximum-tolerated dose has not yet been established and a fifth cohort is currently enrolling.
Efficacy: An interim efficacy assessment demonstrated evidence of anti-tumor effects for the combination of vantictumab with chemotherapy. Of the 21 patients evaluable for response, the overall response rate was 48 percent with 10 patients achieving partial response. Further, the clinical benefit rate was 86 percent as an additional eight patients achieved stable disease. PFS and OS data are not yet mature. Nine of 24 patients were on study greater than 168 days with two patients on study for more than a year. At the time of the data cut-off five subjects were still on study treatment.
Biomarker analysis: Exploratory interim analysis of baseline tumors suggested OncoMed's three-gene predictive biomarker successfully identified patients with better overall responses. Of the eight patients whose tumors were positive for the biomarker, seven achieved partial responses and one achieved stable disease.
Data from the vantictumab Phase 1b clinical trial were presented on Saturday, October 8, during the Gastrointestinal Tumors session in a poster titled, "Phase 1b study of WNT inhibitor vantictumab (VAN, human monoclonal antibody) with nab-paclitaxel (Nab-P) and gemcitabine (G) in patients (pts) with previously untreated stage IV pancreatic cancer (PC)" ( abstract #3412).
