Date: 2016-10-10
Type of information: Presentation of results at a congress
phase: 1b
Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2016 Congress
Company: Bayer Healthcare (Germany) OncoMed Pharmaceuticals (USA - CA)
Product: ipafricept (OMP- 54F28 - Fzd8-Fc)
Action
mechanism: fusion protein/Wnt pathways inhibitor. Ipafricept (Fzd8-Fc, OMP-54F28) is a first-in-class fusion protein that inhibits a key signaling pathway in cancer, the Wnt pathway. Ipafricept selectively binds Wnt ligands that are activators of Wnt signaling. Ipafricept has shown broad anti-CSC and anti-tumor activity in patient-derived xenograft tumor models. In a single-agent Phase 1a study in patients with advanced solid tumors, ipafricept was well tolerated and demonstrated on-target Wnt pathway modulation (ASCO 2014). OncoMed is conducting three Phase 1b clinical trials of ipafricept: one in pancreatic cancer (Abraxane(R) +gemcitabine + ipafricept), one in hepatocellular carcinoma (sorafenib + ipafricept), and one in platinum-sensitive ovarian cancer (carboplatin/paclitaxel + ipafricept). Ipafricept is part of OncoMed's collaboration with Bayer. Bayer can elect to exercise its options on ipafricept through completion of Phase 1b trials.
Disease: advanced solid tumor cancers
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: This open-label Phase 1b dose-escalation study to assess the safety, tolerability, and PK of OMP-54F28 when combined with nab-paclitaxel and gemcitabine. OMP-54F28 will be administered IV on Days 1 and 15 of each 28-day cycle. Nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) will be administered IV on Days 1, 8, and 15 of each cycle. The planned dose levels of OMP-54F28are 3.5 mg/kg and 7.0 mg/kg. (NCT02050178) The Phase I clinical trial of OMP-54F28 is an open-label dose escalation study in patients with advanced solid tumors for which there is no remaining standard curative therapy. These patients are assessed for safety, immunogenicity, pharmacokinetics, biomarkers, and initial signals of efficacy (NCT01608867). The trial is being conducted at Pinnacle Oncology Hematology in Scottsdale, Arizona, the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, and the University of Colorado Cancer Center under the direction of Principal Investigators Dr. Michael S. Gordon, Dr. David Smith and Dr. Antonio Jimeno, respectively.
Latest
news: * On October 10, 2016, OncoMed Pharmaceuticals announced the presentation of interim clinical data from its ongoing Phase 1b trials of ipafricept (FZD8-Fc, OMP-54F28)at the European Society of Medical Oncology (ESMO) 2016 Congress. * On September 4, 2014, OncoMed Pharmaceuticals announced that the FDA removed the partial clinical hold on the company's ipafricept (FZD8-Fc, OMP-54F28) 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. Ipafricept is being studied in combination with standard-of-care in three Phase 1b studies. OncoMed submitted a substantial clinical safety and efficacy data package for ipafricept along with revised study protocols to the FDA's Division of Oncology Products, which resulted in the removal of the partial clinical hold. 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 May 31, 2014, results in Phase I trial of OMP-54F28, a Wnt inhibitor targeting cancer stem cells, have been presented at the 50th Annual Meeting of the American Society for Clinical Oncology (ASCO). University of Colorado Cancer Center researchers reported that the drug was generally well tolerated, and several of the 26 patients with advanced solid tumors experienced stable disease for greater than six months. Three trials are now open for OMP-54F28 (FZD8-Fc) in combinations with standard therapy for pancreatic, ovarian and liver cancers, being offered at the CU Cancer Center and elsewhere. The most common adverse events, mild to moderate and manageable, included dysgeusia (altered taste), fatigue, muscle spasms, decreased appetite, alopecia and nausea. One related Grade 3 or greater adverse event of Grade 3 increased blood phosphorus was reported. One moderate sacral insufficiency fracture occurred in one patient at the highest tested dose of 20 mg/kg every three weeks after 6 cycles. OMP- 54F28 is also being developed in combination with standard of care in three Phase 1b clinical trials, in pancreatic, ovarian and liver cancers. * On July 12, 2012, OncoMed Pharmaceuticals, a clinical-stage company developing novel therapeutics that target cancer stem cells (CSCs), or tumor-initiating cells, has announced that patient dosing has begun in a Phase I clinical trial of OMP-54F28 in patients with advanced solid tumor cancers. OMP-54F28 is OncoMed’s fourth drug to enter clinical development and the second Wnt pathway modulator to enter the clinic as part of the collaboration between OncoMed and Bayer HealthCare Pharmaceuticals. OncoMed believes that OMP-54F28 is a potent antagonist of the Wnt pathway, OncoMed has worked collaboratively with Bayer’s US affiliate Bayer HealthCare, LLC to manufacture the clinical supply of OMP-54F28 for this program. Bayer Pharma AG retains an option to exclusively license OMP-54F2 at any point through completion of certain Phase I trials.
Ipafricept is a first-in-class Wnt pathways inhibitor that is 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.
The ipafricept Phase 1b clinical trial has enrolled a total of 22 patients in four dose cohorts. Median follow up for the subjects was 5.9 months (range 0.97-17.5months) as of the data cut-off of August 1, 2016.
Safety: Interim safety results showed that the combination of ipafricept with chemotherapy was well tolerated. The most common toxicities were fatigue, nausea and decreased appetite and vomiting. No Grade 4 or 5 ipafricept-related toxicities were observed. Ipafricept did not appear to enhance chemotherapy-related toxicities.
Following the incidence of bone fractures in the Phase 1a clinical trials 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. Twelve of 22 patients received bone protective therapy on study and no fragility fractures were observed. A maximum-tolerated dose has not yet been established and a fourth cohort is currently enrolling.
Efficacy: An interim efficacy assessment demonstrated evidence of anti-tumor effects for the combination of ipafricept with chemotherapy. Of the 18 patients evaluable for response, the overall response rate was 39 percent with seven patients achieving partial response. Another eight patients have achieved stable disease for a clinical benefit rate of 83 percent. Early evidence of durability was observed, with nine patients on study greater than 168 days and two patients on study for greater than one year. Progression-free survival (PFS) and overall survival (OS) data are not yet mature. At the time of the data cut-off eight subjects were still on study treatment.
Biomarker analysis: Interim analysis showed that patients with higher expression of Wnt pathway genes at baseline had greater than 40 percent reduction in tumor size compared to those patients with lower Wnt pathway gene expression at baseline, suggesting activated Wnt pathway signaling at baseline may be predictive of patients with a more favorable response to treatment.
A poster discussion of data from the ipafricept Phase 1b clinical trial was presented on Sunday, October 9, during the Developmental Therapeutics session in a poster titled, "Phase 1b study of WNT inhibitor ipafricept (IPA, decoy receptor for WNT ligands) with nab-paclitaxel (Nab-P) and gemcitabine (G) in patients (pts) with previously untreated stage IV pancreatic cancer (PC)" (Abstract #3410).
