VAN is a first-in-class antibody that blocks WNT signaling by interacting with 5 Frizzled receptors (1, 2, 5, 7, 8). VAN, with Nab-P and G, was very effective in causing tumor regression in pt-derived PC xenografts. A biomarker signature was developed in these models. In Phase (P) 1a, VAN was tolerated well except for fragility fractures. Thus, serum markers of bone turnover and bone density were monitored with triggers for zoledronic acid (ZA). Target modulation was seen in tumor tissues at VAN ≥0.5 mg/kg every 2 weeks (q2w).
Dose escalation began with intravenous VAN q2w with a standard 3 + 3 design and was then pursued for q4w with 6-pt cohorts (with baseline ZA, if indicated, increased monitoring and more sensitive ZA triggers). Nab-P at 125 mg/m2 and G at 1000 mg/m2 were given on Days 1, 8 and 15 of 28-day cycles. Objectives were determination of safety, maximum tolerated dose, recommended P2 dose, pharmacokinetics (PK), immunogenicity, pharmacodynamics, predictive biomarkers and efficacy.
19 pts have been treated to date, the 1st 8 pts in 2 q2w cohorts (3.5 & 7 mg/kg). After 2 Grade (G) 2 fragility fractures, 11 pts were treated with a revised safety plan in 2 q4w cohorts (3 & 5 mg/kg) without further fragility fractures. With a PK half-life of 4 days (unchanged by chemotherapy), q4w dosing allowed drug washout that correlated with less fracture risk. ZA at baseline or on-study was triggered for 9 of 11 (82%) pts. VAN-related adverse events (AEs) ≥10% were nausea, fatigue, dysgeusia, rash and constipation. Only related G ≥ 3 AEs were fatigue (1) and nausea (1), both G3. No dose limiting toxicities were observed. Of 15 evaluable pts, 8 (53%) had a partial response and 4 (27%) stable disease. Median progression free survival (PFS) was 7.2 months, 95% CI [1.8, 9.2] (9/19 with PFS events).
VAN can be safely administered at relevant doses in combination with Nab-P and G in pts with stage IV PC. A revised safety plan appears to have addressed bone toxicity encountered early in the study. Updated results, including predictive biomarker analyses in pt tumors, with PFS and overall survival, will be presented.
Clinical trial identification
Legal entity responsible for the study
W. Messersmith, C. Weekes: This clinical trial was sponsored by OncoMed, which had a contract with the University of Colorado. I am named in the contract, so I am disclosing it as "research support" even though funding went to the University of Colorado. S. Cohen: Fox-Chase Cancer Ctr received funding for this study. Dr. Cohen has done an Ad Board for Bayer. S. Shahda, B. O'Neil: The University of Indiana received funding for this trial from OncoMed. H-J. Lenz: Advisory board and lectures for Bayer, which has partnered with OncoMed for this agent. E. Dotan: Fox-Chase Cancer Ctr received funding from OncoMed to perform this trial. C. Denlinger: Fox-Chase Cancer Ctr received funding for this study. Dr. Denlinger has done an Ad Board for Bayer. A. Kapoun, C. Zhang, F. Cattaruzza, L. Xu, J. Dupont, R. Brachmann, S. Uttamsingh: employee of OncoMed and owns OncoMed stock. R. Henner: employee of OncoMed, owns stock. A. Farooki: research support and consultant, OncoMed. J. Berlin: This clinical trial was sponsored by OncoMed, which had a contract with the Vanderbilt. I am named in the contract. The same applies to Bayer (research funding for clinical trials).