The first-in-class recombinant fusion protein IPA blocks WNT signaling by binding WNT ligands. IPA, with Nab-P and G, caused tumor regression in pt-derived PC xenografts. In Phase (P) 1a, IPA was tolerated well with dysgeusia, fatigue, muscle spasms and anorexia as most common adverse events (AEs). Based on vantictumab (VAN, 2nd Wnt inhibitor) data, serum bone turnover markers and/or loss of bone density were used to trigger zoledronic acid (ZA). Target modulation was observed in hair follicles at ≥2.5 mg/kg every 3 weeks (q3w).
Dose escalation started with intravenous IPA q2w with a standard 3 + 3 design and was then pursued for q4w with 6-pt cohorts (baseline ZA, if indicated, increased monitoring & more sensitive ZA triggers). The change was made after fragility fractures in (mainly) VAN and IPA P1 studies. 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.
To date, 19 pts have been treated; in 1 q2w cohort (5 pts, 3.5 mg/kg) and 2 q4w cohorts (14 pts, 3 & 5 mg/kg, revised safety plan). IPA has a PK half-life of 4 days (not significantly changed by Nab-P/G) and a low immunogenicity rate. IPA-related AEs ≥20% were fatigue, nausea, dysgeusia, vomiting, decreased appetite, alopecia and pyrexia. Only related G ≥ 3 AEs were 2 aspartate aminotransferase increased, and 1 each of nausea, maculopapular rash, vomiting and white blood cell count decreased (all G3). No dose limiting toxicities or fragility fractures were observed. ZA was given at baseline or on study for 6 of 14 (43%) pts. Of 14 evaluable pts, 4 (29%) had a partial response and 7 (50%) stable disease. Median progression free survival (PFS) was 3.9 months, 95% CI [1.7, 7.5] (7/19 with PFS events).
IPA can be safely administered in combination with Nab-P and G in pts with stage IV PC. No fragility fractures were observed. Updated results, including biomarker analysis in pt tumors, with PFS and overall survival, will be presented.
Clinical trial identification
Legal entity responsible for the study
Onco med Pharmaceuticals
C. Weekes: Research Funding from OncoMed Research Funding from Celgene Research Funding From Bayer. J. Berlin: Celgene Advisory Board; OncoMed Research Support. H-J. Lenz: Bayer - Advisory Board and Lectures. W. Messersmith: Research Funding OncoMed. S. Cohen: Celgene Advisory Board Bayer Advisory Board. C. Dendinger: Celgene: Research Funding, Advisory Board Bayer:Research Funding, Advisory Board OncoMed:Research Funding, Advisory Board. A. Kapoun, C. Zhang, R. Jenner, F. Cattaruzza, L. Xu, J. Dupont, R. Brachmann, S. Uttamsingh: OncoMed employee. A. Farooki: Bayer Advisory Board. All other authors have declared no conflicts of interest.