Phase Ib Study Of Wnt Inhibitor Ipafricept With Gemcitabine And Nab-Paclitaxel In Patients With Previously Untreated Stage Iv Pancreatic Cancer

Purpose: The recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nabpaclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel+ gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC).Patients and Methods: Dose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different antiWnt agents, following cohorts had >= 6 patients treated with ipafricept 3 to 5 mg/ kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 ( ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics,Results: A total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2-4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade >= 3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4-18.4], median overall survival was 9.7 m (95% CI, 7.0-14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use.Conclusions: Ipafricept can be administeredwith nab-paclitaxel+ gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.