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 nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel þ gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC). Patients and Methods: Dose escalation started with standard dose nab-paclitaxel þ 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 þ gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy. 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 administered with nab-paclitaxel þ gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.