Phase 1b study of Wnt inhibitor ipafricept (IPA) with gemcitabine and nab-paclitaxel in patients with previously untreated stage IV pancreatic cancer (mPDAC).

Background The recombinant fusion protein ipafricept (IPA) blocks Wnt signaling, and in combination with gemcitabine (G) and nab-paclitaxel (Nab-P) caused tumor regression in xenografts. This phase 1b study evaluated the combination of IPA with Nab-P+G in untreated metastatic PDAC (mPDAC) patients. Methods Dose escalation started with standard dose Nab-P+G and IPA (3.5 mg/kg days 1, 15). Due to fragility fractures seen with different anti-Wnt agents, following cohorts had >=6 patients treated with IPA 3 - 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. Based on pre-clinical data sequential dosing was evaluated in cohort 4 (IPA day 1 followed Nab-P+G day 3). Objectives included safety, MTD, RP2D, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy. Results 26 patients were enrolled, 5 in the cohort 1 and 7 each in cohorts 2-4. IPA-related AEs of any grade included fatigue, nausea, vomiting, anorexia and pyrexia. IPA-related AEs >=grade3 included 2 events of AST elevation, and 1 each of nausea, rash, vomiting and leucopenia. No DLTs or fragility fractures were observed. Nine patients (34.6%) had PR, 12 (46.2%) SD as best response, with clinical benefit rate of 81%. Median PFS was 5.9m (95%CI 3.4-18.4), median OS was 9.7m (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 IPA can be administered with Nab-P+G with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.