A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer

Abstract

Vantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. This phase Ib study evaluated vantictumab in combination with nab-paclitaxel and gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma. Patients received vantictumab at escalating doses in combination with standard dosing of nab-paclitaxel and gemcitabine according to a 3 + 3 design. A total of 31 patients were treated in 5 dosing cohorts. Fragility fractures attributed to vantictumab occurred in 2 patients in Cohort 2 (7 mg/kg every 2 weeks), and this maximum administered dose (MAD) on study was considered unsafe. The dosing schedule was revised to every 4 weeks for Cohorts 3 through 5, with additional bone safety parameters added. Sequential dosing of vantictumab followed by nab-paclitaxel and gemcitabine was also explored. No fragility fractures attributed to vantictumab occurred in these cohorts; pathologic fracture not attributed to vantictumab was documented in 2 patients. The study was ultimately terminated due to concerns around bone-related safety, and thus the maximum tolerated dose (MTD) of the combination was not determined. The MAD of vantictumab according to the revised dosing schedule was 5 mg/kg (n = 16).

Keywords: Gemcitabine; Metastatic pancreatic adenocarcinoma; Nab-paclitaxel; Phase 1b; Vantictumab.

Fig. 1

Treatment schedule across study cohorts a Treatment schedule for vantictumab every 2 weeks with nab-paclitaxel and gemcitabine weekly for weeks 1–3 in Cohorts 1 and 2 b Treatment schedule for vantictumab dosed every 4 weeks with nab-paclitaxel and gemcitabine weekly for weeks 1–3 in Cohorts 3 and 4 c. Sequential dosing of vantictumab followed by nab-paclitaxel and gemcitabine in Cohort 5

Fig. 2

Waterfall plot of maximum percent change in tumor size across all cohorts Response documented according to RECIST v1.1 in the intent to treat population per investigator assessment. Progressive disease (PD) is indicated by red bars, stable disease (SD) is indicated by gray bars, and partial response (PR) or complete response (CR) is indicated by green bars

Fig. 3

Distribution of 3-gene signature by best overall response A total of 10 baseline FFPE tissues were evaluated for the 3 gene biomarker. In this sample of patients, low biomarker signature scores were noted in patients with progressive disease (PD), while higher scores were documented in patients with partial response (PR) and stable disease (SD)