A Phase Ib Dose Escalation Study of Vantictumab (VAN) in Combination with Nab-Paclitaxel (Nab-P) and Gemcitabine (G) in Patients with Previously Untreated Stage IV Pancreatic Cancer

249 Background: Vantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. A phase Ib study of VAN in combination with Nab-P and G was performed in patients with untreated stage IV pancreatic adenocarcinoma. Methods: Patients received VAN at escalating doses (3-7 mg/kg) in combination with standard dosing of Nab-P and G according to a 3+3 design. Due to fragility fractures occurring in this and other related clinical trials, dosing on an every 2 week schedule in cohorts 1 and 2 was transitioned to every 4 week dosing for cohorts 3 through 5. In these later cohorts, a minimum of six patients were treated at each dose level and additional criteria for maximum tolerated dose (MTD) integrating bone safety parameters were added. The bone safety plan was also revised for these cohorts. Sequential dosing of VAN followed by Nab-P and G was explored in cohort 5. Results: Thirty-one patients (52% male, 48% female) were enrolled and treated in 5 dosing cohorts. Median age was 66. Most common study-treatment related adverse events were nausea (68%) and fatigue (52%). One dose limiting toxicity (DLT) event occurred in the study population—grade 3 dehydration in 1 of 9 patients in cohort 4 (5 mg/kg q4w). Fragility fractures attributed to VAN occurred in two patients in cohort 2 (7 mg/kg q2w). Once the dosing schedule was revised to every 4 weeks, the maximum administered VAN dose was 5 mg/kg. No fragility fractures attributed to VAN occurred in these cohorts; pathologic fracture not attributed to VAN was documented in 2 patients. The study was terminated due to lack of an acceptable therapeutic index. Partial response was documented in 13 patients (42%) and stable disease in 11 (36%). Conclusions: The MTD of VAN plus Nab-P and G was not determined, but the maximum administered dose (MAD) of VAN, 7 mg/kg every 2 weeks, was considered unsafe related to bone toxicity, a known effect of WNT inhibition. After the study was revised, the MAD was 5 mg/kg every 4 weeks, with no protocol-specified bone toxicity observed (n = 16). Clinical trial information: NCT02005315.