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Davis SL , Cardin DB , Shahda S , Lenz HJ , Dotan E , O'Neil BH , Kapoun AM , Stagg RJ , Berlin J , Messersmith WA , Cohen SJ
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
Investigational New Drugs. 2020 Jun;38(3) :821-830
PMID: 31338636    PMCID: PMC7211194    URL: https://www.ncbi.nlm.nih.gov/pubmed/31338636
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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).
Notes
Davis, S. Lindsey Cardin, Dana B. Shahda, Safi Lenz, Heinz-Josef Dotan, Efrat O'Neil, Bert H. Kapoun, Ann M. Stagg, Robert J. Berlin, Jordan Messersmith, Wells A. Cohen, Steven J. Hopkins, Katie/0000-0001-7279-5322 1573-0646