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

  • Invest New Drugs. 2020 Jun;38(3):821-830. doi: 10.1007/s10637-019-00824-1.
S Lindsey Davis  1 ,  Dana B Cardin  2 ,  Safi Shahda  3 ,  Heinz-Josef Lenz  4 ,  Efrat Dotan  5 ,  Bert H O'Neil  3 ,  Ann M Kapoun  6 ,  Robert J Stagg  6 ,  Jordan Berlin  2 ,  Wells A Messersmith  7 ,  Steven J Cohen  8
Affiliations
  • 1. University of Colorado Cancer Center, Aurora, CO, USA. [email protected].
  • 2. Vanderbilt University, Nashville, TN, USA.
  • 3. Indiana University, Indianapolis, IN, USA.
  • 4. University of Southern California, Los Angeles, CA, USA.
  • 5. Fox Chase Cancer Center, Philadelphia, PA, USA.
  • 6. OncoMed Pharmaceuticals, Redwood City, CA, USA.
  • 7. University of Colorado Cancer Center, Aurora, CO, USA.
  • 8. Jefferson Health/Abington Memorial Hospital, Abington, PA, USA.
PMID: 31338636 DOI: 10.1007/s10637-019-00824-1
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.
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