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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).

SUBMITTER: Davis SL

PROVIDER: S-EPMC7211194 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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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.

Davis S Lindsey SL Cardin Dana B DB Shahda Safi S Lenz Heinz-Josef HJ Dotan Efrat E O'Neil Bert H BH Kapoun Ann M AM Stagg Robert J RJ Berlin Jordan J Messersmith Wells A WA Cohen Steven J SJ

Investigational new drugs 20190723 3

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. Fra ...[more]

PMID: 31338636

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Project description:PurposeThe recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel + gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC).Patients and methodsDose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different anti-Wnt agents, following cohorts had ≥6 patients treated with ipafricept 3 to 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 (ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy.ResultsA total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2-4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade ≥3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4-18.4], median overall survival was 9.7 m (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.ConclusionsIpafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.

Dataset Information

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.

Publications

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.

Similar Datasets

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