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01-02-2019 | PHASE I STUDIES

Phase Ib trial combining capecitabine, erlotinib and bevacizumab in pancreatic adenocarcinoma - REBECA trial

Authors: Christian Dittrich, Robert Königsberg, Martina Mittlböck, Klaus Geissler, Azra Sahmanovic-Hrgovcic, Johannes Pleiner-Duxneuner, Martin Czejka, Philipp Buchner

Published in: Investigational New Drugs | Issue 1/2019

Summary

Background Purpose of this phase Ib trial was to establish the maximum tolerable dose (MTD) of capecitabine and to escalate the dosages of erlotinib and bevacizumab to determine the recommended phase II dose (RP2D) in patients with advanced/metastatic pancreatic adenocarcinoma not pretreated for metastatic disease. Methods Starting doses were capecitabine 500 mg/m² bid orally continuously, erlotinib 100 mg orally daily, and bevacizumab 5 mg/kg intravenously q 2 weeks. Dose escalation was performed according to a 3 + 3 design for capecitabine until MTD, for erlotinib and bevacizumab until the maximum doses registered by applying a substance-related, toxicity-based scheme accompanied by pharmacokinetic analysis. Circulating tumor cells (CTCs) were determined pretherapeutically by immunohistochemical identification after enrichment with immunomagnetic separation. Results Thirty patients were evaluable at six dose levels. 900 mg/m² bid were determined as MTD for capecitabine based on dose-limiting toxicities: cutaneous in two patients and vascular in another. The most severe (Grade (G)3/4) drug-related treatment-emergent adverse events (toxicities) belonged to the categories gastrointestinal, vascular, cutaneous, cardiovascular, metabolic/nutritional or hematological. G3 toxicities occurred in 14 (47%), G3 + G4 in a single (3%) patient. 2 out of 28 patients (7%) exerted partial response, 17 (61%) stable disease. Pharmacokinetic evaluation revealed lack of drug-drug interaction between capecitabine and erlotinib and their metabolites. Presence of CTCs was associated with shorter progression-free survival (p = 0.009). Conclusions The study met the primary objective. RP2D was capecitabine 800 mg/m² bid continuously, erlotinib 150 mg daily, and bevacizumab 10 mg/kg q 2 weeks. The regimen could be applied safely, but demonstrated limited efficacy.

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Title: Phase Ib trial combining capecitabine, erlotinib and bevacizumab in pancreatic adenocarcinoma - REBECA trial
Authors: Christian Dittrich
Robert Königsberg
Martina Mittlböck
Klaus Geissler
Azra Sahmanovic-Hrgovcic
Johannes Pleiner-Duxneuner
Martin Czejka
Philipp Buchner
Publication date: 01-02-2019
Publisher: Springer US
Published in: Investigational New Drugs / Issue 1/2019
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-018-0639-0

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