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A phase I study of afatinib combined with paclitaxel and bevacizumab in patients with advanced solid tumors

Spicer, J; Irshad, S; Ang, JE; Enting, D; Kristeleit, RS; Uttenreuther-Fischer, M; Pemberton, K; ... De Bono, J; + view all (2017) A phase I study of afatinib combined with paclitaxel and bevacizumab in patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology , 79 (1) pp. 17-27. 10.1007/s00280-016-3189-1. Green open access

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Abstract

Purpose: The combination of afatinib, an irreversible ErbB family blocker, with paclitaxel and bevacizumab was assessed in patients with advanced solid tumors. / Methods: This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel and bevacizumab. Safety, pharmacokinetics, and anti-tumor activity were also assessed. The starting dose was oral afatinib 40 mg once daily plus intravenous paclitaxel (fixed dose 80 mg/m2, Days 1, 8, and 15 of a 4-week cycle) and intravenous bevacizumab 5 mg/kg every 2 weeks. / Results: Twenty-nine patients were enroled. The afatinib dose was de-escalated to 30 mg and then 20 mg after 2/6 and 2/5 evaluable patients developed dose-limiting toxicities at 40 and 30 mg, respectively, when combined with paclitaxel and bevacizumab 5 mg/kg. The bevacizumab dose was subsequently escalated to 10 mg/kg, and MTD was defined as afatinib 20 mg plus paclitaxel 80 mg/m2 and bevacizumab 10 mg/kg. Frequent (any grade) treatment-related adverse events (AEs) included diarrhea (83%), rash/acne (83%), fatigue (79%), mucosal inflammation (59%), and nausea (59%). Based on overall safety, bevacizumab was amended to 7.5 mg/kg for the recommended phase II dose. Pharmacokinetic analyses suggested no relevant drug–drug interactions. Three (10%) confirmed partial responses were observed; 15 (52%) patients had stable disease. / Conclusions: The recommended phase II dose schedule was afatinib 20 mg/day with paclitaxel 80 mg/m2 (Days 1, 8, and 15 every 4 weeks) and bevacizumab 7.5 mg/kg every 2 weeks. At this dose schedule, AEs were manageable, and anti-tumor activity was observed.

Type: Article
Title: A phase I study of afatinib combined with paclitaxel and bevacizumab in patients with advanced solid tumors
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s00280-016-3189-1
Publisher version: http://dx.doi.org/10.1007/s00280-016-3189-1
Language: English
Additional information: Copyright © The Author(s) 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: Afatinib, Paclitaxel, Bevacizumab, Phase I, Solid tumors
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/1529515
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