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

Research output: Contribution to journalArticle

James Spicer, Sheeba Irshad, Joo Ern Ang, Deborah Enting, Rebecca Kristeleit, Martina Uttenreuther-Fischer, Karine Pemberton, Katy Pelling, David Schnell, Johann de Bono

Original languageEnglish
Pages (from-to)17-27
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Issue number1
Early online date21 Nov 2016
Publication statusPublished - Jan 2017


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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/m(2), 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/m(2) 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/m(2) (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.

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