464P - A Phase I Study of Daily Afatinib, an Irreversible Erbb Family Blocker, Combined With Weekly Paclitaxel and 2-Weekly Bevacizumab in Patients with Advanced Solid Tumours

Abstract

ABSTRACT Background The clinical efficacy of cytotoxic agents can be enhanced both by ErbB inhibition and by bevacizumab (Bev). The primary objective of this study was to determine the maximum tolerated dose (MTD) of afatinib (A), an oral, irreversible ErbB Family Blocker, in combination with paclitaxel (P) and Bev. Afatinib (mg/day) Paclitaxel (mg/m2 Days 1, 8, 15) Bevacizumab (mg/kg Days 1, 15) All pts/Evaluable pts/Pts with DLT DLT (all Grade 3) 40 80 5 7/6/2 Fatigue/diarrhoea; fatigue 30 80 5 5/5/2 Diarrhoea; paronychia 20 80 5 3/3/0 20 80 7.5 6/6/1 Mucositis (recommended dose) 20 80 10 8/6/1 Dysphonia (MTD) Overall, the most frequent (any grade) adverse events (AEs) included diarrhoea (86%), fatigue (86%), rash (69%), mucositis (59%), and nausea (59%). Partial responses were confirmed in pts with non-small cell lung (n = 2) and cervical (n = 1) cancer. Eleven pts completed at least 6 treatment cycles of combination therapy. Methods A Phase I open-label 3 + 3 design dose-escalation trial was undertaken to determine safety, pharmacokinetics (PK), and antitumour efficacy of A combined with P (fixed dose 80 mg/m2 on Days 1, 8 and 15 of a 4-week cycle), and Bev (5 mg/kg starting dose to be escalated to 10 mg/kg) administered on Days 1 and 15 in patients (pts) with advanced solid tumours. After at least 6 cycles of triplet combination therapy, pts benefiting and tolerating treatment were eligible to continue treatment with A and Bev. The PK data of P and Bev (± A), as well as the steady state PK of A combined with P and Bev will be presented. Results Twenty-nine pts were enrolled (12 male; median age: 58 years [range: 21–73]; ECOG PS 0/1: 3/26). The MTD dose previously established for A (40 mg/day) in combination with P only (above schedule; Spicer et al. ESMO 2008) had to be de-escalated to 30 mg and then to 20 mg after 2/6 pts developed dose-limiting toxicities (DLTs) at 40 mg A and 2/5 at 30 mg A when combined with P and Bev 5 mg/kg. Conclusions Promising antitumour activity was seen with the combination of A at 20 mg/day with weekly P 80 mg/m2 and 2-weekly Bev 7.5 mg/kg, the recommended dose for a Phase II study. At this dose, AEs of A combined with P and Bev were generally mild to moderate and manageable. Disclosure M. Uttenreuther-Fischer: Employee of Boehringer-Ingelheim. K. Pemberton: Employee of Boehringer Ingelheim. K. Pelling: Employee of Boehringer Ingelheim. D. Schnell: Employee of SocraMetrics/Boehringer Ingelheim. J.S. de Bono: I have served as a paid consultant for Boehringer Ingelheim. J. Spicer: Honoraria from Boehringer Ingelheim. All other authors have declared no conflicts of interest.