494P - Phase I Safety and Tolerability of Once Daily Oral Afatinib (A) in Combination with Docetaxel (D) in Patients (PTS) with Relapsed or Refractory Advanced Solid Tumours

Abstract

ABSTRACT Background A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability and pharmacokinetics (PK) of A, in two parallel dose cohort expansion parts, in combination with either gemcitabine (Part A) or D (Part B) in pts with relapsed or refractory solid tumours. Preliminary results from Part B are presented here. Methods Eligible pts (advanced solid tumours, Eastern Cooperative Oncology Group Performance Status 0–1) received once daily, oral dosing of A with D, given intravenously on Day 1 of every 3 week cycle. Primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLT) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 pts using a 3 + 3 design. Initial starting dose level was A 30 mg/day and D 60 mg/m2, escalating up to A 50 mg/day and D 75 mg/m2 until the MTD was reached, and followed by a PK expansion cohort of 12 pts at the MTD level. Results To date, 27 pts have been treated in Part B, 18 pts in the escalation phase with A (30–50 mg/day) and D (60–75 mg/m2), and 9 pts in the expansion phase with A 40 mg/day and D 75 mg/m2. Baseline characteristics were mean age (56.4 years), female (44.4%), and number of prior chemotherapies (≤ 2: 48%; >2: 52%). Adverse events (AEs) were manageable and the MTD was not exceeded in the tested dose range up to A 50 mg/day and D 75 mg/m2. AEs were diarrhoea (92.6%) and asthenia (77.8%). Selected dose level for the expansion cohort (A 40 mg/d with D 75 mg/m2) was based on the potential for diarrhoea and rash during later cycles. At this dosage, events qualifying for DLT such as febrile neutropenia (2), diarrhoea Grade 3, hypokalaemia Grade 3, hyponatraemia Grade 3, increase of creatininaemia Grade 2 and oral mucositis, were observed in 7 pts. Conclusions Based on the rate of DLTs observed at 40 mg/day A + 75 mg/m2 D, the decision was made to evaluate further the A 30 mg/day + D 75 mg/m2 dose regimen in an additional cohort of 12 pts. Additional safety data and preliminary evidence of activity are anticipated to be available at the time of presentation. Disclosure J. Bennouna: I have received honoraria from roche, boeringher, amgen for advisory board. It is for myself. H. De Mont-Serrat: Employee of Boehringer Ingelheim. P. Squiban: Employee of Boehringer Ingelheim. I. Tschoepe: Employee of Boehringer Ingelheim. All other authors have declared no conflicts of interest.