, Volume 31, Issue 2, pp 399-408,
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A Phase I, open-label, dose escalation study of afatinib, in a 3-week-on/1-week-off schedule in patients with advanced solid tumors

Summary

Background A Phase I study to determine the maximum tolerated dose (MTD) and pharmacokinetics of afatinib (BIBW 2992), a novel irreversible ErbB Family Blocker, administered orally once daily in a 3-week-on/1-week-off dosing schedule. Methods Patients with advanced solid tumors received single-agent afatinib at 10, 20, 40, 55 or 65 mg/day. Safety, antitumor activity, pharmacokinetics and pharmacodynamic modulation of biomarkers were assessed. Results: Forty-three patients were enrolled. Dose-limiting toxicities (DLTs) occurred in five patients in the dose escalation phase (1/8 at 40 mg/day; 1/6 at 55 mg/day; 3/6 at 65 mg/day). The MTD was established at 55 mg/day. In the expansion cohort at the MTD, 6 patients experienced a DLT in the first 28-day treatment period. The most frequent DLT was diarrhea. The most common adverse events were diarrhea, rash, nausea, vomiting and fatigue. Overall, the afatinib safety profile in a 3-week-on/1-week-off dose schedule was similar to that of our daily-continuous schedule. Afatinib displayed dose-dependent pharmacokinetics at doses up to and including 55 mg/day, with a terminal half-life suitable for once-daily dosing. Signs of clinical antitumor activity were observed. In biopsies taken from clinically normal forearm skin, afatinib caused a reduced proliferation rate, with a concomitant increase in differentiation of epidermal keratinocytes. Conclusion Afatinib in a 3-week-on/1-week-off schedule showed a good safety profile. The MTD was 55 mg/day, although excess DLTs in the expansion cohort indicated that the 40 mg/day dose would have an acceptable safety profile for future studies. Dose cohorts between 40 and 55 mg/day were not examined in this study.

Previous presentation: Results from this study have been presented previously at the 17th Annual Symposium of the American Association for Cancer Research–European Organisation for Research and Treatment of Cancer–National Cancer Institute International Conference on “Molecular Targets and Cancer Therapeutics”, November 14–18 2005, Philadelphia, PA, USA, and at the 42nd Annual Meeting of the American Society of Clinical Oncology, 2–6 June 2006, Atlanta, GA, USA.