PHASE I STUDIES

Investigational New Drugs

, Volume 31, Issue 3, pp 734-741

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

Phase I study of pulsatile 3-day administration of afatinib (BIBW 2992) in combination with docetaxel in advanced solid tumors

  • A. H. AwadaAffiliated withInstitut Jules Bordet Brussels, Université Libre de Bruxelles Email author 
  • , H. DumezAffiliated withDepartment of General Medical Oncology and Laboratory of Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, Catholic University Leuven
  • , A. HendliszAffiliated withInstitut Jules Bordet Brussels, Université Libre de Bruxelles
  • , P. WolterAffiliated withDepartment of General Medical Oncology and Laboratory of Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, Catholic University Leuven
  • , T. Besse-HammerAffiliated withInstitut Jules Bordet Brussels, Université Libre de Bruxelles
  • , M. Uttenreuther-FischerAffiliated withBoehringer Ingelheim, Pharma GmbH & Co KG
  • , P. StopferAffiliated withBoehringer Ingelheim, Pharma GmbH & Co KG
  • , F. FleischerAffiliated withBoehringer Ingelheim, Pharma GmbH & Co KG
  • , M. PiccartAffiliated withInstitut Jules Bordet Brussels, Université Libre de Bruxelles
    • , P. SchöffskiAffiliated withDepartment of General Medical Oncology and Laboratory of Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, Catholic University Leuven

Summary

Background A phase I study to assess the maximum tolerated dose (MTD) of a short course of afatinib in combination with docetaxel for the treatment of solid tumors. Methods Patients with advanced solid malignancies received docetaxel 75 mg/m2 intravenously on day 1 and oral afatinib once daily on days 2–4, in 3-week treatment cycles. The afatinib dose was escalated in successive cohorts of 3–6 patients until dose-limiting toxicity (DLT). The MTD cohort was expanded to 13 patients. Pharmacokinetic parameters were assessed. Results Forty patients were treated. Afatinib doses were escalated to 160 mg/day in combination with 75 mg/m2 docetaxel. Three patients had drug-related DLTs during cycle 1. The MTD was defined as 90 mg/day afatinib (days 2–4) with docetaxel 75 mg/m2. The most frequent drug-related adverse events (all grades) were alopecia, diarrhea, stomatitis (all 50 %) and rash (40 %, all grade ≤2). Three patients had confirmed responses, two patients had unconfirmed responses and nine patients had durable stable disease >6 cycles. No pharmacokinetic interaction was observed. Conclusion Afatinib 90 mg administered for 3 days after docetaxel 75 mg/m2 is the MTD for this treatment schedule and the recommended phase II/phase III dose. This combination showed anti-tumor activity in phase I, with a manageable adverse-event profile.

Keywords

Phase I BIBW 2992 Afatinib Epidermal growth factor receptor Tyrosine kinase inhibitor Pharmacokinetics