title: Phase I study of pulsatile 3-day administration of afatinib (BIBW 2992) in combination with docetaxel in advanced solid tumors.
abstract: 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/m(2) 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/m(2) 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/m(2). 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.
  
  
  CONCLUSIONS
  Afatinib 90 mg administered for 3 days after docetaxel 75 mg/m(2) 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.
authors.affiliation: Institut Jules Bordet Brussels, Université Libre de Bruxelles, 121 Boulevard de Waterloo, Brussels, Belgium. ahmad.awada@bordet.be
authors.forename: A H
authors.initials: AH
authors.lastname: Awada
authors.forename: H
authors.initials: H
authors.lastname: Dumez
authors.forename: A
authors.initials: A
authors.lastname: Hendlisz
authors.forename: P
authors.initials: P
authors.lastname: Wolter
authors.forename: T
authors.initials: T
authors.lastname: Besse-Hammer
authors.forename: M
authors.initials: M
authors.lastname: Uttenreuther-Fischer
authors.forename: P
authors.initials: P
authors.lastname: Stopfer
authors.forename: F
authors.initials: F
authors.lastname: Fleischer
authors.forename: M
authors.initials: M
authors.lastname: Piccart
authors.forename: P
authors.initials: P
authors.lastname: Schöffski
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012871:Skin Diseases / Q000139:chemically induced; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; D000077716:Afatinib