title: A Phase I, open-label, dose-escalation study of continuous once-daily oral treatment with afatinib in patients with advanced solid tumors.
abstract: BACKGROUND
  This trial evaluated the safety, tolerability and maximum tolerated dose (MTD) of afatinib, a novel ErbB Family Blocker.
  
  
  METHODS
  In this open-label, dose-escalation Phase I study, afatinib was administered continuously, orally, once-daily for 28 days to patients with advanced or metastatic solid tumors. Dose escalation was performed in a 3 + 3 design, with a starting dose of 10 mg/day (d); doses were doubled for each successive cohort until the MTD was defined. The MTD cohort was expanded to a total of 19 patients. Incidence and severity of adverse events (AEs), antitumor activity and pharmacokinetics were assessed.
  
  
  RESULTS
  Thirty patients received at least one dose of afatinib. Twenty-nine patients were evaluable for response. Dose-limiting toxicities (DLTs) consisting of Grade 3 diarrhea were observed in two out of three patients treated at 60 mg/d. The MTD was determined at 40 mg/d. The most frequent treatment-related AEs were diarrhea and mucosal inflammation reported in 76.7% and 43.3% of patients respectively. Five patients had stable disease with a median progression-free survival of 111 days. No objective responses occurred. Pharmacokinetic data showed no deviation from dose-proportionality and steady-state was reached on Day 8 at the latest.
  
  
  CONCLUSIONS
  Afatinib was well tolerated with manageable side effects when administered once-daily, continuously at a dose of 40 mg.
authors.affiliation: Pinnacle Oncology Hematology, 9055 E Del Camino, Suite 100, Scottsdale, AZ 85258, USA. mgordon@azpoh.com
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.forename: David S
authors.initials: DS
authors.lastname: Mendelson
authors.forename: Mitchell
authors.initials: M
authors.lastname: Gross
authors.forename: Martina
authors.initials: M
authors.lastname: Uttenreuther-Fischer
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Ould-Kaci
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhao
authors.forename: Peter
authors.initials: P
authors.lastname: Stopfer
authors.forename: David B
authors.initials: DB
authors.lastname: Agus
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011379:Prognosis; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014018:Tissue Distribution
chemical_list: D011799:Quinazolines; D000077716:Afatinib