title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA. marshalj@georgetown.edu
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.forename: Jimmy
authors.initials: J
authors.lastname: Hwang
authors.forename: Ferry A L M
authors.initials: FA
authors.lastname: Eskens
authors.forename: Herman
authors.initials: H
authors.lastname: Burger
authors.forename: Shakun
authors.initials: S
authors.lastname: Malik
authors.forename: Martina
authors.initials: M
authors.lastname: Uttenreuther-Fischer
authors.forename: Peter
authors.initials: P
authors.lastname: Stopfer
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Ould-Kaci
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Lewis
mesh_terms: D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; 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