title: Safety and pharmacokinetics of high-dose gefitinib in patients with solid tumors: results of a phase I study.
abstract: OBJECTIVE
  Previous studies established the safety of continuous gefitinib 250 or 500 mg daily. It was postulated that a higher dose may have increased efficacy by inhibiting signaling in both the mitogen-activated protein kinase and AKT pathways. This study investigated the tolerability, pharmacokinetics, and antitumor activity of high-dose gefitinib in patients with refractory solid malignancies.
  
  
  METHODS
  Sequential cohorts received oral gefitinib once or twice-weekly, with dose escalation from 1,500 to 3,500 mg.
  
  
  RESULTS
  Twenty-three patients received gefitinib at seven dose levels (1,500, 2,000, 2,500, 3,000, and 3,500 mg once-weekly; 1,500 and 2,000 mg twice-weekly). Gefitinib was well tolerated, with no dose-limiting toxicities. The maximum tolerated dose was not reached. The most common gefitinib-related adverse events were nausea and diarrhea, vomiting, and rash. Pharmacokinetic data demonstrated no consistent increase in exposure to gefitinib with increasing dose across cohorts. Consequently, the study was stopped early and gefitinib 2,000 mg twice-weekly was the highest dose administered. One of eight patients with non-small-cell lung cancer achieved a partial response.
  
  
  CONCLUSIONS
  Exposure to gefitinib did not increase consistently with increasing dose beyond gefitinib 1,500 mg once-weekly or twice-weekly. These data do not support further evaluation of gefitinib at high-dose schedules.
authors: Center for Applied Molecular Medicine, University of Southern California Westside Cancer Center, Beverly Hills, CA, USA. mitchell.gross@usc.edu
authors: Mitchell E
authors: ME
authors: Gross
authors: Lawrence
authors: L
authors: Leichman
authors: Elizabeth S
authors: ES
authors: Lowe
authors: Alan
authors: A
authors: Swaisland
authors: David B
authors: DB
authors: Agus
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077156:Gefitinib