title: Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types.
abstract: OBJECTIVE
  To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types.
  
  
  METHODS
  This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited.
  
  
  RESULTS
  Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for >or= 3 months; seven of these patients remained on study drug for >or= 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway.
  
  
  CONCLUSIONS
  ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.
authors.affiliation: Vall d'Hebron University Hospital, Barcelona, Spain. baselga@hg.vhebron.es
authors.forename: J
authors.initials: J
authors.lastname: Baselga
authors.forename: D
authors.initials: D
authors.lastname: Rischin
authors.forename: M
authors.initials: M
authors.lastname: Ranson
authors.forename: H
authors.initials: H
authors.lastname: Calvert
authors.forename: E
authors.initials: E
authors.lastname: Raymond
authors.forename: D G
authors.initials: DG
authors.lastname: Kieback
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
authors.forename: L
authors.initials: L
authors.lastname: Gianni
authors.forename: A
authors.initials: A
authors.lastname: Harris
authors.forename: T
authors.initials: T
authors.lastname: Bjork
authors.forename: S D
authors.initials: SD
authors.lastname: Averbuch
authors.forename: A
authors.initials: A
authors.lastname: Feyereislova
authors.forename: H
authors.initials: H
authors.lastname: Swaisland
authors.forename: F
authors.initials: F
authors.lastname: Rojo
authors.forename: J
authors.initials: J
authors.lastname: Albanell
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D001706:Biopsy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D012867:Skin / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077156:Gefitinib