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

• DOI: 10.1200/jco.2002.03.100
• Publication Date: 2002-10-30T18:22:42Z
• Authors: J. Baselga; D. Rischin; M. Ranson; H. Calvert; E. Raymond; D.G. Kieback; S.B. Kaye; L. Gianni; A. Harris; T. Bjork; S.D. Averbuch; A. Feyereislova; H. Swaisland; F. Rojo; J. Albanell
• Keywords: Tolerability; Pharmacodynamics

To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, to explore its pharmacokinetic pharmacodynamic effects in patients with selected solid tumor types.This was phase I dose-escalating trial oral 150 mg/d maximum 1,000 given once daily for at least 28 days. Patients either advanced non-small-cell lung, ovarian, head neck, prostate, or colorectal cancer were recruited.Eighty-eight received (150 mg/d). At mg/d, five 12 experienced dose-limiting toxicity (grade 3 diarrhea [four patients] grade somnolence [one patient]). The most frequent drug-related adverse events (AEs) acne-like rash (64%) (47%), which generally mild 1/2) reversible on cessation treatment. No change profile observed prolonged administration. Pharmacokinetic analysis showed steady-state exposure 98% by day 7. Nineteen had stable disease >or= months; seven these remained study drug 6 months. Serial skin biopsies taken before treatment approximately revealed changes indicative inhibition EGFR signaling pathway.ZD1839 well tolerated, manageable AEs doses up 600 mg/d. resulted clinically meaningful stabilization across range types doses. Pharmacodynamic confirmed signaling, predicted from mode action ZD1839.