Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid malignant tumors

• Published in: Annals of oncology Vol. 14; no. 6; pp. 922 - 930
• Main Authors: Nakagawa, K., Tamura, T., Negoro, S., Kudoh, S., Yamamoto, N., Takeda, K., Swaisland, H., Nakatani, I., Hirose, M., Dong, R.-P., Fukuoka, M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.06.2003
• Subjects: Administration, Oral; Adult; Aged; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; Chemotherapy; Dose-Response Relationship, Drug; EGFR inhibitor; ErbB Receptors - antagonists & inhibitors; Female; Gefitinib; Humans; Iressa; Japan; Key words: efficacy; Male; Medical sciences; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Pharmacology. Drug treatments; phase I trial; Protein-Tyrosine Kinases - antagonists & inhibitors; Quinazolines - administration & dosage; Quinazolines - adverse effects; Quinazolines - pharmacokinetics; tolerability; Tomography, X-Ray Computed; Treatment Outcome; ZD1839; Asia; Japan; Antineoplastic agent; Human; Solid tumor; Iressa; Enzyme; Transferases; EGFR inhibitor; Oral administration; Enzyme inhibitor; gefitinib; Malignant tumor; Epidermal growth factor receptor; efficacy; Blood plasma; Chemotherapy; Growth factor receptor; Epidermal growth factor; Treatment; Phase I trial; phase I trial tolerability; Pharmacokinetics; Protein-tyrosine kinase; ZD1839
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdg250

Background: This phase I dose-escalating study investigated the tolerability and toxicity of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid tumors. Thirty-one patients were included. Patients and methods: Patients initially received a single oral dose of gefitinib followed by 10–14 days of observation. Oral gefitinib was subsequently administered on 14 consecutive days, every 28 days. Dose escalation was from 50 mg/day to a maximum of 925 mg/day or dose-limiting toxicity (DLT). Results: Most adverse events were mild (grade 1/2); the most frequent were an acne-like rash and gastrointestinal effects. Two of six patients at 700 mg/day had DLT; no further dose escalation occurred. Cmax was reached within 3–7 h and exposure to gefitinib increased with dose. Mean terminal half-life following multiple dosing was 50.1 h (range 27.8–79.7 h). A partial response (duration 35–361 days) was observed in five of the 23 patients with non-small-cell lung cancer over a range of doses (225–700 mg/day), and seven patients with a range of tumors had disease stabilization (duration 40–127 days). Conclusions: In conclusion, gefitinib showed a favorable tolerability profile in Japanese patients. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study are comparable to those observed in patients from the USA and Europe.