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.

2.50
Hdl Handle:
http://hdl.handle.net/10541/80218
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.
Authors:
Baselga, Jose; Rischin, Danny; Ranson, Malcolm R; Calvert, A Hilary; Raymond, Eric; Kieback, Dirk; Kaye, Stan B; Gianni, L; Harris, A; Björk-Eriksson, Thomas; Averbuch, Steven D; Feyereislova, Andrea; Swaisland, Helen C; Rojo, F; Albanell, Joan
Abstract:
PURPOSE: 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. PATIENTS AND 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. CONCLUSION: 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.
Affiliation:
Vall d'Hebron University Hospital, Barcelona, Spain. baselga@hg.vhebron.es
Citation:
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. 2002, 20 (21):4292-302 J. Clin. Oncol.
Journal:
Journal of Clinical Oncology
Issue Date:
1-Nov-2002
URI:
http://hdl.handle.net/10541/80218
PubMed ID:
12409327
Type:
Article
Language:
en
ISSN:
0732-183X
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorBaselga, Jose-
dc.contributor.authorRischin, Danny-
dc.contributor.authorRanson, Malcolm R-
dc.contributor.authorCalvert, A Hilary-
dc.contributor.authorRaymond, Eric-
dc.contributor.authorKieback, Dirk-
dc.contributor.authorKaye, Stan B-
dc.contributor.authorGianni, L-
dc.contributor.authorHarris, A-
dc.contributor.authorBjörk-Eriksson, Thomas-
dc.contributor.authorAverbuch, Steven D-
dc.contributor.authorFeyereislova, Andrea-
dc.contributor.authorSwaisland, Helen C-
dc.contributor.authorRojo, F-
dc.contributor.authorAlbanell, Joan-
dc.date.accessioned2009-09-08T09:09:57Z-
dc.date.available2009-09-08T09:09:57Z-
dc.date.issued2002-11-01-
dc.identifier.citationPhase 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. 2002, 20 (21):4292-302 J. Clin. Oncol.en
dc.identifier.issn0732-183X-
dc.identifier.pmid12409327-
dc.identifier.urihttp://hdl.handle.net/10541/80218-
dc.description.abstractPURPOSE: 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. PATIENTS AND 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. CONCLUSION: 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.en
dc.language.isoenen
dc.subjectColorectal Canceren
dc.subjectHead and Neck Canceren
dc.subjectLung Canceren
dc.subjectOvarian Canceren
dc.subjectProstatic Canceren
dc.subject.meshAdministration, Oral-
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshAged, 80 and over-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshBiopsy-
dc.subject.meshCarcinoma, Non-Small-Cell Lung-
dc.subject.meshColorectal Neoplasms-
dc.subject.meshDiarrhea-
dc.subject.meshDisease Progression-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshFemale-
dc.subject.meshHead and Neck Neoplasms-
dc.subject.meshHumans-
dc.subject.meshLung Neoplasms-
dc.subject.meshMale-
dc.subject.meshMiddle Aged-
dc.subject.meshOvarian Neoplasms-
dc.subject.meshProstatic Neoplasms-
dc.subject.meshQuinazolines-
dc.subject.meshSkin-
dc.subject.meshTreatment Outcome-
dc.titlePhase 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.en
dc.typeArticleen
dc.contributor.departmentVall d'Hebron University Hospital, Barcelona, Spain. baselga@hg.vhebron.esen
dc.identifier.journalJournal of Clinical Oncologyen

Related articles on PubMed

All Items in Christie are protected by copyright, with all rights reserved, unless otherwise indicated.