Annals of Oncology Advance Access originally published online on August 17, 2005
Annals of Oncology 2005 16(12):1867-1873; doi:10.1093/annonc/mdi393
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© 2005 European Society for Medical Oncology
Gefitinib (ZD1839) combined with weekly epirubicin in patients with metastatic breast cancer: a phase I study with biological correlate
1 Division of Medical Oncology, San Filippo Neri Hospital, Rome; 2 Associazione ABO and Regional Center for the Study of Biological Markers of Malignancy, General Hospital, Venice, Italy
* Correspondence to: Professor G. Gasparini, Division of Medical Oncology ‘San Filippo Neri’ Hospital, Via Martinotti 20, 00135 Rome, Italy. Tel: +39-06-33062237; Fax: +39-06-33062445; E-mail: gasparini.oncology{at}tiscalinet.it
Purpose: Epidermal growth factor receptor (EGFR) is overexpressed in approximately 50% of invasive breast carcinomas and it is correlated with hormone resistance and poor prognosis. EGFR suppression by gefitinib, a quinazoline derivative that inhibits phosphorylation of the specific receptor, represents a novel therapeutic strategy. A dose-finding study was performed to evaluate the combination of gefitinib with weekly epirubicin in patients with pretreated metastatic breast cancer.
Methods: Fifteen patients were enrolled at four sequential dose levels. Gefitinib was administered orally, at the fixed daily dose of 250 mg. The starting dose of epirubicin was 20 mg/m2. Escalating dose levels of epirubicin were planned by increments of 5 mg/m2 per level, up to the maximum tolerated dose (MTD). Pharmacodynamic studies were performed by determining serum and tissue ERBB2 and EGFR.
Results: At the first three dose levels tested no patient experienced a dose-limiting toxicity (DLT). In cohort 4, two patients experienced DLTs (grade 4 dyspnea and asthenia, grade 3 diarrhea and thrombocytopenia) identifying the MTD of epirubicin as 35 mg/m2. Of the 14 cases assessable for response, partial response was documented in two patients, and stable disease in seven, giving an overall disease control rate of 64.2%. The comparison of pre- and post-therapy ERBB2 and EGFR values was not statistically significant between the subgroups of patients regarding responsiveness to treatment.
Conclusions: The recommended dose of epirubicin for phase II studies is 30 mg/m2 in combination with gefitinib at the daily dose of 250 mg. Pharmacodynamic studies did not identify any biomarker predictive of response.
Key words: breast cancer, epirubicin, gefitinib, phase I study
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