title: Gefitinib (ZD1839) combined with weekly epirubicin in patients with metastatic breast cancer: a phase I study with biological correlate.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Medical Oncology, San Filippo Neri Hospital, Rome, Italy. gasparini.oncology@tiscalinet.it
authors.forename: G
authors.initials: G
authors.lastname: Gasparini
authors.forename: R
authors.initials: R
authors.lastname: Sarmiento
authors.forename: S
authors.initials: S
authors.lastname: Amici
authors.forename: R
authors.initials: R
authors.lastname: Longo
authors.forename: D
authors.initials: D
authors.lastname: Gattuso
authors.forename: M
authors.initials: M
authors.lastname: Zancan
authors.forename: M
authors.initials: M
authors.lastname: Gion
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin / Q000008:administration & dosage; D066246:ErbB Receptors / Q000097:blood; D005260:Female; D000077156:Gefitinib; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood
chemical_list: D015251:Epirubicin; D066246:ErbB Receptors; D000077156:Gefitinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases