title: Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin.
abstract: OBJECTIVE
  The epidermal growth factor (EGF) receptor is frequently overexpressed in epithelial tumors. C225 is a human-to-murine chimeric monoclonal antibody that binds to the receptor and inhibits growth of cancer cells expressing the receptor. We evaluated the pharmacokinetics and toxicity of C225 in patients with advanced tumors overexpressing EGF receptors.
  
  
  METHODS
  We treated 52 patients in three successive phase I clinical trials of C225 as a single dose (n = 13), weekly multiple dose (n = 17), and weekly multiple dose with cisplatin (n = 22). C225 dose levels were 5, 20, 50, and 100 mg/m(2). In the study combining C225 with cisplatin, limited to patients with either head and neck or non-small-cell lung cancer, C225 was further escalated to 200 and 400 mg/m(2). Cisplatin was given at a dose of 60 mg/m(2) once every 4 weeks, and treatment was continued for up to 12 weeks if no disease progression occurred.
  
  
  RESULTS
  C225 displayed nonlinear pharmacokinetics, with antibody doses in the range of 200 to 400 mg/m(2) being associated with complete saturation of systemic clearance. C225 clearance did not change with repeated administration or with coadministration of cisplatin. Antibodies against C225 were detected in only one patient, and C225-associated toxicity was minimal. Patients experiencing disease stabilization were seen in all studies. In the study combining C225 and cisplatin, nine (69%) of 13 patients treated with antibody doses >/= 50 mg/m(2) completed 12 weeks of therapy, and two partial responses were observed.
  
  
  CONCLUSIONS
  C225 has dose-dependent pharmacokinetics, and doses that achieve saturation of systemic clearance are well tolerated. C225 given in combination with cisplatin has biologic activity at pharmacologically relevant doses.
authors.affiliation: Department of Medicine, Breast Cancer Medicine and Genitourinary Medicine Services, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. baselga@hg.vhebron.es
authors.forename: J
authors.initials: J
authors.lastname: Baselga
authors.forename: D
authors.initials: D
authors.lastname: Pfister
authors.forename: M R
authors.initials: MR
authors.lastname: Cooper
authors.forename: R
authors.initials: R
authors.lastname: Cohen
authors.forename: B
authors.initials: B
authors.lastname: Burtness
authors.forename: M
authors.initials: M
authors.lastname: Bos
authors.forename: G
authors.initials: G
authors.lastname: D'Andrea
authors.forename: A
authors.initials: A
authors.lastname: Seidman
authors.forename: L
authors.initials: L
authors.lastname: Norton
authors.forename: K
authors.initials: K
authors.lastname: Gunnett
authors.forename: J
authors.initials: J
authors.lastname: Falcey
authors.forename: V
authors.initials: V
authors.lastname: Anderson
authors.forename: H
authors.initials: H
authors.lastname: Waksal
authors.forename: J
authors.initials: J
authors.lastname: Mendelsohn
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000628:therapy; D000068818:Cetuximab; D002945:Cisplatin / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000628:therapy; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy / Q000628:therapy; D008297:Male; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012074:Remission Induction; D012449:Safety
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D066246:ErbB Receptors; D000068818:Cetuximab; D002945:Cisplatin