title: Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor.
abstract: OBJECTIVE
  To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR).
  
  
  METHODS
  This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity.
  
  
  RESULTS
  Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000. Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity.
  
  
  CONCLUSIONS
  Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.
authors.affiliation: Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Hufelandstrasse 55, 45122 Essen, Germany. udo.vanhoefer@uni-essen.de
authors.forename: Udo
authors.initials: U
authors.lastname: Vanhoefer
authors.forename: Mitra
authors.initials: M
authors.lastname: Tewes
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.forename: Olaf
authors.initials: O
authors.lastname: Dirsch
authors.forename: Norbert
authors.initials: N
authors.lastname: Schleucher
authors.forename: Oliver
authors.initials: O
authors.lastname: Rosen
authors.forename: Joachim
authors.initials: J
authors.lastname: Tillner
authors.forename: Andreas
authors.initials: A
authors.lastname: Kovar
authors.forename: Ada H
authors.initials: AH
authors.lastname: Braun
authors.forename: Tanja
authors.initials: T
authors.lastname: Trarbach
authors.forename: Siegfried
authors.initials: S
authors.lastname: Seeber
authors.forename: Andreas
authors.initials: A
authors.lastname: Harstrick
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000502:physiology; D005260:Female; D005334:Fever / Q000209:etiology; D006261:Headache / Q000209:etiology; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000068818:Cetuximab