title: Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer.
abstract: OBJECTIVE
  To determine the antitumor activity of ABX-EGF, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFr), in previously treated patients with metastatic renal cell carcinoma, and to characterize its toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics.
  
  
  METHODS
  The antitumor activity, as well as the toxicity, pharmacokinetics, pharmacodynamics, and immunogenicity of ABX-EGF, were assessed.
  
  
  RESULTS
  Eighty-eight patients were treated with ABX-EGF doses of 1.0, 1.5, 2.0, or 2.5 mg/kg weekly with no loading dose. EGFr immunostaining was performed on 76 tumor biopsy specimens (86%), and 69 (91%) scored positive. Major responses occurred in three patients, and two patients had minor responses. Forty-four patients (50%) also had stable disease at their first 8-week assessment, and the median progression-free survival (PFS) was 100 days (95% CI, 58 to 140 days). Low hemoglobin and high alkaline phosphatase predicted for short PFS. The principal toxicity, an acneiform rash, occurred in 68%, 95%, 87%, and 100% of patients who received at least three doses of ABX-EGF at 1.0, 1.5, 2.0, and 2.5 mg/kg/wk, respectively. A trend indicated that the severity of the rash may relate to PFS. No human antihuman antibodies were detected. ABX-EGF pharmacokinetics fit a model that incorporated both linear and saturable EGFr-mediated clearance mechanisms, and interindividual variability was low. At 2.5 mg/kg/wk, ABX-EGF concentrations throughout treatment exceeded those estimated to saturate nonlinear clearance and inhibit xenograft growth by 90%.
  
  
  CONCLUSIONS
  ABX-EGF was generally well tolerated. The objective response rate was low in previously treated patients with metastatic renal cell carcinoma. Although skin rash may be a pharmacodynamic marker of drug action, its potential as a surrogate marker of clinical benefit requires further evaluation.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, 7979 Wurzbach Rd, 4th Floor, Zeller Building, San Antonio, TX 78229, USA. erowinsk@idd.org
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Garry H
authors.initials: GH
authors.lastname: Schwartz
authors.forename: Jared A
authors.initials: JA
authors.lastname: Gollob
authors.forename: John A
authors.initials: JA
authors.lastname: Thompson
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: Robert
authors.initials: R
authors.lastname: Figlin
authors.forename: Ronald
authors.initials: R
authors.lastname: Bukowski
authors.forename: Naomi
authors.initials: N
authors.lastname: Haas
authors.forename: Pamela
authors.initials: P
authors.lastname: Lockbaum
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Li
authors.forename: Rosalin
authors.initials: R
authors.lastname: Arends
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Foon
authors.forename: Gisela
authors.initials: G
authors.lastname: Schwab
authors.forename: Janice
authors.initials: J
authors.lastname: Dutcher
mesh_terms: D000469:Alkaline Phosphatase / Q000097:blood; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D003875:Drug Eruptions / Q000209:etiology; D005260:Female; D005500:Follow-Up Studies; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000077544:Panitumumab; D012449:Safety
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D006454:Hemoglobins; D000077544:Panitumumab; D000469:Alkaline Phosphatase