title: A phase I pharmacologic study of necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody directed against EGFR in patients with advanced solid malignancies.
abstract: OBJECTIVE
  This study aimed to determine a maximum tolerated dose (MTD) and recommended dose for disease-directed studies of necitumumab (IMC-11F8), a fully human IgG(1) monoclonal antibody directed at the epidermal growth factor receptor, and to characterize the safety profile, pharmacokinetics, preliminary antitumor activity, and immunogenicity of necitumumab.
  
  
  METHODS
  Patients with advanced solid malignancies were treated with 100 to 1,000 mg (flat dosing) necitumumab followed by a 2-week pharmacokinetics sampling period, before beginning 6-week cycles of therapy.
  
  
  RESULTS
  Sixty patients received necitumumab weekly (29 patients) or every other week (31 patients). Two patients receiving 1,000 mg every 2 weeks experienced dose-limiting toxicities (DLT; grade 3 headache), accompanied by grade 3 nausea and vomiting in one patient. Occurring hours after the initial dose, these DLTs established 800 mg as the MTD. Mild dose-related skin toxicity was the most common drug-related toxicity (80%). One patient in each arm experienced grade 3 acneform rash, which responded to oral antibiotics and topical therapy. Toxicity was similar on both schedules. Necitumumab exhibited saturable elimination and nonlinear pharmacokinetics. At 800 mg (both arms), its half-life was approximately 7 days. All patients treated with >or=600 mg necitumumab achieved target trough concentrations (>or=40 microg/mL). Antibodies against necitumumab were not detected. Partial response and stable disease were experienced by 2 and 16 patients, respectively.
  
  
  CONCLUSIONS
  Well tolerated, necitumumab is associated with preliminary evidence of antitumor activity, and achieves biologically relevant concentrations throughout the dosing period. The recommended dose of necitumumab for further clinical development is 800 mg (flat dose) weekly or every 2 weeks based on the clinical setting.
authors.affiliation: Department of Oncology, Free University Hospital of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Kuenen
authors.forename: Petronella O
authors.initials: PO
authors.lastname: Witteveen
authors.forename: Rita
authors.initials: R
authors.lastname: Ruijter
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
authors.forename: Aruna
authors.initials: A
authors.lastname: Dontabhaktuni
authors.forename: Floyd
authors.initials: F
authors.lastname: Fox
authors.forename: Terry
authors.initials: T
authors.lastname: Katz
authors.forename: Hagop
authors.initials: H
authors.lastname: Youssoufian
authors.forename: Junming
authors.initials: J
authors.lastname: Zhu
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C527969:necitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors