title: Phase I and pharmacokinetic study of cetuximab and irinotecan in children with refractory solid tumors: a study of the pediatric oncology experimental therapeutic investigators' consortium.
abstract: OBJECTIVE
  To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors.
  
  
  METHODS
  This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m(2)) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m(2)/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected.
  
  
  RESULTS
  Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m(2) weekly plus irinotecan 16 mg/m(2)/d (pediatric) or 20 mg/m(2)/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%).
  
  
  CONCLUSIONS
  The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. trippet1@mskcc.org
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Trippett
authors.forename: Cynthia
authors.initials: C
authors.lastname: Herzog
authors.forename: James A
authors.initials: JA
authors.lastname: Whitlock
authors.forename: Johannes
authors.initials: J
authors.lastname: Wolff
authors.forename: John
authors.initials: J
authors.lastname: Kuttesch
authors.forename: Rochelle
authors.initials: R
authors.lastname: Bagatell
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Jessica
authors.initials: J
authors.lastname: Boklan
authors.forename: Amy A
authors.initials: AA
authors.lastname: Smith
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Arceci
authors.forename: Howard M
authors.initials: HM
authors.lastname: Katzenstein
authors.forename: Christopher
authors.initials: C
authors.lastname: Harbison
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.forename: Haolan
authors.initials: H
authors.lastname: Lu
authors.forename: Christiane
authors.initials: C
authors.lastname: Langer
authors.forename: Martin
authors.initials: M
authors.lastname: Weber
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
mesh_terms: D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068818:Cetuximab; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077146:Irinotecan; D000068818:Cetuximab; D002166:Camptothecin