title: Phase 1 and pharmacokinetic study of concurrent carboplatin and irinotecan in subjects aged 1 to 21 years with refractory solid tumors.
abstract: BACKGROUND
  Preclinical testing suggests the combination of carboplatin and irinotecan has at least additive antitumor activity. The primary objectives of the current study were to determine the maximum tolerated doses (MTDs) and recommended phase 2 doses of carboplatin administered with irinotecan to pediatric patients with refractory solid tumors.
  
  
  METHODS
  This was a multicenter, open-label, single-arm dose escalation study in which subjects with refractory solid tumors received 21-day treatment cycles of intravenous carboplatin on Day 1 followed by intravenous irinotecan administered daily for 10 days within 2 consecutive weeks. The plasma pharmacokinetics of ultrafiltrable platinum, irinotecan, and 2 irinotecan metabolites were determined during Cycle 1. The interpatient plan for dose escalation at study initiation was to increase irinotecan first followed by increases in carboplatin.
  
  
  RESULTS
  Twenty-eight patients with a median age of 8.5 years (range, 1-21 years) were enrolled with a variety of solid tumors. Two of 6 subjects at the first dose level (carboplatin target area under the curve [AUC], 4.0 mg/mL*min; irinotecan, 18 mg/m2/dose) experienced dose-limiting gastrointestinal toxicities requiring a dose de-escalation scheme (carboplatin AUC, 4.0 mg/mL*min; irinotecan, 15 mg/m2/dose). Three of 6 subjects at the second dose level experienced dose-limiting gastrointestinal complications and bone marrow suppression. A further dose de-escalation to carboplatin AUC of 4.0 mg/mL*min and irinotecan of 12 mg/m2/dose resulted in dose-limiting bone marrow suppression in 1 of 13 patients treated at that dose, and therefore was determined to be the MTD. One complete response (in a patient with medulloblastoma) and 3 partial responses (in patients with neuroblastoma, medulloblastoma, and lymphoendothelial carcinoma, respectively) were observed.
  
  
  CONCLUSIONS
  The recommended phase 2 dose in heavily pretreated pediatric patients is carboplatin (AUC, 4 mg/mL*min on Day 1) and irinotecan (12 mg/m2/dayx10 days) given every 21 days.
authors.affiliation: Department of Pediatric Hematology/Oncology, Children's Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, New York 10467, USA. adlevy@montefiore.org
authors.forename: Adam S
authors.initials: AS
authors.lastname: Levy
authors.forename: Paul A
authors.initials: PA
authors.lastname: Meyers
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Wexler
authors.forename: Regina
authors.initials: R
authors.lastname: Jakacki
authors.forename: Anne
authors.initials: A
authors.lastname: Angiolillo
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Ringuette
authors.forename: Marvin B
authors.initials: MB
authors.lastname: Cohen
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000077146:Irinotecan; D016190:Carboplatin; D002166:Camptothecin