title: A phase I study of irinotecan as a 3-week schedule in children with refractory or recurrent solid tumors.
abstract: OBJECTIVE
  A phase I study was performed to determine the maximum-tolerated dose (MTD) and safety profile of irinotecan (CPT-11) administered as a single intravenous infusion every 3 weeks in children with recurrent or refractory solid tumors.
  
  
  METHODS
  Eighty-one patients were enrolled, including 48 less heavily, and 33 heavily pretreated patients (cranial irradiation and/or high-dose chemotherapy). Children received CPT-11 as a 120-minute infusion at doses ranging from 200 to 720 mg/m2. The dose-limiting toxicities (DLT) on first cycle were determined in both cohorts.
  
  
  RESULTS
  One hundred twenty-two cycles and 81 cycles were administered in less heavily, and heavily pretreated patients, respectively. The primary DLT was delayed diarrhea in less heavily pretreated patients, and neutropenia in heavily pretreated patients. MTD was 600 mg/m2 in both cohorts. Grade 3 to 4 neutropenia occurred in 33% and 38% of cycles in less heavily, and heavily pretreated patients, respectively. Grade 3 to 4 nonhematologic toxicities included nausea/vomiting (7% and 4% of cycles in less heavily, and heavily pretreated patients, respectively), asthenia (7% and 4% of cycles, respectively), and delayed diarrhea (6% and 2.5% of cycles, respectively). Four partial responses at 600 mg/m2 (high-grade glioma, neuroblastoma, medulloblastoma, and rhabdomyosarcoma) and 21 minor responses and stable diseases were observed. Pharmacokinetic analysis of CPT-11 and SN-38 was performed in 77 patients. The mean +/- standard deviation (SD) CPT-11 plasma clearance was 20.7 +/- 9.5 L/h/m2 (range, 5 to 54). The mean +/- SD SN-38 metabolic ratio was 1.5% +/- 1.1% (range, 0.15% to 5.55%).
  
  
  CONCLUSIONS
  The recommended phase II dose of CPT-11 in a 3-week schedule is 600 mg/m2 in less heavily, and heavily pretreated children with solid tumors.
authors.affiliation: Department of Pediatric Oncology, Institut Gustave Roussy, Villejuif, France. gvassal@igr.fr
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: Francois
authors.initials: F
authors.lastname: Doz
authors.forename: Didier
authors.initials: D
authors.lastname: Frappaz
authors.forename: Karima
authors.initials: K
authors.lastname: Imadalou
authors.forename: Evelyn
authors.initials: E
authors.lastname: Sicard
authors.forename: Alexandre
authors.initials: A
authors.lastname: Santos
authors.forename: John
authors.initials: J
authors.lastname: O'Quigley
authors.forename: Caroline
authors.initials: C
authors.lastname: Germa
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Risse
authors.forename: Dominique
authors.initials: D
authors.lastname: Mignard
authors.forename: Francois
authors.initials: F
authors.lastname: Pein
mesh_terms: D000293:Adolescent; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D002675:Child, Preschool; D004334:Drug Administration Schedule; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D000077146:Irinotecan; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin