title: Phase I trial of oral irinotecan and temozolomide for children with relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy consortium study.
abstract: OBJECTIVE
  Irinotecan and temozolomide have single-agent activity and schedule-dependent synergy against neuroblastoma. Because protracted administration of intravenous irinotecan is costly and inconvenient, we sought to determine the maximum-tolerated dose (MTD) of oral irinotecan combined with temozolomide in children with recurrent/resistant high-risk neuroblastoma.
  
  
  METHODS
  Patients received oral temozolomide on days 1 through 5 combined with oral irinotecan on days 1 through 5 and 8 through 12 in 3-week courses. Daily oral cefixime was used to reduce irinotecan-associated diarrhea.
  
  
  RESULTS
  Fourteen assessable patients received 75 courses. Because neutropenia and thrombocytopenia were initially dose-limiting, temozolomide was reduced from 100 to 75 mg/m(2)/d for subsequent patients. Irinotecan was then escalated from 30 to 60 mg/m2/d. First-course grade 3 diarrhea was dose-limiting in one of six patients treated at the irinotecan MTD of 60 mg/m2/d. Other toxicities were mild and reversible. The median SN-38 lactone area under the plasma concentration versus time curve at this dose was 72 ng . hr/mL. One patient with bulky soft tissue disease had a complete response through six courses. Six additional patients received a median of seven courses (range, three to 22 courses) before progression.
  
  
  CONCLUSIONS
  This all-oral regimen was feasible and well tolerated in heavily pretreated children with resistant neuroblastoma, and seven (50%) of 14 assessable patients had response or disease stabilization for three or more courses in this phase I trial. SN-38 lactone exposures were similar to those reported with protracted intravenous irinotecan. The dosages recommended for further study in this patient population are temozolomide 75 mg/m2/d plus irinotecan 60 mg/m2/d when given with cefixime.
authors.affiliation: Department of Hematology/Oncology Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 7015, Cincinnati, OH 45229, USA. lars.wagner@cchmc.org
authors.forename: Lars M
authors.initials: LM
authors.lastname: Wagner
authors.forename: Judith G
authors.initials: JG
authors.lastname: Villablanca
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Kristine R
authors.initials: KR
authors.lastname: Crews
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Julie R
authors.initials: JR
authors.lastname: Park
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Randall A
authors.initials: RA
authors.lastname: Hawkins
authors.forename: Heike E
authors.initials: HE
authors.lastname: Daldrup-Link
authors.forename: Hollie A
authors.initials: HA
authors.lastname: Jackson
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D009447:Neuroblastoma / Q000188:drug therapy*; D012008:Recurrence; D000077204:Temozolomide; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D003606:Dacarbazine; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000077204:Temozolomide; D000099148:UGT1A1 Enzyme