title: Protracted intermittent schedule of topotecan in children with refractory acute leukemia: a pediatric oncology group study.
abstract: OBJECTIVE
  To determine dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of a protracted, intermittent schedule of daily 30-minute infusions of topotecan (TPT) for up to 12 consecutive days, every 3 weeks, in children with refractory leukemia.
  
  
  METHODS
  Forty-nine children were enrolled onto this phase I trial (24 with acute nonlymphoblastic leukemia [ANLL] and 25 with acute lymphoblastic leukemia [ALL]). TPT dosage was escalated from 2.0 to 5.2 mg/m(2)/d for 5 days and 2.4 mg/m(2)/d from 7 days to the same dose for 9 and 12 days in cohorts of three to six patients when no DLT was identified. TPT pharmacokinetics were studied in 33 children once or twice (first and last doses in patients who received TPT for > 7 days).
  
  
  RESULTS
  Seventy assessable courses of TPT were administered to 49 children who had refractory leukemia. DLTs were typhlitis, diarrhea, and mucositis, and the MTD was 2.4 mg/m(2)/d for 9 days in this group of heavily pretreated children. In 33 patients, the median TPT lactone clearance after the first dose was 19.2 L/h/m(2) (range, 9.4 to 45.9 L/h/m(2)) and did not change during the course. There were significant responses (one complete response [CR] and four partial responses [PR] in patients with ANLL and one CR and two PRs in patients with ALL), and all but one were at dosages of TPT given for at least 9 days.
  
  
  CONCLUSIONS
  The MTD was 2.4 mg/m(2)/d for 9 days. Further testing is warranted of TPT's schedule dependence in children with leukemia.
authors.affiliation: Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN, USA. wayne.furman@stjude.edu
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Furman
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Mark
authors.initials: M
authors.lastname: Kirstein
authors.forename: James L
authors.initials: JL
authors.lastname: Kepner
authors.forename: Mark L
authors.initials: ML
authors.lastname: Bernstein
authors.forename: Faith
authors.initials: F
authors.lastname: Kung
authors.forename: Teresa J
authors.initials: TJ
authors.lastname: Vietti
authors.forename: C Philip
authors.initials: CP
authors.lastname: Steuber
authors.forename: David Lee
authors.initials: DL
authors.lastname: Becton
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baruchel
authors.forename: Charles
authors.initials: C
authors.lastname: Pratt
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D019772:Topotecan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan