title: Phase I study of combination topotecan and carboplatin in pediatric solid tumors.
abstract: OBJECTIVE
  We conducted a phase I trial of escalating doses of topotecan (TOPO) in association with a fixed systemic exposure of carboplatin (CARBO) with or without granulocyte colony-stimulating factor (G-CSF) in children.
  
  
  METHODS
  Two separate cohorts of patients (pts) with solid tumors were studied: (A) pts with refractory or recurrent disease and (B) pts with no prior myelosuppressive therapy or newly diagnosed tumors for which there was no standard chemotherapy. CARBO was given on day 1 at an area under the curve of 6.5, followed by TOPO as a continuous infusion for 3 days; the starting dose of TOPO was 0.50 mg/m(2)/d. Cycles were repeated every 21 days. G-CSF was given at a dose of 5 microg/kg/d starting on day 4.
  
  
  RESULTS
  Forty-eight of 51 pts were assessable for toxicity. In group A, dose-limiting myelosuppression persisted despite de-escalation of TOPO to 0.3 mg/m(2)/d and use of G-CSF. In group B, the maximum-tolerated dose of TOPO was 0.5 mg/m(2)/d for 3 days, and 0.6 mg/m(2)/d for 3 days with G-CSF. No significant nonhematologic toxicities were observed. Among 46 pts assessable for response, one had complete response, five had partial response, and 18 had stable disease.
  
  
  CONCLUSIONS
  Although this combination possesses antineoplastic activity in pediatric solid tumors, hematologic toxicity precluded any meaningful TOPO dose escalation. The addition of G-CSF did not alter this. The potential for preservation of activity and diminution of toxicity with alternative sequences and schedules of administration (topoisomerase followed by alkylating or platinating agents) should be evaluated.
authors.affiliation: Department of Hematology-Oncology, Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
authors.forename: Uma H
authors.initials: UH
authors.lastname: Athale
authors.forename: Clinton
authors.initials: C
authors.lastname: Stewart
authors.forename: John F
authors.initials: JF
authors.lastname: Kuttesch
authors.forename: Albert
authors.initials: A
authors.lastname: Moghrabi
authors.forename: William
authors.initials: W
authors.lastname: Meyer
authors.forename: Charles
authors.initials: C
authors.lastname: Pratt
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Richard L
authors.initials: RL
authors.lastname: Heideman
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D016013:Likelihood Functions; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D016879:Salvage Therapy / Q000379:methods*; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D019772:Topotecan; D016190:Carboplatin