title: Phase I study of topotecan in combination with temozolomide (TOTEM) in relapsed or refractory paediatric solid tumours.
abstract: OBJECTIVE
  To evaluate maximum tolerated dose and recommended dose (RD) for phase II studies of topotecan (TPT) combined with temozolomide (TMZ) (TOTEM) in children and adolescents with relapsed or refractory solid malignancies.
  
  
  METHODS
  Multicentre, phase I study with a standard '3+3' design in five dose increments. Eligible patients: aged 6 months to 21 years, diagnosis of a solid malignancy failed at least 2 previous lines of therapy. TMZ was administered orally, starting at 100 mg/m(2)/d, and TPT intravenously over 30 min, starting at 0.75 mg/m(2)/d over 5 consecutive days every 28 d. A pharmacokinetics analysis was performed on Day 1 and Day 5 of cycle 1.
  
  
  RESULTS
  Between February and October 2007, 16 patients were treated. The median age was 8.5 years (range, 3-19 years). Dose-limiting toxicity (grade 4 neutropenia and/or thrombocytopenia lasting more than 7 d) during the first cycle occurred in 2 of 3 patients at level 3 (TMZ 150 mg/m(2)/d and TPT 1.0 mg/m(2)/d) and was always manageable. Confirmed complete and partial responses were observed in 4 patients (25%), three with metastatic neuroblastoma and one with high-grade glioma. Seven patients had a stable disease. Pharmacokinetic data show a wide inter-individual variability. No significant differences were observed between plasma TMZ and TPT concentrations on Day 1 and Day 5 indicating the absence of pharmacokinetic interaction between the drugs.
  
  
  CONCLUSIONS
  The RD for the combination is TMZ 150 mg/m(2)/d and TPT 0.75 mg/m(2)/d with dose-limiting haematological toxicity. The observed activity deserves further evaluation in paediatric malignancies.
authors.affiliation: Hôpital des Enfants, Toulouse, France. rubie.h@chu-toulouse.fr
authors.forename: Hervé
authors.initials: H
authors.lastname: Rubie
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
authors.forename: Didier
authors.initials: D
authors.lastname: Frappaz
authors.forename: Antonin
authors.initials: A
authors.lastname: Schmitt
authors.forename: Pierre
authors.initials: P
authors.lastname: Leblond
authors.forename: Anna
authors.initials: A
authors.lastname: Ndiaye
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aerts
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Le Deley
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Gentet
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
authors.forename: Pascal
authors.initials: P
authors.lastname: Chastagner
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dias
authors.forename: Latifa
authors.initials: L
authors.lastname: Djafari
authors.forename: Marlène
authors.initials: M
authors.lastname: Pasquet
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.forename: Judith
authors.initials: J
authors.lastname: Landman-Parker
authors.forename: Nadège
authors.initials: N
authors.lastname: Corradini
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D007223:Infant; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy*; D000077204:Temozolomide; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D000090324:Tumor Protein, Translationally-Controlled 1; D055815:Young Adult
chemical_list: D000090324:Tumor Protein, Translationally-Controlled 1; D003606:Dacarbazine; D019772:Topotecan; D000077204:Temozolomide