title: A comparative analysis of paediatric dose-finding trials of molecularly targeted agent with adults' trials.
abstract: BACKGROUND
  Dose-finding phase I trials in children are usually carried out once clinical data have already been accumulated in the adult population. The objectives, place and role of paediatric dose-finding trials are investigated in the era of molecularly targeted agents (MTAs).
  
  
  METHODS
  Phase I paediatric oncology trials of MTAs approved in adults before June 15th, 2012 were reviewed. The recommended phase II dose (RPIID) was compared to the body surface area (BSA)-adjusted approved dose in adults. Toxicity profile was compared to the findings from the corresponding adult phase I trials.
  
  
  RESULTS
  Fifteen MTAs out of a total of 25 MTAs approved in the adult population have been evaluated in 19 single-agent phase I paediatric trials. Trials included a median of 30 children with a median of four dose levels. The paediatric RPIID ranged between 90% and 130% of the BSA-adjusted approved dose in adults for 70% of the trials (75% of compounds). Overall, 63% of children did not receive an optimal dose. The most marked discrepancy involved sunitinib. Safety profiles described in phase I paediatric trials were usually similar to those reported in the adult population.
  
  
  CONCLUSIONS
  These data suggest that dose-finding studies might not be necessary for all the MTAs in children. Except in the case of a narrow therapeutic index, early-phase trials validating pharmacokinetics, pharmacodynamic markers and efficacy findings from adults while controlling for toxicity appear to be a possible alternative to accelerate drug development in paediatric oncology.
authors.affiliation: Biostatistics department, Institut Curie, Paris, France. xavier.paoletti@curie.net
authors.forename: Xavier
authors.initials: X
authors.lastname: Paoletti
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
authors.forename: François
authors.initials: F
authors.lastname: Doz
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.forename: François
authors.initials: F
authors.lastname: Lokiec
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Tourneau
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005076:Exanthema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents