title: Defining dose-limiting toxicity for phase 1 trials of molecularly targeted agents: results of a DLT-TARGETT international survey.
abstract: BACKGROUND
  It is increasingly clear that definitions of dose-limiting toxicity (DLT) established for phase 1 trials of cytotoxic agents are not suitable for molecularly targeted agents because of specific toxicity profiles. An international survey collected expertise on the definition of DLT, as part of an initiative aimed at presenting new guidelines for phase 1 trials of targeted agents.
  
  
  METHODS
  A 15-question survey was sent to corresponding authors of phase 1 reports. Questions involved: duration of the DLT assessment period, incorporation of specific grade 1 (G1) or G2 toxicity and their minimum duration to qualify as DLT, exclusion of specific G3 and inclusion of dose modification/delay.
  
  
  RESULTS
  Among the 400 investigators contacted, 93 replied of whom 65 completed the questionnaires. A total of 87% opted for an extended DLT assessment period beyond cycle 1, with the proviso not to delay patient accrual. Reanalysis at the end of the study of all safety data was proposed in order to recommend the phase 2 dose. Most respondents (92%) suggested including dose modification in the definition of DLT when dose intensity was decreased to 70%. Whilst moderate toxicity was deemed relevant by 70%, the G1/2 toxicities selected to define DLT however varied.
  
  
  CONCLUSIONS
  The majority of experts favoured a longer DLT assessment period as well as incorporation of specific G2 toxicities into the DLT definition. However, no clear consensus existed on a re-definition of DLT. Therefore analyses of a large international data warehouse were also used to develop guidelines presented in a companion paper.
authors.affiliation: Institut Curie, Biostatistics dpt & INSERM U900, Paris, France. Electronic address: xavier.paoletti@curie.fr.
authors.forename: Xavier
authors.initials: X
authors.lastname: Paoletti
authors.affiliation: Institut Curie, Medical Oncology dpt & INSERM U900, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Tourneau
authors.affiliation: Erasmus University MC, Department of Medical Oncology, Rotterdam, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.affiliation: Princess Margaret Hospital, Toronto, Canada.
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.affiliation: National Cancer Institute of Canada Clinical Trials Group & Queen's University, Kingston, Canada.
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.affiliation: Gustave Roussy Cancer Campus, DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Villejuif, France; Université Paris-Sud XI, Orsay, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Postel-Vinay
authors.affiliation: European Organisation for Research and Treatment of Cancer Headquarter, Brussels, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Collette
authors.affiliation: European Organisation for Research and Treatment of Cancer Headquarter, Brussels, Belgium.
authors.forename: Elisa
authors.initials: E
authors.lastname: Rizzo
authors.affiliation: National Cancer Institute and Cancer Therapy Evaluation Program, Rockville, USA.
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.affiliation: Prostate Cancer Clinical Research Unit, Clinical Research Programme Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Olmos
authors.affiliation: Gustave Roussy Cancer Campus, DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Villejuif, France; Université Paris-Sud XI, Orsay, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Massard
authors.affiliation: European Organisation for Research and Treatment of Cancer Headquarter, Brussels, Belgium.
authors.forename: Denis
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: Royal Marsden Hospital/Institute for Cancer Research, Drug Development Unit, Sutton, UK.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.affiliation: Gustave Roussy Cancer Campus, DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Villejuif, France; Université Paris-Sud XI, Orsay, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D012107:Research Design
chemical_list: D000970:Antineoplastic Agents
keywords: Assessment period; Dose intensity; Dose-limiting toxicity; Experts; Phase 1; Recommended phase 2 dose