title: [Dose finding methods for targeted agents: new perspectives].
abstract: BACKGROUND
  The definition of the optimal dose of a new compound and the design for identifying this dose have been set up for treatment with cytotoxic activity. The optimal dose is typically the Maximum Tolerated Dose (MTD) defined by the occurrence of severe toxic side effects during the first course of treatment. In the era of molecularly targeted therapies (MTA), where the mechanistic relations between the dose, the activity and the toxicity are probably different, how relevant these definitions and designs are?
  
  
  METHODS
  We present here a review of the outcomes of potential interest for defining the optimal dose and we present several statistical innovative dose finding methods. Longitudinal data (tumour growth, repeated evaluation of toxic side effects) and continuous outcomes appear particularly promising for early phase trials.
  
  
  CONCLUSIONS
  Phase I dose finding method for molecularly targeted agents should continue to identify the MTD, but the dose recommended for phase II trials should not be systematically defined as the MTD and should incorporate other endpoints. In particular, more sensitive and more discriminatory endpoints are necessary. They needn't be good surrogate of the clinical benefit, but they should allow for ranking several doses. Experience from other medical specialties, such as phase II dose-ranging trials could be considered.
authors.affiliation: Service de biostatistique, Inserm U900, Institut Curie, 26, rue d'Ulm, Paris, France. xavier.paoletti@curie.net
authors.forename: X
authors.initials: X
authors.lastname: Paoletti
authors.forename: S
authors.initials: S
authors.lastname: Postel-Vinay
authors.forename: V
authors.initials: V
authors.lastname: Servois
authors.forename: A
authors.initials: A
authors.lastname: Doussau
authors.forename: L
authors.initials: L
authors.lastname: Ollivier
authors.forename: C
authors.initials: C
authors.lastname: Le Tourneau
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood; D002470:Cell Survival; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D020714:Maximum Tolerated Dose; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000175:diagnosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib