title: Using the continual reassessment method: lessons learned from an EORTC phase I dose finding study.
abstract: Many clinicians often do not feel comfortable with the Continual Reassessment Method (CRM). This article reviews its implementation, showing the characteristics, advantages and limitations of this method in Phase I studies as an alternative to the classical 'Fibonacci' escalation schema. A two center, dose escalation phase I study of rViscumin was carried out. Thirty-seven patients were included at 14 different dose-levels (10 to 6400 ng/kg). The complete clinical results are presented elsewhere. A 2-step CRM design enables one to speed-up the study and most importantly to obtain an accurate estimate of the maximum tolerated dose (MTD). Different management issues related to a multicenter study are illustrated and we show how the method can go wrong when severe toxicity, or dose limiting toxicity (DLT), is not considered by the clinician as being sufficient to limit dose escalation (here a grade 3 asthenia related to the drug). This would have affected any dose finding methods. We believe that CRM is a good alternative to the standard method from both a statistical and a practical point of view but further methodological research is necessary to address the issues related to the composite nature of the endpoint.
authors.affiliation: Inserm, U738, F-75018 Paris, France. x.paoletti@institutcancer.fr
authors.forename: Xavier
authors.initials: X
authors.lastname: Paoletti
authors.forename: Benoît
authors.initials: B
authors.lastname: Baron
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.forename: Denis
authors.initials: D
authors.lastname: Lacombe
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marreaud
authors.forename: Richard
authors.initials: R
authors.lastname: Sylvester
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D020714:Maximum Tolerated Dose; D008517:Phytotherapy / Q000379:methods; D028321:Plant Preparations / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010940:Plant Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D054790:Ribosome Inactivating Proteins, Type 2; D012307:Risk Factors; D014118:Toxins, Biological / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D028321:Plant Preparations; D010940:Plant Proteins; D054790:Ribosome Inactivating Proteins, Type 2; D014118:Toxins, Biological; C488862:mistletoe lectin I