title: [The role of the expansion cohort in phase I trials in oncology: guidelines of the phase I HUB].
abstract: At the end of the dose escalation step of phase I trials in oncology, it is increasingly frequent to include patients in expansion cohorts. However, the objective of the expansion cohorts, the number of patients included and their justification are insufficiently explained in the protocols. These cohorts are sometimes of considerable size. The aim of this article is to outline the methodology of expansion cohorts in order to provide recommendations for their planning in practice. This work has been undertaken in collaboration with the statisticians of the early phase investigation centers (CLIP(2)), supported by INCA. First, we have outlined the recent articles published on the expansion cohorts in phase I. We then proposed recommendations, in terms of objectives and number of patients to be included, to guide investigators and facilitate the use of these expansion cohorts in practice. Manji et al. have identified 149 phase I clinical trials using expansion cohorts in oncology with a review of the literature between 2006 and 2011 (Manji et al., 2013). Objectives of the expansion cohort were reported in 111 trials (74%). In these trials, safety was the most reported objective (80% of trials), followed by efficacy (45%). According to this review, the number of patients included in these cohorts was insufficiently justified. This result was confirmed by the study of literature that we conducted over the period 2011-2014. We propose to define the number of patients to be included in expansion cohorts in terms of (1) their objectives, (2) the statistical criteria and (3) the clinical context of the trial. The toxicity study remains the primary objective to evaluate in the expansion phase. In some contexts, the activity study is considered as co-primary objective, either for identifying preliminary signs of activity in studies like screening, or for studying the activity when the target population is known. This study is then considered as phase I/II, and experience plans of phase II can be adapted for planning expansion cohorts. Recommendations for the size of expansion cohorts are proposed. Despite the exploratory character of the expansion cohort, a justification of their size based on assumptions statistically defined is recommended in order to provide an interpretable conclusion and to quantify the risk of errors.
authors.affiliation: Institut Curie, département de biostatistique, Inserm U900, 25, rue d'Ulm, 75005 Paris, France. Electronic address: monia.ezzalfani-gahlouzi@curie.fr.
authors.forename: Monia
authors.initials: M
authors.lastname: Ezzalfani
authors.affiliation: Unité de recherche clinique, CLCC François-Baclesse, 3, avenue du Général-Harris, 14000 Caen, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Dugué
authors.affiliation: Institut régional du cancer Montpellier, service de biostatistique, 31, rue de Croix-Verte, 34298 Montpellier cedex 5, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Mollevi
authors.affiliation: Institut Bergonié, CTD, unité de recherche et d'épidémiologie cliniques, 229, cours de l'Argonne, 33076 Bordeaux cedex, France.
authors.forename: Marina
authors.initials: M
authors.lastname: Pulido
authors.affiliation: CHRU Besançon et CTD GERCOR, unité de méthodologie et qualité de vie en cancérologie, 2, place Saint-Jacques, 25000 Besançon, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Bonnetain
authors.affiliation: Institut Claudius-Regaud, Bureau des essais cliniques, 20-24, rue du Pont-Saint-Pierre, 31052 Toulouse cedex, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.affiliation: Centre Antoine-Lacassagne, unité statistiques, 33, avenue de Valombrose, 06189 Nice cedex 2, France.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Gal
authors.affiliation: Centre de Georges-François-Leclerc, unité de biostatistique et d'épidémiologie, 1, rue Professeur-Marion, 21079 Dijon cedex, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Gauthier
authors.affiliation: Service de biostatistique et d'épidémiologie, Gustave-Roussy, 39, rue Camille-Desmoulins, 94805 Villejuif cedex, France.
authors.forename: Marie Cécile
authors.initials: MC
authors.lastname: Le Deley
authors.affiliation: Institut Curie, département d'oncologie médicale, 5, rue d'Ulm, 75005 Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Tourneau
authors.affiliation: Hôpital européen Georges-Pompidou, service de cancérologie médicale, 20, rue Leblanc, 75015 Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Médioni
authors.affiliation: Centre hospitalier universitaire Nantes, service d'épidémiologie et de biostatistique, 85, rue Saint-Jacques, 44093 Nantes, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Nguyen
authors.affiliation: Centre Léon-Bérard, unité de biostatistique et d'évaluation des thérapeutiques/Direction de la recherche et de l'innovation, 28, rue Laënnec, 69373 Lyon cedex 08, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chabaud
authors.affiliation: Hôpital Saint-Antoine, service de médecine interne et oncologie médicale, 1, avenue Claude-Vellefaux, 75475 Paris cedex 10, France.
authors.forename: Luis
authors.initials: L
authors.lastname: Teixeira
authors.affiliation: Centre Jean-Perrin, unité de recherche clinique, Clermont-Ferrand, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Thivat
authors.affiliation: Centre d'investigation de thérapeutiques en oncologie et hématologie de Lyon, chemin du Grand Revoyet, 69495 Pierre-Bénite, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: You
authors.affiliation: Centre Oscar-Lambret, unité de méthodologie et biostatistiques, 3, rue Frédéric-Combemale, 59020 Lille, France.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kramar
authors.affiliation: Institut Curie, département de biostatistique, Inserm U900, 25, rue d'Ulm, 75005 Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Paoletti
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic / Q000592:standards* / Q000706:statistics & numerical data; D015331:Cohort Studies; D006801:Humans; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D018401:Sample Size
chemical_list: D000970:Antineoplastic Agents
keywords: Cohortes d’expansion; Essais cliniques de phase I; Expansion cohorts; HUB phase I; Oncologie; Oncology; Phase I HUB; Phase I trials