Ezzalfani Monia, Dugué Audrey, Mollevi Caroline, Pulido Marina, Bonnetain Franck, Filleron Thomas, Gal Jocelyn, Gauthier Mélanie, Le Deley Marie Cécile, Le Tourneau Christophe, Médioni Jacques, Nguyen Jean-Michel, Chabaud Sylvie, Teixeira Luis, Thivat Emilie, You Benoît, Kramar Andrew, Paoletti Xavier
Institut Curie, département de biostatistique, Inserm U900, 25, rue d'Ulm, 75005 Paris, France.
Unité de recherche clinique, CLCC François-Baclesse, 3, avenue du Général-Harris, 14000 Caen, France.
Bull Cancer. 2015 Jan;102(1):73-82. doi: 10.1016/j.bulcan.2014.10.001. Epub 2015 Jan 2.
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.
在肿瘤学I期试验的剂量递增阶段结束时，将患者纳入扩展队列的情况越来越常见。然而，方案中对扩展队列的目标、纳入患者的数量及其理由的解释并不充分。这些队列有时规模相当大。本文旨在概述扩展队列的方法，以便为其在实际中的规划提供建议。这项工作是在国家癌症研究所（INCA）的支持下，与早期研究中心（CLIP(2)）的统计学家合作开展的。首先，我们概述了最近发表的关于I期扩展队列的文章。然后，我们就目标和纳入患者数量提出了建议，以指导研究者并便于在实际中使用这些扩展队列。曼吉等人通过回顾2006年至2011年的文献，确定了149项在肿瘤学中使用扩展队列的I期临床试验（曼吉等人，2013年）。111项试验（74%）报告了扩展队列的目标。在这些试验中，安全性是最常报告的目标（80%的试验），其次是疗效（45%）。根据这项综述，这些队列中纳入患者的数量理由不充分。我们在2011 - 2014年期间进行的文献研究证实了这一结果。我们建议根据以下方面确定扩展队列中纳入患者的数量：（1）其目标，（2）统计标准，以及（3）试验的临床背景。毒性研究仍然是扩展阶段要评估的主要目标。在某些情况下，活性研究被视为共同主要目标，要么是为了在筛查等研究中识别活性的初步迹象，要么是当目标人群已知时研究活性。此时该研究被视为I/II期，II期的经验计划可适用于扩展队列的规划。本文提出了关于扩展队列规模的建议。尽管扩展队列具有探索性，但建议基于统计定义的假设对其规模进行论证，以便得出可解释的结论并量化错误风险。
