Jia Xiaoyu, Ivanova Anastasia, Lee Shing M
a Department of Population Health Science and Policy , Institute for Healthcare Delivery Science, Icahn School of Medicine at Mount Sinai , New York , New York , USA.
b Department of Biostatistics , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina , USA.
J Biopharm Stat. 2017;27(3):495-506. doi: 10.1080/10543406.2017.1290650. Epub 2017 Feb 7.
In the two-stage continual reassessment method (CRM), model-based dose escalation is preceded by a pre-specified escalating sequence starting from the lowest dose level. This is appealing to clinicians because it allows a sufficient number of patients to be assigned to each of the lower dose levels before escalating to higher dose levels. While a theoretical framework to build the two-stage CRM has been proposed, the selection of the initial dose-escalating sequence, generally referred to as the initial design, remains arbitrary, either by specifying cohorts of three patients or by trial and error through extensive simulations. Motivated by a currently ongoing oncology dose-finding study for which clinicians explicitly stated their desire to assign at least one patient to each of the lower dose levels, we proposed a systematic approach for selecting the initial design for the two-stage CRM. The initial design obtained using the proposed algorithm yields better operating characteristics compared to using a cohort of three initial design with a calibrated CRM. The proposed algorithm simplifies the selection of initial design for the two-stage CRM. Moreover, initial designs to be used as reference for planning a two-stage CRM are provided.
在两阶段连续重新评估方法(CRM)中,基于模型的剂量递增之前是从最低剂量水平开始的预先指定的递增序列。这对临床医生很有吸引力,因为它允许在递增到更高剂量水平之前,将足够数量的患者分配到每个较低剂量水平。虽然已经提出了构建两阶段CRM的理论框架,但初始剂量递增序列(通常称为初始设计)的选择仍然是任意的,要么通过指定三名患者的队列,要么通过广泛模拟的试错法。受当前正在进行的肿瘤学剂量探索研究的启发,临床医生明确表示他们希望将至少一名患者分配到每个较低剂量水平,我们提出了一种系统方法来选择两阶段CRM的初始设计。与使用校准的CRM的三名患者队列的初始设计相比,使用所提出算法获得的初始设计具有更好的操作特性。所提出的算法简化了两阶段CRM初始设计的选择。此外,还提供了用作规划两阶段CRM参考的初始设计。