title: Selection of the initial design for the two-stage continual reassessment method.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jia
authors.affiliation: b Department of Biostatistics , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina , USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Ivanova
authors.affiliation: c Department of Biostatistics , Mailman School of Public Health, Columbia University , New York , New York , USA .
authors.forename: Shing M
authors.initials: SM
authors.lastname: Lee
mesh_terms: D000465:Algorithms; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020714:Maximum Tolerated Dose; D008495:Medical Oncology; D012107:Research Design
keywords: Adaptive design; CRM; dose finding; indifference intervals; initial design; phase I study; start-up rule