Selection of the initial design for the two-stage continual reassessment method.

TitleSelection of the initial design for the two-stage continual reassessment method.
Publication TypeJournal Article
Year of Publication2017
AuthorsJia, Xiaoyu, Anastasia Ivanova, and Shing M. Lee
JournalJ Biopharm Stat
Volume27
Issue3
Pagination495-506
Date Published2017
ISSN1520-5711
KeywordsAlgorithms, Clinical Trials, Phase I as Topic, Dose-Response Relationship, Drug, Humans, Maximum Tolerated Dose, Medical Oncology, Research Design
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.

DOI10.1080/10543406.2017.1290650
Alternate JournalJ Biopharm Stat
Original PublicationSelection of the initial design for the two-stage continual reassessment method.
PubMed ID28300466
PubMed Central IDPMC5383510
Grant ListP01 CA142538 / CA / NCI NIH HHS / United States
P30 CA196521 / CA / NCI NIH HHS / United States