• Lili Zhao, Julia Lee, Rajen Mody, and Thomas M Braun.
• Biostatistics Unit, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA. zhaolili@umich.edu
• Clin Trials. 2011 Aug 1; 8 (4): 361-9.

BackgroundThe rolling six design (RSD) is currently being used by the Children's Oncology Group (COG) as their standard design for Phase I trials. Because the COG has large multi-center trials with fast accrual, the motivation for adopting the RSD is to hasten accrual and shorten the duration of their trials. However, trial suspension due to completion of follow-up still cannot be entirely avoided by the RSD. Therefore, a design that allows continuous enrollment of patients throughout the entire trial is needed.PurposeTo demonstrate the superior performance of the Time-to-Event Continual Reassessment Method (TITE-CRM) with continuous patient recruitment relative to the RSD, in terms of identifying the maximum tolerated dose (MTD) and reducing exposure of patients to toxic doses.MethodsUsing scenarios that were based on an actual pediatric Phase I trial at the University of Michigan, Monte Carlo simulations were used to investigate the operational characteristics of RSD and TITE-CRM.ResultsThe TITE-CRM treated all available patients, identified the MTD more accurately than the RSD and did not increase the probability of exposing patients to toxic doses.LimitationsBoth the TITE-CRM and RSD assume that the probability of dose limiting toxicity increases with higher dose level.ConclusionsThe TITE-CRM, which allows for continual enrollment of patients, provides a safe design for pediatric oncology Phase I trials with better accuracy than the RSD.

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