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Comparative Study
, 30 (17), 2130-43

Practical Modifications to the Time-To-Event Continual Reassessment Method for Phase I Cancer Trials With Fast Patient Accrual and Late-Onset Toxicities

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Comparative Study

Practical Modifications to the Time-To-Event Continual Reassessment Method for Phase I Cancer Trials With Fast Patient Accrual and Late-Onset Toxicities

Mei-Yin C Polley. Stat Med.

Abstract

The goal of phase I cancer trials is to determine the highest dose of a treatment regimen with an acceptable toxicity rate. Traditional designs for phase I trials, such as the Continual Reassessment Method (CRM) and the 3 + 3 design, require each patient or a cohort of patients to be fully evaluated for the dose-limiting toxicity (DLT) before new patients can be enrolled. As such, the trial duration may be prohibitively long. The Time-to-Event Continual Reassessment Method (TITE-CRM, Cheung and Chappell, 2000) circumvents this limitation by allowing staggered patient accrual without the need for complete DLT follow-up of previously treated patients. However, in the setting of fast patient accrual and late-onset toxicities, the TITE-CRM results in overly aggressive dose escalation and exposes a considerable number of patients to toxic doses. We examine a modification to the TITE-CRM proposed by the original TITE-CRM creator and propose an alternative approach useful in this setting by incorporating an accrual suspension rule. A simulation study designed based on a neuro-oncology trial indicates that the modified methods provide a much improved degree of safety than the TITE-CRM while maintaining desirable design accuracy. The practical aspects of the proposed designs are discussed. The modifications presented are useful when planning phase I trials involving chemoradiation therapy.

Figures

Figure 1
Figure 1
Adaptive wait time function in Design D.
Figure 2
Figure 2
Average dose level assigned over the course of the trial for each design. Dose indicated for each patient represents the mean dose based on available simulation runs. Since trials may stop before the planned maximum sample size (24) is exhausted, the mean dose may be based on fewer than 1000 simulations.

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