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Stat Methods Med Res. 2012 Nov 1. [Epub ahead of print]

A Phase I/II trial design when response is unobserved in subjects with dose-limiting toxicity.

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  • 1Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.


We propose a Phase I/II trial design in which subjects with dose-limiting toxicity are not followed for response, leading to three possible outcomes for each subject: dose-limiting toxicity, absence of therapeutic response without dose-limiting toxicity, and presence of therapeutic response without dose-limiting toxicity. We define the latter outcome as a 'success,' and the goal of the trial is to identify the dose with the largest probability of success. This dose is commonly referred to as the most successful dose. We propose a design that accumulates information on subjects with regard to both dose-limiting toxicity and response conditional on no dose-limiting toxicity. Bayesian methods are used to update the estimates of dose-limiting toxicity and response probabilities when each subject is enrolled, and we use these methods to determine the dose level assigned to each subject. Due to the need to explore doses more fully, each subject is not necessarily assigned the current estimate of the most successful dose; our algorithm may instead assign a dose that is in a neighborhood of the current most successful dose. We examine the ability of our design to correctly identify the most successful dose in a variety of settings via simulation and compare the performance of our design to that of competing approaches.

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