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Dose-finding in phase I clinical trials based on toxicity probability intervals

Department of Bioinformatics and Computational Biology, University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA, yuanji{at}mdanderson.org

Yisheng Li

Department of Biostatistics, University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA

B. Nebiyou Bekele

Department of Biostatistics, University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA

Background Most phase I clinical trials conducted at the M. D. Anderson Cancer Center use the algorithmic 3 + 3 design, despite the availability of more advanced model-based designs such as the continual reassessment method.

Purpose Through simple statistical modeling and computing, we develop a dose-finding design that can be easily understood and implemented by non-statisticians.

Methods We propose a beta/binomial Bayesian model and a probabilistic up-and-down rule that allow all possible dose-assignment actions to be tabulated in a spreadsheet. We have developed an Excel macro (available at http://odin.mdacc. tmc.edu/~yuanj) that generates trial monitoring tables, which contain the dose-assignment actions corresponding to various toxicity outcomes.

Results The new design outperforms the 3 + 3 design and performs comparably to other model-based methods in the literature.

Limitations The proposed method assumes that the observed toxicity is a binary variable and that toxicity increases with dose level.

Conclusion The new dose-finding design enables physicians to readily determine dose assignments for new patients by referencing a trial monitoring table. Clinical Trials 2007; 4: 235—244; http://ctj.sagepub.com

Clinical Trials, Vol. 4, No. 3, 235-244 (2007)
DOI: 10.1177/1740774507079442


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