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Activity Number: 449
Type: Contributed
Date/Time: Tuesday, August 11, 2015 : 2:00 PM to 2:45 PM
Sponsor: Biopharmaceutical Section
Abstract #317729
Title: Dose Escalation with Over-Dose and Under-Dose Control in Phase I/II Clinical Trials
Author(s): Zhengjia Chen* and Ying Yuan and Zheng Li and Michael Kutner and Taofeek Owonikoko and Walter J. Curran and Fadlo Khuri and Jeanne Kowalski
Companies: Emory University and MD Anderson Cancer Center and Emory University and Emory University and Emory University and Emory University and Emory University and Emory University
Keywords: Escalation with over-dose control ; Escalation with under-dose control ; Gumbel copula model ; Phase I/II clinical trial ; Bayesian data augmentation ; Utility function
Abstract:

Escalation with over-dose control (the EWOC) is a Bayesian adaptive Phase I clinical trial design that can accurately estimate the maximum tolerated dose (MTD) level and control the probability of overdosing patients during the dose allocation phase. In this paper, we extend EWOC to Phase I/II clinical trials by controlling for under-dosing with a Gumbel Copula model to provide patients with at least minimum drug efficacy. We propose a utility function to measure the composite effect of toxicity and efficacy and select the optimal dose. To deal with the common issue that the efficacy endpoint often cannot be quickly ascertained, we employ Bayesian data augmentation to handle delayed efficacy and allow for flexible patient accrual without a waiting period. Extensive simulations demonstrate that the proposed new design not only provides better therapeutic effect by reducing the probability of treating patients at under-dose levels while protecting patients from being overdosed, but also improves trial efficiency and increases the accuracy of dose recommendation for subsequent clinical trials. We apply the proposed design to a Phase I/II solid tumor trial.


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