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Abstract:
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A well-designed and conducted dose escalation study lays the foundation for successful clinical development. With patient centric drug development, the focus of dose finding switches from targeting the maximum tolerated dose (MTDs) to more comprehensive evaluation of the drug effects on patients. For example, rather than reporting the dose limiting toxicity (DLTs) as main outcome of drug toxicity effect, one could report different toxicity grades summarized as a total toxicity burden. In addition, accounting for time-to-event outcomes may allow faster enrollment speed, leading to shorter trials. We propose a Bayesian design to incorporate time-to-event total toxicity burden in dose finding. The design allows rolling patient enrollment based on the assessment of total toxicity burden. We show that the proposed design can speed up the trial process and better characterize the toxicity profile of each dose. Through simulation study, we report the operating characteristics of the design in terms of duration of the trial and the success in finding the most promising dose with acceptable toxicity profile for later drug development.
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