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Joint Modelling of Efficacy and Toxicity in the Dose Escalation Phase I Studies

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Document pages: 11 pages

Abstract: Most Phase I oncology trials are primarily concernedwith establishing the safety profile of a new treatment and focus on toxicityalone to determine the maximum tolerated dose (MTD) defined as the highest dosewith the probability of toxicity less than a pre-specified target toxicity rate.When additional data are available, there is an interest in selecting a recommendeddose based on PK, PD, efficacy data, etc. We propose a method that uses modelingof both toxicity and efficacy to further guide the estimation of the recommendeddose(s) by finding an optimal dose or range of doses that maximizes the efficacywhile safety is controlled. The toxicity model is a Bayesian Logistic RegressionModel (BLRM) assessing the dose-toxicity relationships. The efficacy model is apolynomial logistic regression model describing the dose-response relationships.This model generalizes the monotonic dose-response relationship and allows for differentdose-response shapes. In addition, the association between toxicity and efficacyis included in the modelling using global cross-ratio method. All analyses are performedin the Bayesian framework. The proposed method is evaluated by intensive simulationanalyses and operating characteristics are provided. The design identifies adequatelythe range of the recommended doses while safety is controlled and potentially shortensthe duration of a trial by enrolling fewer patients.

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