Escalation with Overdose Control using a Toxicity Score for Personalized Maximum Tolerated Dose in Phase I Clinical Trials Público
Zhuang, Run (2016)
Abstract
The goal of many cancer Phase I clinical trials is to establish the level of dose toxicity tolerance in order to estimate the maximum tolerated dose (MTD) used for future trials. Common methods are divided into rule-based and model-based methods for dose escalation. The most popular method currently used is the 3+3 rule-based design. This method is simple and convenient, but has been shown to predict the true MTD in about 35% of trials. Model-based designs establish a dose response relationship that is equal to a pre-specified probability of dose limiting toxicity (DLT). Escalation with overdose control (EWOC) is a Bayesian adaptive design for selecting dose levels in cancer Phase I clinical trials while controlling the posterior probability of exceeding the MTD. We extend EWOC to incorporate a novel toxicity score with the addition of covariates for personalized medicine (EWOC-NETS with covariates). Under our extensions, we found significant differences in the estimated MTD between EWOC, EWOC-NETS, and EWOC-NETS with covariates for 4 simulated scenarios. Our developed method is also safer with respect to toxicity and overdosing.
Table of Contents
List of Tables i
List of Figures ii
1 Introduction 1
1.1 Rule-Based Methods in Phase I Trials 2
1.2 Model-Based Methods in Phase I Trials 3
1.3 Escalation with Overdose Control (EWOC) 4
1.4 Extensions and Goals 6
2 Methods 7
2.1 EWOC 8
2.2 NETS 10
2.3 EWOC-NETS 12
2.4 EWOC-NETS with a Discrete Covariate 14
2.5 EWOC-NETS with a Continuous Covariate 16
2.6 Simulation Settings and Methods 17
3 Results 21
3.1 Discrete Covariate 21
3.2 Continuous Covariate 24
4 Discussion 28
5 Bibliography 30
6 Appendix 32
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