Nonparametric overdose control with late-onset toxicity in phase I clinical trials
Nonparametric overdose control with late-onset toxicity in phase I clinical trials
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DOI：
10.1093/biostatistics/kxw038
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发表时间：
2017-01-01
期刊：
影响因子：
2.1
通讯作者：
Yin, Guosheng
中科院分区：
文献类型：
--
作者：
Lin, Ruitao;Yin, Guosheng
在贝叶斯模型选择的框架下，我们提出了一个非参数过剂量控制（NOC）设计的剂量发现在I期临床试验。通过可行性界限指导每次剂量分配，从而可以控制分配到过度毒性剂量水平的患者数量。NOC设计的几个方面进行了探讨，包括剂量分配的一致性属性，设计参数的校准，和最大耐受剂量（MTD）的选择。我们进一步提出了一种分数NOC（fNOC）设计，结合所谓的分数插补方法，以解释迟发性毒性结局。已经进行了广泛的模拟研究表明，NOC和fNOC设计具有强大的和令人满意的有限样本性能相比，现有的剂量发现设计。所提出的方法还具有几个理想的特性：更安全地治疗患者，并且当毒性结果是迟发性时，还中和了过度毒性剂量的积极升级。fNOC设计以真实的癌症I期试验为例。
Under the framework of Bayesian model selection, we propose a nonparametric overdose control (NOC) design for dose finding in phase I clinical trials. Each dose assignment is guided via a feasibility bound, which thereby can control the number of patients allocated to excessively toxic dose levels. Several aspects of the NOC design are explored, including the coherence property in dose assignment, calibration of design parameters, and selection of the maximum tolerated dose (MTD). We further propose a fractional NOC (fNOC) design in conjunction with a so-called fractional imputation approach, to account for late-onset toxicity outcomes. Extensive simulation studies have been conducted to show that both the NOC and fNOC designs have robust and satisfactory finite-sample performance compared with the existing dose-finding designs. The proposed methods also possess several desirable properties: treating patients more safely and also neutralizing the aggressive escalation to overly toxic doses when the toxicity outcomes are late-onset. The fNOC design is exemplified with a real cancer phase I trial.