Dose escalation with over-dose and under-dose controls in Phase I/II clinical trials.
Dose escalation with over-dose and under-dose controls in Phase I/II clinical trials.
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DOI：
10.1016/j.cct.2015.05.014
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发表时间：
2015-07
影响因子：
2.2
通讯作者：
Kowalski J
中科院分区：
文献类型：
--
作者：
Chen Z;Yuan Y;Li Z;Kutner M;Owonikoko T;Curran WJ;Khuri F;Kowalski J
为了节省新药开发的宝贵时间和资源，以毒性控制和药物疗效为双主要终点的I/II期临床试验越来越受欢迎。EWOC是一种贝叶斯自适应I期临床试验设计，可以准确估计最大耐受剂量（MTD）水平，并在剂量分配阶段控制过量患者的概率。在本文中，我们将EWOC扩展到I/II期临床试验，通过Gumbel Copula模型控制剂量不足，为患者提供至少最小的药物疗效。我们提出了一个效用函数来衡量毒性和疗效的综合效应，并选择最佳剂量。为了解决通常无法快速确定疗效终点的常见问题，我们采用贝叶斯数据增强来处理延迟疗效，并允许灵活的患者累积而无需等待期。大量的模拟实验表明，新设计不仅通过降低治疗剂量不足的概率，同时保护患者不被过量用药，提供了更好的治疗效果，而且还提高了试验效率，提高了后续临床试验剂量推荐的准确性。我们将提出的设计应用于I/II期实体瘤试验。
To save valuable time and resources in new drug development, Phase I/II clinical trials with toxicity control and drug efficacy as dual primary endpoints have become increasingly popular. 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.