Integrating the escalation and dose expansion studies into a unified Phase I clinical trial.
Integrating the escalation and dose expansion studies into a unified Phase I clinical trial.
复制标题
将升级和剂量扩展研究整合到统一的I期临床试验中。
DOI：
10.1016/j.cct.2016.06.010
复制
发表时间：
2016-09
影响因子：
2.2
通讯作者：
O'Quigley J
中科院分区：
文献类型：
--
作者：
Iasonos A;O'Quigley J
我们专注于目前正在进行的第一阶段剂量探索研究。这些试验的设计和分析在过去几年中发生了变化，特别是，现在 I 期研究很少不包括一个或多个剂量扩展队列 (DEC)。 DEC 涉及数百名患者是很常见的，最初的剂量递增研究可能不超过 20 至 30 名患者。最近，研究人员将注意力集中在 DEC 的设计和 DEC 数据的分析上。明确考虑 MTD 估计的不确定性是合理的，MTD 是目前整个 DEC 所依据的剂量。在本文中，我们重点关注 DEC 之前的剂量递增阶段，目的是使其适应 DEC 的需要。具体来说，在开始 DEC 阶段之前，我们需要确定将纳入 DEC 的剂量水平。为此，我们定义了一个有用的概念，co-MTD，结果支持估计的 MTD 和 co-MTD 以高概率包含真实的 MTD。我们还提供了数据支持何时可以结束剂量递增以及何时可以开始剂量扩展的停止规则。模拟试验支持所提出方法的使用，并提供有关该方法与当前实践如何比较的更多信息。
We focus on Phase I dose finding studies as they are currently undertaken. The design and analysis of these trials has changed over the last years and, in particular, it is now rare for a Phase I study to not include one or more dose- expansion cohorts (DEC). It is common to see DEC involving several hundred patients, building on an initial dose escalation study that may have no more than 20 to 30 patients. There has been recent focus by researchers on the design of DEC and the analysis of DEC data. It is reasonable to explicitly account for the uncertainty in the estimation of the MTD, the dose upon which the whole of the DEC is currently based. In this paper, we focus on the dose escalation phase prior to the DEC, with the purpose of adapting it to the needs of DEC. Specifically, before beginning the DEC phase, we need to identify those dose levels that will be taken into the DEC. We define a useful concept for this purpose, the co-MTD, and the results support that the estimated MTD and co-MTD contain the true MTD with high probability. We also provide stopping rules for when the data support that the dose escalation can end and the dose expansion can begin. Simulated trials support the use of the proposed approach and provide additional information on how this approach compares with current practice.