Zhang Liangcai, Yuan Ying
Department of Statistics, Rice University, Houston, 77005, TX, U.S.A.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, U.S.A.
Stat Med. 2016 Nov 30;35(27):4924-4936. doi: 10.1002/sim.7095. Epub 2016 Aug 31.
Drug combination therapy has become the mainstream approach to cancer treatment. One fundamental feature that makes combination trials different from single-agent trials is the existence of the maximum tolerated dose (MTD) contour, that is, multiple MTDs. As a result, unlike single-agent phase I trials, which aim to find a single MTD, it is often of interest to find the MTD contour for combination trials. We propose a new dose-finding design, the waterfall design, to find the MTD contour for drug combination trials. Taking the divide-and-conquer strategy, the waterfall design divides the task of finding the MTD contour into a sequence of one-dimensional dose-finding processes, known as subtrials. The subtrials are conducted sequentially in a certain order, such that the results of each subtrial will be used to inform the design of subsequent subtrials. Such information borrowing allows the waterfall design to explore the two-dimensional dose space efficiently using a limited sample size and decreases the chance of overdosing and underdosing patients. To accommodate the consideration that doses on the MTD contour may have very different efficacy or synergistic effects because of drug-drug interaction, we further extend our approach to a phase I/II design with the goal of finding the MTD with the highest efficacy. Simulation studies show that the waterfall design is safer and has higher probability of identifying the true MTD contour than some existing designs. The R package "BOIN" to implement the waterfall design is freely available from CRAN. Copyright © 2016 John Wiley & Sons, Ltd.
联合药物治疗已成为癌症治疗的主流方法。联合试验与单药试验不同的一个基本特征是存在最大耐受剂量（MTD）轮廓，即多个MTD。因此，与旨在找到单一MTD的单药I期试验不同，找到联合试验的MTD轮廓通常是有意义的。我们提出了一种新的剂量探索设计——瀑布式设计，用于找到联合药物试验的MTD轮廓。采用分而治之的策略，瀑布式设计将寻找MTD轮廓的任务分解为一系列一维剂量探索过程，即子试验。子试验按特定顺序依次进行，使得每个子试验的结果将用于指导后续子试验的设计。这种信息借用使瀑布式设计能够使用有限的样本量有效地探索二维剂量空间，并降低患者用药过量和用药不足的可能性。为了考虑到由于药物相互作用，MTD轮廓上的剂量可能具有非常不同的疗效或协同效应，我们进一步将我们的方法扩展为一种I/II期设计，目标是找到具有最高疗效的MTD。模拟研究表明，与一些现有设计相比，瀑布式设计更安全，识别真实MTD轮廓的概率更高。实现瀑布式设计的R包“BOIN”可从CRAN免费获得。版权所有© 2016约翰威立父子有限公司。
