Yuan Ying, Yin Guosheng
Department of Biostatistics, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ann Appl Stat. 2011 Jan 1;5(2A):924-942. doi: 10.1214/10-AOAS433.
We propose a new integrated phase I/II trial design to identify the most efficacious dose combination that also satisfies certain safety requirements for drug-combination trials. We first take a Bayesian copula-type model for dose finding in phase I. After identifying a set of admissible doses, we immediately move the entire set forward to phase II. We propose a novel adaptive randomization scheme to favor assigning patients to more efficacious dose-combination arms. Our adaptive randomization scheme takes into account both the point estimate and variability of efficacy. By using a moving reference to compare the relative efficacy among treatment arms, our method achieves a high resolution to distinguish different arms. We also consider groupwise adaptive randomization when efficacy is late-onset. We conduct extensive simulation studies to examine the operating characteristics of the proposed design, and illustrate our method using a phase I/II melanoma clinical trial.
我们提出了一种新的I/II期联合试验设计，以确定最有效的剂量组合，同时满足药物联合试验的某些安全要求。我们首先采用贝叶斯Copula型模型进行I期剂量探索。在确定一组可接受的剂量后，我们立即将整个剂量组推进到II期。我们提出了一种新颖的自适应随机化方案，以便更倾向于将患者分配到更有效的剂量组合组。我们的自适应随机化方案同时考虑了疗效的点估计和变异性。通过使用移动参考来比较各治疗组之间的相对疗效，我们的方法具有高分辨率，能够区分不同的组。当疗效出现较晚时，我们还考虑分组自适应随机化。我们进行了广泛的模拟研究，以检验所提出设计的操作特性，并使用一项I/II期黑色素瘤临床试验来说明我们的方法。
