Escalation with overdose control for phase I drug-combination trials
Escalation with overdose control for phase I drug-combination trials
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DOI：
10.1002/sim.5832
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发表时间：
2013-11-10
影响因子：
2
通讯作者：
Yin, Guosheng
中科院分区：
文献类型：
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作者：
Shi, Yun;Yin, Guosheng
联合用药的剂量发现在肿瘤药物开发中迅速增长。EWOC方法是单药I期临床试验中常用的基于模型的剂量探索方法。当两种药物联合治疗时，我们提出了一种基于四参数logistic回归模型的二维EWOC剂量发现设计。在试验进行期间，我们不断更新最大耐受剂量（MTD）组合的后验分布，以找到每个患者队列的最合适剂量组合。下一个分配的剂量组合超过MTD组合的概率可以通过可行性界限来控制，该可行性界限基于MTD分布的预先规定的分位数水平，以降低过量给药的可能性。我们通过分别沿着两种药物组合矩阵中的行和列搜索MTD组合来确定剂量递增、递减或保持相同剂量。我们进行模拟研究，以检查各种实际情况下的二维EWOC设计的性能，并说明它与一个试用的例子。版权所有（c）2013约翰威利父子有限公司
Dose finding for combined drugs has grown rapidly in oncology drug development. The escalation with overdose control (EWOC) method is a popular model-based dose-finding approach to single-agent phase I clinical trials. When two drugs are combined as a treatment, we propose a two-dimensional EWOC design for dose finding on the basis of a four-parameter logistic regression model. During trial conduct, we continuously update the posterior distribution of the maximum tolerated dose (MTD) combination to find the most appropriate dose combination for each cohort of patients. The probability that the next assigned dose combination exceeds the MTD combination can be controlled by a feasibility bound, which is based on a prespecified quantile level of the MTD distribution such as to reduce the possibility of overdosing. We determine dose escalation, de-escalation, or staying at the same doses by searching the MTD combination along the rows and columns in a two-drug combination matrix, respectively. We conduct simulation studies to examine the performance of the two-dimensional EWOC design under various practical scenarios, and illustrate it with a trial example. Copyright (c) 2013 John Wiley & Sons, Ltd.