Two-stage approach based on zone and dose findings for two-agent combination Phase I/II trials
Two-stage approach based on zone and dose findings for two-agent combination Phase I/II trials
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DOI：
10.1080/10543406.2018.1434190
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发表时间：
2018-11-02
影响因子：
1.1
通讯作者：
Hirakawa, Akihiro
中科院分区：
文献类型：
--
作者：
Shimamura, Fumiya;Hamada, Chikuma;Hirakawa, Akihiro
在两种药物联合治疗的I/II期试验中，理想情况下，我们希望在I期试验中以有限的样本量探索尽可能多的剂量组合，并在进入II期试验之前减少未尝试的剂量组合的数量。在I期有效收集毒性数据将最终提高II期最佳剂量组合鉴定的准确性。在本文中，我们开发了一种新的剂量发现方法的基础上的疗效和毒性结果的两种药物组合的I/II期试验。我们提出了一个“区域发现阶段”，确定剂量组合矩阵上最可接受的毒性区域，随后从I期的该区域中选择分配给下一位患者的剂量组合。在完成该区域发现阶段后，我们将下一名患者分配至通过适应性随机化II期可接受的毒性和疗效剂量组合确定的剂量组合。仿真研究表明，所提出的区域发现阶段的效用，并证明所提出的方法的操作特性并不比现有的方法差。还检查了所提出的方法的灵敏度，以及当疗效结果延迟时该方法的操作特性。
In Phase I/II trials for a combination therapy of two agents, we ideally want to explore as many dose combinations as possible with limited sample size in Phase I and to reduce the number of untried dose combinations before moving to Phase II. Efficient collection of toxicity data in Phase I would eventually improve the accuracy of optimal dose combination identification in Phase II. In this paper, we develop a novel dose-finding method based on efficacy and toxicity outcomes for two-agent combination Phase I/II trials. We propose a "zone-finding stage" that determines the most admissible toxicity zone on the dose combination matrix and subsequently select the dose combination allocated to the next patient from that zone in Phase I. Upon completion of this zone-finding stage, we allocate the next patient to the dose combination determined by adaptive randomization of the admissible toxicity and efficacy dose combinations in Phase II. Simulation studies demonstrated the utility of the proposed zone-finding stage and proved that the operating characteristic of the proposed method was no worse than the existing method. The sensitivity of the proposed method, as well as the operating characteristic of this method when the efficacy outcome is delayed, was also examined.