Fan Shenghua Kelly, Venook Alan P, Lu Ying
Department of Statistics and Biostatistics, California State University, East Bay, Hayward, California, USA.
J Biopharm Stat. 2009;19(3):509-23. doi: 10.1080/10543400902802433.
Combination therapy of two antitumor agents may provide treatment additivity or synergy. Phase I trials for combination therapy search for the maximum tolerated dose (MTD) for combined agents. The conventional approach is to preselect an escalation path, usually increasing the dose of one agent and then another, and to use the standard 3 + 3 design. However, this procedure may miss the optimum dose combination, prolong the time it takes, and increase the number of patients necessary to reach the MTD. In this study, we present strategies for a comprehensive search for MTD for a two-agent combination therapy. We evaluate algorithms based on two-stage and three-stage design as well as variations in cohort size. A two-dimensional isotonic estimation method for toxicity rate is provided. We use simulation methods to compare 2 + 1 + 3 vs. 3 + 3 cohort sizes. We conclude that the comprehensive search proposed in our study can be more practical and efficient in identifying the MTD in combination-therapy of two agents.
两种抗肿瘤药物的联合治疗可能会产生治疗相加或协同作用。联合治疗的I期试验旨在寻找联合用药的最大耐受剂量（MTD）。传统方法是预先选择一种剂量递增路径，通常先增加一种药物的剂量，然后再增加另一种药物的剂量，并采用标准的3+3设计。然而，这种方法可能会错过最佳剂量组合，延长达到MTD所需的时间，并增加达到MTD所需的患者数量。在本研究中，我们提出了全面搜索两种药物联合治疗MTD的策略。我们评估基于两阶段和三阶段设计以及队列大小变化的算法。提供了一种毒性率的二维等渗估计方法。我们使用模拟方法比较2+1+3与3+3队列大小。我们得出结论，我们研究中提出的全面搜索在识别两种药物联合治疗的MTD方面可能更实用、更有效。
