An adaptive phase I design for identifying a biologically optimal dose for dual agent drug combinations
An adaptive phase I design for identifying a biologically optimal dose for dual agent drug combinations
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DOI：
10.1002/sim.2707
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发表时间：
2007-05-20
影响因子：
2
通讯作者：
Sargent, Daniel J.
中科院分区：
文献类型：
--
作者：
Mandrekar, Sumithra J.;Cui, Yue;Sargent, Daniel J.
从历史上看，使用化疗药物组合的剂量寻求试验的设计一直致力于寻找最大耐受剂量，安全性作为主要结局。对于剂量-功效曲线未知且剂量-毒性关系可能最小的靶向药物，需要替代设计。在本文中，我们提出了一个自适应单剂剂量发现设计以前报道的扩展。推广的延续比模型，允许单独的毒性和疗效曲线的每一种药物在一个双药剂组合，生成一个剂量成功的组合，提出。采用了一种连续的重新评估方法，该方法采用了一种直接的剂量选择标准，该标准使用了所有接受治疗的患者的累积数据。我们的模拟研究在各种情况下，在实验和推荐率以及平均样本量方面表现出有利的操作特性。所提出的方法允许将每种药物的毒性和疗效纳入组合的最佳给药区域的鉴定中，这是新颖的，值得进一步考虑。版权所有（C）2006约翰威利父子有限公司
Historically, designs for dose seeking trials using chemotherapeutic drug combinations have been geared towards finding the maximum tolerated dose, with safety as the primary outcome. With target based agents whose dose-efficacy curves are unknown and dose-toxicity relationships may be minimal, alternative designs are needed. In this paper, we propose an extension to an adaptive single agent dose-finding design previously reported. A generalization of the continuation ratio model allowing separate toxicity and efficacy curves for each agent in a dual agent combination, generating a dose success surface for the combination, is proposed. A continual reassessment approach with a straightforward dose selection criterion using the accumulated data from all patients treated to that point is employed. Our simulation studies demonstrate favourable operating characteristics in terms of experimentation and recommendation rates, and the average sample size, under a variety of scenarios. The proposed approach allowing the incorporation of both the toxicity and efficacy of each agent into the identification of an optimal dosing region for a combination is novel and warrants further consideration. Copyright (C) 2006 John Wiley & Sons, Ltd.