Mandrekar Sumithra J, Cui Yue, Sargent Daniel J
Division of Biostatistics, Mayo Clinic, Rochester, MN 55905, USA.
Stat Med. 2007 May 20;26(11):2317-30. doi: 10.1002/sim.2707.
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.
从历史上看，使用化疗药物组合进行剂量探索试验的设计一直旨在找到最大耐受剂量，并将安全性作为主要结果。对于那些剂量-疗效曲线未知且剂量-毒性关系可能很微小的靶向药物，需要采用替代设计。在本文中，我们提出了对先前报道的自适应单药剂量探索设计的一种扩展。提出了连续比例模型的一种推广形式，该模型允许在双药组合中为每种药物分别设置毒性和疗效曲线，从而生成组合的剂量成功表面。采用了一种连续重新评估方法，该方法使用截至该时间点所有接受治疗患者的累积数据，具有直接的剂量选择标准。我们的模拟研究表明，在各种情况下，该方法在实验和推荐率以及平均样本量方面具有良好的操作特性。所提出的方法允许将每种药物的毒性和疗效都纳入组合最佳给药区域的确定中，这是新颖的，值得进一步考虑。
