Journal of Biopharmaceutical Statistics ( IF 1.1 ) Pub Date : 2020-09-23 , DOI: 10.1080/10543406.2020.1815033 Jun Yin 1 , Ying Yuan 2
ABSTRACT
The rise of targeted therapy and immunotherapy has challenged the conventional more-is-better phase I trial design paradigm that focuses on finding the MTD. In this article, we propose a novel model-assisted phase I/II design, called checkerboard design, that considers both toxicity and efficacy. As an extension of the keyboard design, the checkerboard design models the joint distribution of toxicity and efficacy, and divides toxicity and efficacy domain into a series of equal-width intervals or keys. In light of interim data, the checkerboard design continuously updates the posterior distribution of toxicity and efficacy, and adaptively determine the optimal dose for treating the next cohort of patients based on the posterior probability of toxicity and efficacy keys. As a model-assisted design, one important advantage of the checkerboard design is that its decision rule can be pretabulated, greatly simplifying its implementation. We also extend the checkerboard design to handle continuous efficacy endpoint. Simulations study shows that the checkerboard design yields competitive performance comparable to existing model-based phase I/II designs, but is simpler and easier to implement in real applications.
中文翻译:
棋盘格:I/II 期剂量探索试验的贝叶斯功效和毒性区间设计
摘要
靶向治疗和免疫治疗的兴起对专注于寻找 MTD 的传统 I 期试验设计范式提出了挑战。在本文中,我们提出了一种新的模型辅助 I/II 期设计,称为棋盘设计,它同时考虑了毒性和功效。作为键盘设计的延伸,棋盘设计模拟了毒效的联合分布,将毒效域划分为一系列等宽的间隔或键。根据中期数据,棋盘设计不断更新毒性和疗效的后验分布,并根据毒性和疗效关键的后验概率自适应确定治疗下一组患者的最佳剂量。作为模型辅助设计,棋盘设计的一个重要优点是它的决策规则可以预先制表,大大简化了它的实现。我们还扩展了棋盘设计以处理持续的功效端点。仿真研究表明,棋盘设计的性能可与现有的基于模型的 I/II 阶段设计相媲美,但在实际应用中更简单、更容易实现。