STEIN: A simple toxicity and efficacy interval design for seamless phase I/II clinical trials
STEIN: A simple toxicity and efficacy interval design for seamless phase I/II clinical trials
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DOI：
10.1002/sim.7428
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发表时间：
2017-11-20
影响因子：
2
通讯作者：
Yin, Guosheng
中科院分区：
文献类型：
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作者：
Lin, Ruitao;Yin, Guosheng
无缝的I/II期剂量探索试验如今在肿瘤学的早期药物开发中引起了越来越多的关注。大多数现有的I/II期剂量探索方法使用复杂但不可检验的模型来量化剂量-毒性和剂量-疗效关系，这总是使它们难以在实践中实施。为了简化实际应用，我们将贝叶斯最优区间设计从寻找最大耐受剂量扩展到寻找I/II期临床试验的最优生物剂量。特别地，通过最小化不正确分类的概率，分别导出毒性和功效的优化间隔。如果在当前剂量下观察到的毒性和有效性概率对位于有希望区域内，则保留当前剂量;如果观察到的概率在有希望区域外，则通过最大化下一剂量福尔斯的应答率落在预定有效性概率区间内的后验概率，同时仍然控制毒性水平，提出一种分配规则。建议的区间设计是无模型的，因此适用于各种剂量-反应关系。我们进行了广泛的模拟研究，以证明在各种情况下的小样本和大样本的性能所提出的方法。与现有的I/II期剂量探索设计相比，我们的间隔设计不仅易于在实践中实施，而且还具有理想和稳健的操作特性。
Seamless phase I/II dose-finding trials are attracting increasing attention nowadays in early-phase drug development for oncology. Most existing phase I/II dose-finding methods use sophisticated yet untestable models to quantify dose-toxicity and dose-efficacy relationships, which always renders them difficult to implement in practice. To simplify the practical implementation, we extend the Bayesian optimal interval design from maximum tolerated dose finding to optimal biological dose finding in phase I/II trials. In particular, optimized intervals for toxicity and efficacy are respectively derived by minimizing probabilities of incorrect classifications. If the pair of observed toxicity and efficacy probabilities at the current dose is located inside the promising region, we retain the current dose; if the observed probabilities are outside of the promising region, we propose an allocation rule by maximizing the posterior probability that the response rate of the next dose falls inside a prespecified efficacy probability interval while still controlling the level of toxicity. The proposed interval design is model-free, thus is suitable for various dose-response relationships. We conduct extensive simulation studies to demonstrate the small-and large-sample performance of the proposed method under various scenarios. Compared to existing phase I/II dose-finding designs, not only is our interval design easy to implement in practice, but it also possesses desirable and robust operating characteristics.