As diseases like cancer are increasingly understood on a molecular level, clinical trials are being designed to reveal or validate subpopulations in which an experimental therapy has enhanced benefit. Such biomarker-driven designs, particularly “adaptive enrichment” designs that initially enroll an unselected population and then allow for later restriction of accrual to “marker-positive” patients based on interim results, are increasingly popular. Many biomarkers of interest are naturally continuous, however, and most existing design approaches either require upfront dichotomization or force monotonicity through algorithmic searches for a single marker threshold, thereby excluding the possibility that the continuous biomarker has a nondisjoint and truly nonlinear or nonmonotone prognostic relationship with outcome or predictive relationship with treatment effect. To address this, we propose a novel trial design that leverages both the actual shapes of any continuous marker effects (both prognostic and predictive) and their corresponding posterior uncertainty in an adaptive decision-making framework. At interim analyses, this marker knowledge is updated and overall or marker-driven decisions are reached such as continuing enrollment to the next interim analysis or terminating early for efficacy or futility. Using simulations and patient-level data from a multi-center Children's Oncology Group trial in Acute Lymphoblastic Leukemia, we derive the operating characteristics of our design and compare its performance to a traditional approach that identifies and applies a dichotomizing marker threshold.

中文翻译：

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具有可能非线性或非单调预后或预测效果的连续生物标志物的贝叶斯自适应试验设计


随着癌症等疾病在分子水平上得到越来越多的了解，临床试验的目的是揭示或验证实验疗法在哪些亚群中具有增强的益处。这种生物标志物驱动的设计，特别是“适应性富集”设计，最初招募未经选择的人群，然后根据中期结果将应计限制于“标志物阳性”患者，越来越受欢迎。然而，许多感兴趣的生物标志物自然是连续的，并且大多数现有的设计方法要么需要预先二分，要么通过算法搜索单个标志物阈值强制单调性，从而排除连续生物标志物与以下因素具有非不相交且真正非线性或非单调预后关系的可能性：结果或与治疗效果的预测关系。为了解决这个问题，我们提出了一种新颖的试验设计，该设计在自适应决策框架中利用任何连续标记效应（预后和预测）的实际形状及其相应的后验不确定性。在中期分析中，该标记知识会被更新，并做出总体或标记驱动的决策，例如继续参加下一次中期分析或因有效性或无效而提前终止。使用来自多中心儿童肿瘤组急性淋巴细胞白血病试验的模拟和患者水平数据，我们得出了我们设计的操作特征，并将其性能与识别和应用二分标记阈值的传统方法进行了比较。