TEPI-2 and UBI: designs for optimal immuno-oncology and cell therapy dose finding with toxicity and efficacy
TEPI-2 and UBI: designs for optimal immuno-oncology and cell therapy dose finding with toxicity and efficacy
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TEPI-2 和 UBI：最佳免疫肿瘤学和细胞治疗剂量发现的设计以及毒性和疗效
DOI：
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发表时间：
2020
影响因子：
1.1
通讯作者：
Yuan Ji
中科院分区：
文献类型：
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作者：
Pin Li;Rachael Liu;Jianchang Lin;Yuan Ji
肿瘤药物开发中传统的剂量寻找设计以确定最大耐受剂量（MTD）为目标，并假设MTD在已确定的耐受剂量水平中具有最大的临床活性潜力。然而，免疫肿瘤学（I-O）和细胞治疗领域可能缺乏剂量-功效单调性，这给剂量发现试验的统计设计带来了重大挑战。理想的设计应使试验能够确定具有可容忍毒性和可接受功效的正确剂量水平。这样的剂量被称为最佳生物剂量（OBD），它比MTD更适合作为I-O和细胞治疗首次人体试验的主要目标。在这种情况下，我们提出了两种模型辅助设计：毒性和疗效概率区间-2 （TEPI-2）设计和基于效用的区间（UBI）设计，它们同时包含毒性和疗效结果，并确定具有高概率可接受疗效和可控毒性的剂量。提出的设计可以在试验开始前生成决策表，以促进实际和易于实现的应用。通过仿真研究，我们提出的新设计在精度，效率和安全性方面表现出卓越的性能。此外，它们还可以减少患者数量，缩短临床开发时间。我们还通过重新设计CAR - t细胞治疗多发性骨髓瘤的I期临床试验来说明所提出方法的优势，并在讨论部分总结了我们的建议。
ABSTRACT Conventional dose finding designs in oncology drug development target on the identification of the maximum tolerated dose (MTD), with the assumption that the MTD has the most potential of clinical activity among those identified tolerable dose levels. However, immuno-oncology (I-O) and cell therapy area, may lack dose-efficacy monotonicity, posing significant challenges in the statistical designs for dose finding trials. A desirable design should empower the trial to identify the right dose level with tolerable toxicity and acceptable efficacy. Such dose is called as optimal biological dose (OBD), which is more appropriate to be considered as the primary objective of the first-in-human trial in I-O and cell therapy than MTD. We propose two model-assisted designs in this setting: the toxicity and efficacy probability interval-2 (TEPI-2) design and the utility-based interval (UBI) design that incorporate the toxicity and efficacy outcomes simultaneously and identify a dose that has high probability of acceptable efficacy with manageable toxicity. The proposed designs can generate decision tables before trial starts to facilitate practical and easy-to-implement applications. Through simulation studies, our proposed novel designs demonstrate superior performance in accuracy, efficiency, and safety. Additionally, they can reduce the number of patients and shorten clinical development timeline. We also illustrate the advantages of proposed methods by redesigning a CAR T-cell therapy phase I clinical trial for multiple myeloma and summarize our recommendations in the discussion section.