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.

摘要

肿瘤药物开发中的常规剂量寻找设计目标是确定最大耐受剂量 (MTD)，并假设 MTD 在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 (IO) 和细胞治疗领域可能缺乏剂量效应单调性，这对剂量发现试验的统计设计构成了重大挑战。理想的设计应该使试验能够确定具有可耐受毒性和可接受功效的正确剂量水平。这种剂量被称为最佳生物剂量（OBD），与MTD相比，它更适合被视为IO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：毒性和有效性概率区间 2 (TEPI-2) 设计和基于效用的区间 (UBI) 设计，它们同时结合了毒性和有效性结果，并确定了具有可接受的有效性和可控毒性的高概率的剂量。所提出的设计可以在试验开始之前生成决策表，以促进实用且易于实施的应用。通过仿真研究，我们提出的新颖设计在准确性、效率和安全性方面表现出卓越的性能。此外，它们可以减少患者数量并缩短临床开发时间。我们还通过重新设计针对多发性骨髓瘤的 CAR T 细胞疗法 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。