Statistical operating characteristics of current early phase dose finding designs with toxicity and efficacy in oncology

Traditional phase I dose finding cancer clinical trial designs aim to determine the maximum tolerated dose (MTD) of the investigational cytotoxic agent based on a single toxicity outcome, assuming a monotone dose-response relationship. However, this assumption might not always hold for newly emerging therapies such as immuno-oncology therapies and molecularly targeted therapies, making conventional dose finding trial designs based on toxicity no longer appropriate. To tackle this issue, numerous early-phase dose finding clinical trial designs have been developed to identify the optimal biological dose (OBD), which takes both toxicity and efficacy outcomes into account. In this article, we review the current model-assisted dose finding designs, BOIN-ET, BOIN12, UBI, TEPI-2, PRINTE, STEIN, and uTPI to identify the OBD and compare their operating characteristics. Extensive simulation studies and a case study using a CAR T-cell therapy phase I trial have been conducted to compare the performance of the aforementioned designs under different possible dose-response relationship scenarios. The simulation results demonstrate that the performance of different designs varies depending on the particular dose-response relationship and the specific metric considered. Based on our simulation results and practical considerations, STEIN, PRINTE, and BOIN12 outperform the other designs from different perspectives.

传统肿瘤学I期剂量探索临床试验设计，旨在基于单一毒性结局确定研究性细胞毒性药物的最大耐受剂量（maximum tolerated dose, MTD），前提是假设存在单调剂量-反应关系。然而，这一假设对于免疫肿瘤治疗、分子靶向治疗等新兴疗法而言未必始终成立，使得基于毒性的传统剂量探索试验设计不再适用。为解决这一问题，学界已开发出众多早期剂量探索临床试验设计，用于识别同时考量毒性与疗效结局的最优生物学剂量（optimal biological dose, OBD）。本文综述了当前用于识别OBD的模型辅助剂量探索设计，包括BOIN-ET、BOIN12、UBI、TEPI-2、PRINTE、STEIN及uTPI，并对比了它们的运行特征。本研究开展了大规模模拟研究，以及一项基于嵌合抗原受体T细胞（CAR-T）疗法I期临床试验的案例分析，以对比前述设计在不同剂量-反应关系场景下的表现。模拟结果显示，不同设计的性能表现取决于具体的剂量-反应关系及所考量的特定指标。基于本次模拟结果与实际应用考量，STEIN、PRINTE及BOIN12从不同维度来看均优于其他设计。