Li Mingyue, Guo Zhonglong, Qiu Yingjie
Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Co-Innovation Center for Sustainable Forestry in Southern China, College of Life Sciences, Nanjing Forestry University, Nanjing, China.
Stat Med. 2025 May;44(10-12):e70098. doi: 10.1002/sim.70098.
A primary objective of oncology dose-finding trials for novel therapies is to determine an optimal biological dose (OBD) that is both tolerable and therapeutically beneficial for patients in subsequent clinical trials. These new therapeutic agents are more likely to induce multiple low- or moderate-grade toxicities rather than dose-limiting toxicities. Additionally, efficacy is evaluated comprehensively, differentiating between complete remission and partial remission, as well as incorporating continuous efficacy endpoints. This important issue was highlighted in the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section open forums and was a significant consideration of the FDA's "Project Optimus." We proposed the UNITED design, a unified, transparent, and efficient Phase I/II trial design to incorporate toxicity and efficacy grades and types, as well as continuous efficacy responses, into dose-finding and optimization. The UNITED design can handle binary, quasi-binary, continuous, and mixed toxicity and efficacy endpoints. We further extended the UNITED design, referred to as TITE-UNITED, to accommodate delayed toxicity and efficacy outcomes. Simulation studies showed that the UNITED and TITE-UNITED designs have desirable operating characteristics, performing comparably to or better than existing designs. A user-friendly software is available for practical implementation.
新型疗法的肿瘤学剂量探索试验的一个主要目标是确定最佳生物学剂量（OBD），该剂量在后续临床试验中对患者而言既耐受又具有治疗益处。这些新治疗药物更有可能引发多种低级别或中级别毒性，而非剂量限制性毒性。此外，会对疗效进行全面评估，区分完全缓解和部分缓解，并纳入连续疗效终点。这一重要问题在美国统计协会（ASA）生物制药（BIOP）分会的公开论坛中得到了强调，也是美国食品药品监督管理局（FDA）“擎天柱计划”的一项重要考量。我们提出了UNITED设计，这是一种统一、透明且高效的I/II期试验设计，将毒性和疗效等级及类型，以及连续疗效反应纳入剂量探索和优化过程。UNITED设计能够处理二元、准二元、连续以及混合的毒性和疗效终点。我们进一步扩展了UNITED设计，即TITE - UNITED，以适应延迟的毒性和疗效结果。模拟研究表明，UNITED和TITE - UNITED设计具有理想的操作特性，其表现与现有设计相当或更优。有一个用户友好型软件可供实际应用。
