Chen Xin, Zhang Jingyi, Jiang Liyun, Yan Fangrong
Research Center of Biostatistics and Computational Pharmacy, 56651China Pharmaceutical University, Nanjing, China.
Stat Methods Med Res. 2023 Mar;32(3):443-464. doi: 10.1177/09622802221129049. Epub 2022 Oct 11.
For novel molecularly targeted agents and immunotherapies, the objective of dose-finding is often to identify the optimal biological dose, rather than the maximum tolerated dose. However, optimal biological doses may not be the same for different indications, challenging the traditional dose-finding framework. Therefore, we proposed a Bayesian phase I/II basket trial design, named "shotgun-2," to identify indication-specific optimal biological doses. A dose-escalation part is conducted in stage I to identify the maximum tolerated dose and admissible dose sets. In stage II, dose optimization is performed incorporating both toxicity and efficacy for each indication. Simulation studies under both fixed and random scenarios show that, compared with the traditional "phase I + cohort expansion" design, the shotgun-2 design is robust and can improve the probability of correctly selecting the optimal biological doses. Furthermore, this study provides a useful tool for identifying indication-specific optimal biological doses and accelerating drug development.
对于新型分子靶向药物和免疫疗法，剂量探索的目标通常是确定最佳生物学剂量，而非最大耐受剂量。然而，不同适应症的最佳生物学剂量可能不同，这对传统的剂量探索框架提出了挑战。因此，我们提出了一种贝叶斯I/II期篮子试验设计，名为“霰弹枪-2”，以确定特定适应症的最佳生物学剂量。在I期进行剂量递增部分，以确定最大耐受剂量和可接受剂量集。在II期，结合每种适应症的毒性和疗效进行剂量优化。固定和随机场景下的模拟研究表明，与传统的“ I期 + 队列扩展”设计相比，霰弹枪-2设计稳健，能够提高正确选择最佳生物学剂量的概率。此外，本研究为确定特定适应症的最佳生物学剂量和加速药物开发提供了一个有用的工具。
