Division of Biostatistics, Department of Research Information Sciences, City of Hope, Duarte, California.
Department of Medical Oncology, City of Hope, Duarte, California.
JAMA Netw Open. 2020 May 1;3(5):e204787. doi: 10.1001/jamanetworkopen.2020.4787.
Phase 1 cancer studies, which guide dose selection for subsequent studies, are almost 3 times more prevalent than phase 3 studies and have a median study duration considerably longer than 2 years, which constitutes a major component of drug development time.
To discern a method to reduce the duration of phase 1 studies in adult and pediatric cancer studies without violating risk limits by better accommodating the accrual and evaluation process (or queue).
The process modeled, the phase 1 queue (IQ), includes patient interarrival time, screening, and dose-limiting toxicity evaluation. For this proof of principle, the rules of the 3 + 3 and rolling 6 phase 1 designs were modified to improve patient flow through the queue without exceeding the maximum risk permitted in the parent designs. The resulting designs, the IQ 3 + 3 and the IQ rolling 6, were each compared with their parent design by simulations in 12 different scenarios.
(1) The time from study opening to determination of the maximum tolerated dose (MTD), (2) the number of patients treated to determine the MTD, and (3) the association of the design with the dose selected as the MTD.
Based on 800 simulations, for all 12 scenarios considered, the IQ 3 + 3 and the IQ rolling 6 designs were associated with reduced expected study durations compared with the parent design. The expected IQ 3 + 3 reduction ranged from 1.6 to 10.4 months (with 3.7 months for the standard scenario), and the expected reduction associated with IQ rolling 6 ranged from 0.4 to 10.5 months (with 3.4 months for the standard scenario). The increase in the mean number of patients treated in the IQ 3 + 3 compared with the 3 + 3 ranged from 0.6 to 3.2 patients. No increase in the number of patients was associated with the IQ rolling 6 compared with the rolling 6 design. The probability of selecting a dose level as the MTD changed by less than 3% for all dose levels and scenarios in both parent designs.
This study found that IQ designs were associated with reduced mean duration of phase 1 studies compared with their parent designs without changing the risk limits or MTD selection operating characteristics. These approaches have been successfully implemented in both hematology and solid tumor phase 1 studies.
指导后续研究剂量选择的 1 期癌症研究比 3 期研究普遍多出近 3 倍，且中位研究持续时间明显长于 2 年，这构成了药物开发时间的主要组成部分。
通过更好地适应入组和评估过程（或队列），找到一种方法来减少成人和儿科癌症研究 1 期研究的持续时间，而不违反风险限制。
所建模的过程是 1 期队列（IQ），包括患者到达时间、筛选和剂量限制性毒性评估。对于这个原理验证，修改了 3+3 和滚动 6 1 期设计的规则，以改善队列中患者的流动，而不超过父设计中允许的最大风险。将得到的设计，IQ 3+3 和 IQ 滚动 6，在 12 种不同情况下的模拟中分别与它们的母设计进行比较。
（1）从研究开始到确定最大耐受剂量（MTD）的时间，（2）确定 MTD 所需治疗的患者数量，以及（3）设计与选定的 MTD 剂量的关系。
基于 800 次模拟，对于考虑的所有 12 种情况，IQ 3+3 和 IQ 滚动 6 设计与母设计相比，预计研究持续时间缩短。IQ 3+3 的预期缩短范围为 1.6 至 10.4 个月（标准情况下为 3.7 个月），IQ 滚动 6 的预期缩短范围为 0.4 至 10.5 个月（标准情况下为 3.4 个月）。与 3+3 相比，IQ 3+3 中治疗患者的平均数量增加了 0.6 至 3.2 人。与滚动 6 设计相比，IQ 滚动 6 中没有增加患者数量。在两个母设计中，所有剂量水平和方案的 MTD 选择操作特征的变化都小于 3%。
本研究发现，与母设计相比，IQ 设计与 1 期研究的平均持续时间缩短，而不改变风险限制或 MTD 选择操作特征。这些方法已成功应用于血液学和实体瘤 1 期研究。
