Chapple Andrew G, Wojcik Janusz J, McDaniel Lee S
Louisiana State University Health Sciences Center, New Orleans, 2020 Gravier Street, New Orleans, LA, 70112, USA.
Contemp Clin Trials Commun. 2019 Jan 30;14:100327. doi: 10.1016/j.conctc.2019.100327. eCollection 2019 Jun.
An extension of the isotonic regression based phase I clinical trial design is presented that incorporates partial follow-up times into estimation of the raw toxicity probabilities. This phase I clinical trial design, called the TITE-IR design, drastically decreases average trial duration by allowing patients to be treated immediately after being enrolled in a phase I clinical trial. The TITE-IR design does not require specification of a prior skeleton of toxicity probabilities like the continual reassessment method, has an additional trial parameter for controlling aggressiveness of dose escalation, and has an easily understood formula for estimating toxicity probabilities. An R statistical software package is described in detail in the appendix for simulating and implementing the design. A simulation study shows that the TITE-IR design outperforms the 3 + 3 design in terms of selecting the true maximum tolerated dose and results in shorter trial times, without a large loss in efficiency, compared to the isotonic regression design and Storer's up-and-down design D. These properties make the TITE-IR design a more appealing option to clinicians than the two most commonly used 3 + 3 designs and the isotonic regression design with larger follow-up windows for toxicity.
本文提出了一种基于等渗回归的I期临床试验设计的扩展方法，该方法将部分随访时间纳入原始毒性概率的估计中。这种I期临床试验设计称为TITE-IR设计，通过允许患者在进入I期临床试验后立即接受治疗，大幅缩短了平均试验持续时间。TITE-IR设计不像连续重新评估方法那样需要预先设定毒性概率的框架，有一个额外的试验参数用于控制剂量递增的激进程度，并且有一个易于理解的毒性概率估计公式。附录中详细描述了一个用于模拟和实施该设计的R统计软件包。一项模拟研究表明，在选择真正的最大耐受剂量方面，TITE-IR设计优于3+3设计，并且与等渗回归设计和斯托勒上下设计D相比，在不损失大量效率的情况下，能缩短试验时间。这些特性使得TITE-IR设计比两种最常用的3+3设计以及具有更大毒性随访窗口的等渗回归设计对临床医生来说更具吸引力。
