Chapple Andrew G, Thall Peter F
Department of Statistics, Rice University, Houston, Texas.
Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Biometrics. 2019 Jun;75(2):371-381. doi: 10.1111/biom.12994. Epub 2019 Apr 3.
Conventionally, evaluation of a new drug, A, is done in three phases. Phase I is based on toxicity to determine a "maximum tolerable dose" (MTD) of A, phase II is conducted to decide whether A at the MTD is promising in terms of response probability, and if so a large randomized phase III trial is conducted to compare A to a control treatment, usually based on survival time or progression free survival time. It is widely recognized that this paradigm has many flaws. A recent approach combines the first two phases by conducting a phase I-II trial, which chooses an optimal dose based on both efficacy and toxicity, and evaluation of A at the selected optimal phase I-II dose then is done in a phase III trial. This paper proposes a new design paradigm, motivated by the possibility that the optimal phase I-II dose may not maximize mean survival time with A. We propose a hybridized design, which we call phase I-II/III, that combines phase I-II and phase III by allowing the chosen optimal phase I-II dose of A to be re-optimized based on survival time data from phase I-II patients and the first portion of phase III. The phase I-II/III design uses adaptive randomization in phase I-II, and relies on a mixture model for the survival time distribution as a function of efficacy, toxicity, and dose. A simulation study is presented to evaluate the phase I-II/III design and compare it to the usual approach that does not re-optimize the dose of A in phase III.
传统上，新药A的评估分为三个阶段。第一阶段基于毒性来确定A的“最大耐受剂量”（MTD），第二阶段用于判定处于MTD的A在反应概率方面是否有前景，如果是，则进行一项大型随机III期试验，将A与对照治疗进行比较，通常基于生存时间或无进展生存时间。人们普遍认识到这种模式存在许多缺陷。最近的一种方法是通过进行I-II期试验将前两个阶段结合起来，该试验根据疗效和毒性选择最佳剂量，然后在III期试验中对选定的最佳I-II期剂量的A进行评估。本文提出了一种新的设计模式，其动机源于最佳I-II期剂量可能无法使A的平均生存时间最大化这一可能性。我们提出了一种混合设计，我们称之为I-II/III期，它通过允许根据I-II期患者和III期第一部分的生存时间数据对选定的最佳I-II期剂量的A进行重新优化，从而将I-II期和III期结合起来。I-II/III期设计在I-II期使用自适应随机化，并依赖于作为疗效、毒性和剂量函数的生存时间分布的混合模型。本文进行了一项模拟研究，以评估I-II/III期设计，并将其与在III期不重新优化A剂量的常规方法进行比较。
