Determining a maximum-tolerated schedule of a cytotoxic agent
Determining a maximum-tolerated schedule of a cytotoxic agent
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DOI：
10.1111/j.1541-0420.2005.00312.x
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发表时间：
2005-06-01
期刊：
影响因子：
1.9
通讯作者：
Thall, PF
中科院分区：
文献类型：
--
作者：
Braun, TM;Yuan, Z;Thall, PF
大多数I期临床试验旨在确定细胞毒性实验性药物的一次初始给药或治疗过程的最大耐受剂量（MTD）。毒性通常被定义为从治疗开始的短时间内是否发生一种或多种特定不良事件的指标。然而，医生经常反复给患者服用药物，并监测由于累积效应引起的长期毒性。我们提出了一种新的方法，这样的设置。它基于至毒性的时间而不是二元结果，目标是确定最大耐受时间表（MTS）而不是传统的MTD。该模型和方法考虑了患者的整个给药序列，其中毒性的总体危害被建模为危害序列的总和，每个危害与一次给药相关。在整个试验期间持续进行数据监测和决策。我们用异基因骨髓移植（BMT）试验来说明该方法，以确定多长时间可以给予重组人生长因子作为急性移植物抗宿主病（aGVHD）的预防，我们提出了一个模拟研究，在这个试验的背景下。
Most phase I clinical trials are designed to determine a maximum-tolerated dose (MTD) for one initial administration or treatment course of a cytotoxic experimental agent. Toxicity usually is defined as the indicator of whether one or more particular adverse events occur within a short time period from the start of therapy. However, physicians often administer an agent to the patient repeatedly and monitor long-term toxicity due to cumulative effects. We propose a new method for such settings. It is based on the time to toxicity rather than a binary outcome, and the goal is to determine a maximum-tolerated schedule (MTS) rather than a conventional MTD. The model and method account for a patients entire sequence of administrations, with the overall hazard of toxicity modeled as the sum of a sequence of hazards, each associated with one administration. Data monitoring and decision making are done continuously throughout the trial. We illustrate the method with an allogeneic bone marrow transplantation (BMT) trial to determine how long a recombinant human growth factor cart be administered as prophylaxis for acute graft-versus-host disease (aGVHD), and we present a simulation study in the context of this trial.