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用于癌症化疗的药物的I期临床试验的适应性剂量探索

Adaptive dose finding for phase I clinical trials of drugs used for chemotherapy of cancer.

作者信息

Potter Douglas M

机构信息

University of Pittsburgh, University of Pittsburgh Cancer Institute, Biostatistics Facility, Suite 325, Sterling Plaza, 201 North Craig St., PA 15213, USA.

出版信息

Stat Med. 2002 Jul 15;21(13):1805-23. doi: 10.1002/sim.1141.

Abstract

Phase I clinical trials of cancer chemotherapy drugs are intended to determine the maximum tolerable dose (MTD). Thestandard method employed is a rule-based dose-escalation scheme in which escalation depends on the number of patients at a dose level that have dose-limiting toxicity (DLT). The MTD is thus defined in terms of the rules and a series of dose levels selected for sampling. For some trials it is desirable to have a more precise definition of the MTD, and to determine the MTD more accurately than possible with the rule-based schemes. Continuous reassessment methods (CRMs) define the MTD to be the dose at which a fixed fraction of patients experience DLT, and thus appear suited to these trials. It is shown, however, that these methods can have failure modes that in fact make them unattractive. An alternative data-driven dose-finding method is described that combines the robustness of the rule-based methods and with features of CRMs. The method has two stages. In the first stage, doses are escalated by a factor of 1.5. In the second stage, which begins at the first instance of DLT, a two-parameter logistic dose-response model estimates the MTD from the DLT experience of all patients. The model is initialized by setting the dose (d10) at which 10 per cent of patients would experience DLT to half the dose at which the first DLT was observed, and the dose (d90) at which 90 per cent would experience DLT to ten times d10. Weights are assigned such that the information at d10 and d90 is equivalent to that of one patient at each of the two doses. Cohorts of three patients are treated in both stages, and the dose for a new cohort in the second stage is the estimated MTD. The only prior information required to specify the design completely is the dose which will be given to the first cohort. Two stopping rules are investigated; among the requirements for these are that at least three (or four) DLTs be observed and at least nine patients be treated in the second stage. Simulations show that a coefficient of variation of approximately 0.4 on a target DLT probability of 0.3 is obtained over a wide variation in dose-response characteristics of the study drug. The performance of the new method is compared to that of rule-based methods.

摘要

癌症化疗药物的一期临床试验旨在确定最大耐受剂量(MTD)。采用的标准方法是基于规则的剂量递增方案,其中剂量递增取决于处于某个剂量水平且出现剂量限制毒性(DLT)的患者数量。因此,MTD是根据规则以及为抽样选择的一系列剂量水平来定义的。对于某些试验,希望对MTD有更精确的定义,并比基于规则的方案更准确地确定MTD。连续重新评估方法(CRM)将MTD定义为有固定比例患者出现DLT的剂量,因此似乎适用于这些试验。然而,结果表明这些方法可能存在失效模式,实际上使其缺乏吸引力。本文描述了一种替代的数据驱动剂量探索方法,该方法结合了基于规则方法的稳健性和CRM的特点。该方法有两个阶段。在第一阶段,剂量以1.5的系数递增。在第二阶段,从首次出现DLT开始,一个双参数逻辑剂量反应模型根据所有患者的DLT经验估计MTD。通过将10%的患者会出现DLT的剂量(d10)设定为首次观察到DLT的剂量的一半,以及将90%的患者会出现DLT的剂量(d90)设定为d10的十倍来初始化模型。分配权重,使得d10和d90处的信息等同于在这两个剂量下各有一名患者的信息。在两个阶段中每组治疗三名患者,第二阶段新一组患者的剂量是估计的MTD。完全指定该设计所需的唯一先验信息是给予第一组患者的剂量。研究了两条停止规则;这些规则的要求包括至少观察到三个(或四个)DLT,并且在第二阶段至少治疗九名患者。模拟结果表明,在研究药物的剂量反应特征有很大差异的情况下,目标DLT概率为0.3时变异系数约为0.4。将新方法的性能与基于规则的方法进行了比较。

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