MODEL-GUIDED DETERMINATION OF MAXIMUM TOLERATED DOSE IN PHASE-I CLINICAL-TRIALS - EVIDENCE FOR INCREASED PRECISION
MODEL-GUIDED DETERMINATION OF MAXIMUM TOLERATED DOSE IN PHASE-I CLINICAL-TRIALS - EVIDENCE FOR INCREASED PRECISION
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DOI：
10.1093/jnci/85.3.217
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发表时间：
1993-02-03
期刊：
影响因子：
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通讯作者：
RATAIN, MJ
中科院分区：
文献类型：
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作者：
MICK, R;RATAIN, MJ
背景：癌症和艾滋病（获得性免疫缺陷综合征）化疗临床试验中广泛使用的 I 期设计允许在三到六名患者的队列中增加剂量。继续升级，直到预定百分比的患者在给定剂量水平下经历不可接受的毒性作用。然后确定 II 期研究的安全最大耐受剂量 (MTD)。这个标准的第一阶段研究设计有严重的缺陷。 MTD 不是基于模型的真实剂量估计，无法产生目标剂量限制毒性率。此外，这种简单化的研究设计使得一些I期研究中的患者接受不太可能产生治疗效果的剂量。目的：我们构建了一种新颖的定量评估设计，通过在小批患者接受治疗后反复拟合和更新药效学模型来重复评估累积的剂量毒性数据。目标是更准确地估计 MTD。方法：通过标准和定量评估 I 期设计模拟了 100 项 I 期研究。我们将使用标准设计模拟的研究中的 MTD 确定、0 级白细胞减少症（无毒性）的频率和研究规模与使用定量评估设计模拟的研究中的研究规模进行了比较。结果：从 100 项研究中确定的两种设计的 MTD 中值几乎相同：标准评估设计和定量评估设计分别为每天 100 毫克/平方米和 95 毫克/平方米。然而，定量评估设计中 MTD 的研究间变异有所减少。此外，研究规模显着缩小（P
Background: A widely used phase I design in clinical trials of chemotherapy for cancer and for AIDS (acquired immunodeficiency syndrome) allows for dose escalation in cohorts of three to six patients. Escalation continues until a predefined percentage of patients experience unacceptable toxic effects at a given dose level. A safe and maximum tolerated dose (MTD) for phase II study is then determined. This standard phase I study design has serious inadequacies. MTD is not a model-based estimate of the true dose that would yield the targeted dose-limiting toxicity rate. Moreover, this simplistic study design allows some patients in the phase I study to be treated at doses unlikely to have therapeutic efficacy. Purpose: We constructed a novel quantitative assessment design that repetitively evaluates accumulating dose-toxicity data by repeatedly fitting and updating a pharmacodynamic model after small cohorts of patients are treated. The goal was to more accurately estimate the MTD. Methods: One hundred phase I studies were simulated by both the standard and quantitative assessment phase I designs. We compared determination of MTD, frequency of grade 0 leukopenia (no toxicity), and study size in the studies simulated using the standard design with those in the studies simulated using the quantitative assessment design. Results: The median MTD determined from the 100 studies was nearly identical for the two designs: 100 and 95 mg/m2 per day for standard and quantitative assessment designs, respectively. However, the interstudy variation in the MTD was decreased in the quantitative assessment design. Moreover, the study size was significantly reduced (P