剂量研究中患者间和患者内n水平反应面通路设计

IF 1.4 Q4 MEDICINE, RESEARCH & EXPERIMENTAL
Sagita Dewi, Veronica Kristiansen, S. lindkær-Jensen, S. Larsen
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引用次数: 9

摘要

背景:剂量发现研究中最常用的递增方法有明显的弱点,贝叶斯方法对临床医生来说难以理解和应用。本研究旨在介绍和评估基于临床的反应面通路(RSP)设计在剂量发现研究中的表现,以一项患者间研究、一项患者内研究和模拟研究为例。方法:患者间研究包括15名IV期乳腺癌女性,患者内研究包括7只转移性乳腺癌雌性犬。研究采用三水平RSP设计来确定一种名为BP-C1的新型抗癌药物的最大耐受剂量(MTD)。剂量从一个设计水平调整到下一个设计水平的依据是k调整系数,该系数估计可确保覆盖整个预定剂量窗口。作为设计水平的患者数量相等的患者序列被纳入患者间设计,而相同的患者被纳入患者内设计的所有设计水平。结果:患者间研究的5组患者序列中有4组和患者内研究的全部7只狗均达到剂量窗上限,且毒性未增加。因此发现BP-C1的MTD高于两组患者预定的累积剂量窗口。在所有三种情况下,RSP设计比传统的3 + 3设计更好地估计了mtd;然而,当目标MTD低于起始剂量时,发现毒性率更高。结论:RSP设计不需要假设的统计模型,使用最小样本量估计MTD可能有用。k调整因子确保完全剂量窗覆盖,设计利用更多的信息,允许多项结果。I期研究按顺序进行,根据先前患者或治疗期观察到的毒性效应,分配给患者的剂量水平。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Between- and within-patient n -level response surface pathway design in dose-finding studies
Background: The most commonly used escalation methods in dose-finding studies have obvious weaknesses, and the Bayesian approach is difficult for clinicians to understand and to apply. The study aims were to introduce and assess the performance of clinically based response surface pathway (RSP) design for dose-finding studies, exemplified by one between-patient study, one within-patient study, and simulation studies. Methods: The between-patient study consisted of 15 women suffering from stage IV breast cancer, while the within-patient study consisted of seven female dogs with metastatic mammary cancer. The studies were conducted to determine the maximum tolerated dose (MTD) of a new anticancer agent named BP-C1 using three-level RSP designs. Adjustment of the dose from one design level to the next was based on a k -adjustment factor estimated to ensure coverage of the entire predefined dose window. Patient sequences with an equal number of patients as design levels were included in the between-patient design, whereas the same patients were included in all the design levels in the within-patient design. Results: Four of the five patient sequences in the between-patient study and all seven dogs in the within-patient study reached the upper limit of the dose windows without any increase in toxicity. The MTD of BP-C1 was thus found to be higher than the predefined cumulative dose window for both patient groups. In all three scenarios, the RSP design estimated MTDs better than the traditional 3 + 3 design; however, the toxicity rates were found to be higher when the target MTD was under the starting dose. Conclusion: The RSP designs do not need an assumed statistical model, and may be useful in estimating MTD, using a minimal sample size. The k -adjustment factor ensures complete dose window coverage and the design utilizes more information by allowing multinomial outcomes. Phase I studies are conducted sequentially, allocating dose levels to patients based on the observed toxicity effect from previous patients or treatment periods.
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来源期刊
Open Access Journal of Clinical Trials
Open Access Journal of Clinical Trials MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.90
自引率
0.00%
发文量
2
审稿时长
16 weeks
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