基于药物毒性反应等级的Up-and-Down设计(英文)

Incorporating Toxicity Grade Information in Up-and-Down Design

Ⅰ期临床试验主要关心毒性,通常划分毒性为五个水平．简单起见,同时兼顾伦理问题,Ⅰ期临床试验通常采用up-and-down序贯设计(例如BCDⅠ,BCDⅡ,K-in-a-row,Narayana,Improved Narayana)．然而,在分配剂量水平时,该设计没有区分已经试验了的病人的严重毒性水平等级,从而有可能分配给病人更高毒性的剂量水平．因此,本文提出了基于药物毒性等级确定最大耐受剂量的up-and-down设计方法,并进一步研究了该设计方法在各种变化的剂量—毒性关系下的运作特征,并且和标准的up-and-down设计作模拟比较,结果表明该设计方法对Ⅰ期临床试验设计的剂量建议具有重要意义．

For phase Ⅰ cancer clinical trials, toxicity is a major concern. Commonly, toxicity is categorized with five levels of severity. A simple sequential design that addresses these ethical concerns is the up-and-down designs （BCD Ⅰ, BCD Ⅱ, k-in-a-row, Narayana, improved Narayana）. However, in the up-and-down designs family, the severity level of graded toxicity of a previous patient＇s response would not be a differentiated factor for the next dose level assignment and doses that are too toxic may also be recommended. In this study, we extend the up-and-down procedure incorporating the idea on the assessments of graded toxicity in the dose escalation. We investigate the operating characteristics of this approach under a variety of dose-toxicity associations and comparison with up-and-down family shows that it can achieve significant improvements to the doses recommended during the phase Ⅰ trial.