Phase I-II cancer clinical trial designs are intended to accelerate drug development. In cases where efficacy cannot be ascertained in a short period of time, it is common to divide the study in two stages: i) a first stage in which dose is escalated based only on toxicity data and we look for the maximum tolerated dose (MTD) set and ii) a second stage in which we search for the most efficacious dose within the MTD set. Current available approaches in the area of continuous dose levels involve fixing the MTD after stage I and discarding all collected stage I efficacy data. However, this methodology is clearly inefficient when there is a unique patient population present across stages. In this article, we propose a two-stage design for the combination of two cytotoxic agents assuming a single patient population across the entire study. In stage I, conditional escalation with overdose control (EWOC) is used to allocate successive cohorts of patients. In stage II, we employ an adaptive randomization approach to allocate patients to drug combinations along the estimated MTD curve, which is constantly updated. The proposed methodology is assessed with extensive simulations in the context of a real case study.
翻译:第一阶段-第二阶段癌症临床试验设计旨在加速药物发展,在短期无法确定效果的情况下,通常将研究分为两个阶段:(一) 第一阶段,剂量仅根据毒性数据上升,我们寻找最大耐受剂量(MTD),(二) 第二阶段,我们寻找MTD组中最有效的剂量。在连续剂量水平方面,目前可用的办法涉及在第一阶段之后确定MTD,并抛弃所有收集的第一阶段效果数据。然而,如果有独特的病人,这一方法显然效率低下。在本条中,我们建议用两阶段设计两种细胞中毒剂的结合,假设整个研究中只有一个病人。在第一阶段,采用有条件的过量控制(EWOC)来分配一系列病人。在第二阶段,我们采用适应性随机化办法,按照不断更新的估计MTD曲线将病人分配到药物组合中。在实际案例研究中,对拟议方法进行了广泛的模拟评估。