Combining Cytotoxic Agents with Continuous Dose Levels in Seamless Phase I-II Clinical Trials
提出一种两阶段设计，在连续剂量水平下联合两种细胞毒性药物，第一阶段基于毒性数据寻找最大耐受剂量集，第二阶段在MTD集内自适应随机化寻找最有效剂量，适用于单一患者群体。
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.