Molecularly targeted agents and immunotherapies have prolonged administration and complicated toxicity and efficacy profiles requiring longer toxicity observation windows and the inclusion of efficacy information to identify the optimal dose. Methods have been proposed to either jointly model toxicity and efficacy, or for prolonged observation windows. However, it is inappropriate to address these issues individually in the setting of dose-finding because longer toxicity windows increase the risk of patients experiencing disease progression and discontinuing the trial, with progression defining a competing event to toxicity, and progression-free survival being a commonly used efficacy endpoint. No method has been proposed to address this issue in a competing risk framework. We propose a seamless phase I/II design, namely the competing risks continual reassessment method (CR-CRM). Given an observation window, the objective is to recommend doses that minimize the progression probability, among a set of tolerable doses in terms of toxicity risk. In toxicity-centered stage of the design, doses are assigned based on toxicity alone, and in optimization stage of the design, doses are assigned integrating both toxicity and progression information. Design operating characteristics were examined in a simulation study compared with benchmark performances, including sensitivity to time-varying hazards and correlated events. The method performs well in selecting doses with acceptable toxicity risk and minimum progression risk across a wide range of scenarios.

中文翻译：

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具有竞争性疾病进展的新型抗癌药物的无缝 I/II 期设计


分子靶向药物和免疫疗法的给药时间长，毒性和疗效特征复杂，需要更长的毒性观察窗并包含疗效信息以确定最佳剂量。已经提出了联合模拟毒性和功效或延长观察窗的方法。然而，在剂量探索的情况下单独解决这些问题是不合适的，因为较长的毒性窗口会增加患者经历疾病进展和终止试验的风险，而进展定义了毒性的竞争事件，而无进展生存期是一个重要因素常用的疗效终点。尚未提出在竞争风险框架中解决此问题的方法。我们提出了无缝的I/II期设计，即竞争风险持续重新评估方法（CR-CRM）。给定观察窗口，目标是在毒性风险方面的一组可耐受剂量中推荐能够最小化进展概率的剂量。在以毒性为中心的设计阶段，仅根据毒性来分配剂量，而在设计的优化阶段，则综合毒性和进展信息来分配剂量。在模拟研究中检查了设计操作特性与基准性能的比较，包括对时变危险和相关事件的敏感性。该方法在多种情况下选择具有可接受的毒性风险和最小进展风险的剂量方面表现良好。