Dose-finding in cancer clinical trials has been dominated by algorithmic designs on the principle that the highest tolerable dose is also the most effective dose. This assumption no longer applies to the biologic treatments that are characterized by different toxicity and/or efficacy profiles to the extent that the best therapeutic dose might be well below any dose that produces serious toxicity. As such, we propose a two-stage design with focus on immunotherapy trials, incorporating both safety and efficacy information. The first stage establishes the safety profile of each dose, with escalation decisions based on likelihood principles. Continuous immunologic outcomes are used to evaluate the relative efficacy of the doses. The second stage employs an adaptive randomization to assign patients to doses showing higher efficacy. Safety is being continuously monitored throughout Stage 2, where some doses may be ‘closed’ due to unacceptable toxicity. The proposed design is compared to the modified toxicity probability interval (mTPI) design using percent dose allocation and estimation of outcomes under different scenarios. We show that by using an efficacy-driven adaptive randomization with safety constraints, the allocation distribution is skewed towards more efficacious doses, and thus limit the number of patients exposed to toxic or non-therapeutic doses. Supplementary materials for this article are available online.

癌症临床试验中的剂量寻找已被算法设计所占据，其原理是最高可耐受剂量也是最有效剂量。这种假设不再适用于以不同的毒性和/或功效特征为特征的生物治疗，其最佳治疗剂量可能远低于产生严重毒性的任何剂量。因此，我们提出了一个针对免疫疗法试验的两阶段设计，并结合了安全性和功效信息。第一阶段建立每种剂量的安全性，并根据似然原理进行逐步升级决策。连续的免疫学结果用于评估剂量的相对功效。第二阶段采用适应性随机分配，将患者分配给显示更高疗效的剂量。在整个阶段2期间，安全性受到持续监控，由于不可接受的毒性，有些剂量可能被“封闭”。使用百分比剂量分配和不同情况下的结果估计，将拟议的设计与改良的毒性概率区间（mTPI）设计进行比较。我们显示，通过使用具有安全性约束的功效驱动的自适应随机方法，分配分布会偏向更有效的剂量，从而限制了暴露于有毒或非治疗剂量的患者数量。可在线获得本文的补充材料。使用百分比剂量分配和不同情况下的结果估计，将拟议的设计与改良的毒性概率区间（mTPI）设计进行比较。我们显示，通过使用具有安全性约束的功效驱动的自适应随机方法，分配分布会偏向更有效的剂量，从而限制了暴露于有毒或非治疗剂量的患者数量。可在线获得本文的补充材料。使用百分比剂量分配和不同情况下的结果估计，将拟议的设计与改良的毒性概率区间（mTPI）设计进行比较。我们显示，通过使用具有安全性约束的功效驱动的自适应随机方法，分配分布会偏向更有效的剂量，从而限制了暴露于有毒或非治疗剂量的患者数量。可在线获得本文的补充材料。