BACKGROUND/AIMS This article describes the proposed design of a phase I study evaluating the safety of ceramide nanoliposome and vinblastine among an initial set of 19 possible dose combinations in patients with relapsed/refractory acute myeloid leukemia and patients with untreated acute myeloid leukemia who are not candidates for intensive induction chemotherapy. METHODS Extensive collaboration between statisticians and clinical investigators revealed the need to incorporate several adaptive features into the design, including the flexibility of adding or eliminating certain dose combinations based on safety criteria applied to multiple dose pairs. During the design stage, additional dose levels of vinblastine were added, increasing the dimension of the drug combination space and thus the complexity of the problem. Increased complexity made application of existing drug combination dose-finding methods unsuitable in their current form. RESULTS Our solution to these challenges was to adapt a method based on isotonic regression to meet the research objectives of the study. Application of this adapted method is described herein, and a simulation study of the design's operating characteristics is conducted. CONCLUSION The aim of this article is to bring to light examples of novel design applications as a means of augmenting the implementation of innovative designs in the future and to demonstrate the flexibility of adaptive designs in satisfying changing design conditions.

中文翻译：

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将等渗剂量发现应用于一组动态的药物组合，并应用于 I 期白血病试验

背景/目的 本文描述了一项 I 期研究的拟议设计，该研究评估了神经酰胺纳米脂质体和长春碱在复发/难治性急性髓系白血病患者和未经治疗的急性髓系白血病患者的初始 19 种可能剂量组合中的安全性。强化诱导化疗的候选者。方法 统计学家和临床研究人员之间的广泛合作表明需要在设计中加入多种适应性特征，包括根据应用于多剂量对的安全标准添加或消除某些剂量组合的灵活性。在设计阶段，增加了额外剂量水平的长春碱，增加了药物组合空间的维度，从而增加了问题的复杂性。增加的复杂性使得现有的药物组合剂量寻找方法不适用于当前形式。结果我们对这些挑战的解决方案是采用基于等渗回归的方法来满足研究的研究目标。此处描述了这种适应方法的应用，并进行了设计运行特性的模拟研究。结论 本文的目的是展示新颖设计应用的示例，作为在未来增强创新设计实施的一种手段，并展示自适应设计在满足不断变化的设计条件方面的灵活性。结果我们对这些挑战的解决方案是采用基于等渗回归的方法来满足研究的研究目标。此处描述了这种适应方法的应用，并进行了设计运行特性的模拟研究。结论 本文的目的是展示新颖设计应用的示例，作为在未来增强创新设计实施的一种手段，并展示自适应设计在满足不断变化的设计条件方面的灵活性。结果我们对这些挑战的解决方案是采用基于等渗回归的方法来满足研究的研究目标。此处描述了这种适应方法的应用，并进行了设计运行特性的模拟研究。结论 本文的目的是展示新颖设计应用的示例，作为在未来增强创新设计实施的一种手段，并展示自适应设计在满足不断变化的设计条件方面的灵活性。