BACKGROUND As our understanding of the etiology and mechanisms of cancer becomes more sophisticated and the number of therapeutic options increases, phase I oncology trials today have multiple primary objectives. Many such designs are now "seamless," meaning that the trial estimates both the maximum tolerated dose and the efficacy at this dose level. Sponsors often proceed with further study only with this additional efficacy evidence. However, with this increasing complexity in trial design, it becomes challenging to articulate fundamental operating characteristics of these trials, such as (1) what is the probability that the design will identify an acceptable, that is., safe and efficacious, dose level? or (2) how many patients will be assigned to an acceptable dose level on average? METHODS In this manuscript, we propose a new modular framework for designing and evaluating seamless oncology trials. Each module is comprised of either a dose assignment step or a dose-response evaluation, and multiple such modules can be implemented sequentially. We develop modules from existing phase I/II designs as well as a novel module for evaluating dose-response using a Bayesian isotonic regression scheme. RESULTS We also demonstrate a freely available R package called seamlesssim to numerically estimate, by means of simulation, the operating characteristics of these modular trials. CONCLUSIONS Together, this design framework and its accompanying simulator allow the clinical trialist to compare multiple different candidate designs, more rigorously assess performance, better justify sample sizes, and ultimately select a higher quality design.

中文翻译：

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用于早期无缝肿瘤学试验的模块化框架

背景随着我们对癌症的病因和机制的理解变得更加复杂以及治疗选择的数量增加，今天的 I 期肿瘤学试验具有多个主要目标。许多这样的设计现在是“无缝的”，这意味着该试验估计了最大耐受剂量和该剂量水平的疗效。申办者通常仅在这些额外的疗效证据下进行进一步的研究。然而，随着试验设计的日益复杂，阐明这些试验的基本操作特征变得具有挑战性，例如（1）设计确定可接受的，即安全有效的剂量水平的概率是多少？或 (2) 平均有多少患者被分配到可接受的剂量水平？方法 在这份手稿中，我们提出了一个新的模块化框架，用于设计和评估无缝肿瘤学试验。每个模块都由剂量分配步骤或剂量反应评估组成，并且可以按顺序实施多个此类模块。我们从现有的 I/II 期设计中开发模块，以及使用贝叶斯等渗回归方案评估剂量反应的新模块。结果 我们还展示了一个免费可用的 R 包，称为无缝模拟，通过模拟数值估计这些模块化试验的操作特性。结论 该设计框架及其随附的模拟器使临床试验人员能够比较多种不同的候选设计，更严格地评估性能，更好地证明样本量的合理性，并最终选择更高质量的设计。