Cleveland Clinic, Cleveland, OH, USA.
Yale University, New Haven, CT, USA.
Clin Trials. 2022 Jun;19(3):297-306. doi: 10.1177/17407745211073624. Epub 2022 Feb 7.
Recent advances in developing "tumor agnostic" oncology therapies have identified molecular targets that define patient subpopulations in a manner that supersedes conventional criteria for cancer classification. These successes have produced effective targeted therapies that are administered to patients regardless of their tumor histology. Trials have evolved as well with master protocol designs. By blending translational and clinical science, basket trials in particular are well-suited to investigate and develop targeted therapies among multiple cancer histologies. However, basket trials intrinsically involve more complex design decisions, including issues of multiple testing across baskets, and guidance for investigators is needed.
The sensitivity of the multisource exchangeability model to prior specification under differing degrees of response heterogeneity is explored through simulation. Then, a multisource exchangeability model design that incorporates control of the false-discovery rate is presented and a simulation study compares the operating characteristics to a design where the family-wise error rate is controlled and to the frequentist approach of treating the baskets as independent. Simulations are based on the original design of a real-world clinical trial, the SUMMIT trial, which investigated Neratinib treatment for a variety of solid tumors. The methods studied here are specific to single-arm phase II trials with binary outcomes.
Values of prior probability of exchangeability in the multisource exchangeability model between 0.1 and 0.3 provide the best trade-offs between gain in precision and bias, especially when per-basket sample size is below 30. Application of these calibration results to a re-analysis of the SUMMIT trial showed that the breast basket exceeded the null response rate with posterior probability of 0.999 while having low posterior probability of exchangeability with all other baskets. Simulations based on the design of the SUMMIT trial revealed that there is meaningful improvement in power even in baskets with small sample size when the false-discovery rate is controlled as opposed to the family-wise error rate. For example, when only the breast basket was active, with a sample size of 25, the power was 0.76 when the false-discovery rate was controlled at 0.05 but only 0.56 when the family-wise error rate was controlled at 0.05, indicating that impractical sample sizes for the phase II setting would be needed to achieve acceptable power while controlling the family-wise error rate in this setting of a trial with 10 baskets.
Selection of the prior exchangeability probability based on calibration and incorporation of false-discovery rate control result in multisource exchangeability model designs with high power to detect promising treatments in the context of phase II basket trials.
最近在开发“肿瘤无偏见”肿瘤疗法方面的进展已经确定了分子靶点，这些靶点以超越癌症分类传统标准的方式定义了患者亚群。这些成功产生了有效的靶向治疗方法，无论患者的肿瘤组织学如何，都可以对其进行治疗。试验也随着主方案设计的发展而发展。通过融合转化和临床科学，篮子试验特别适合在多种癌症组织学中研究和开发靶向治疗方法。然而，篮子试验本质上涉及更复杂的设计决策，包括跨篮子进行多次测试的问题，因此需要为研究人员提供指导。
通过模拟探索了多源可交换性模型在不同程度的反应异质性下对先验规范的敏感性。然后，提出了一种包含虚假发现率控制的多源可交换性模型设计，并进行了一项模拟研究，比较了该设计的操作特征与控制家族错误率的设计以及将篮子视为独立的频率方法。模拟基于真实世界临床试验 SUMMIT 试验的原始设计，该试验研究了 Neratinib 治疗各种实体瘤的效果。这里研究的方法特定于具有二项结局的单臂二期试验。
多源可交换性模型中先验交换可能性的概率值在 0.1 到 0.3 之间，可在提高精度和偏差之间取得最佳折衷，尤其是当每个篮子的样本量低于 30 时。将这些校准结果应用于 SUMMIT 试验的重新分析表明，乳腺篮子的后验无效反应率超过 0.999，而与所有其他篮子的后验交换可能性均较低。基于 SUMMIT 试验设计的模拟表明，即使在篮子的样本量较小时，通过控制错误发现率也可以显著提高功效，而不是控制家族错误率。例如，当只有乳腺篮子活跃，样本量为 25 时，当错误发现率控制在 0.05 时，功效为 0.76，但当家族错误率控制在 0.05 时，功效仅为 0.56，表明在这种具有 10 个篮子的试验中，需要不切实际的二期试验样本量才能在控制家族错误率的情况下达到可接受的功效。
基于校准选择先验交换可能性概率，并纳入错误发现率控制，可在二期篮子试验中设计出具有高功效的多源可交换性模型，以检测有前途的治疗方法。
