Cheung Ying Kuen
Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
J Biopharm Stat. 2009;19(3):494-508. doi: 10.1080/10543400902802425.
The primary objective of Phase II cancer trials is to evaluate the potential efficacy of a new regimen in terms of its antitumor activity in a given type of cancer. Due to advances in oncology therapeutics and heterogeneity in the patient population, such evaluation can be interpreted objectively only in the presence of a prospective control group of an active standard treatment. This paper deals with the design problem of Phase II selection trials in which several experimental regimens are compared to an active control, with an objective to identify an experimental arm that is more effective than the control or to declare futility if no such treatment exists. Conducting a multi-arm randomized selection trial is a useful strategy to prioritize experimental treatments for further testing when many candidates are available, but the sample size required in such a trial with an active control could raise feasibility concerns. In this study, we extend the sequential probability ratio test for normal observations to the multi-arm selection setting. The proposed methods, allowing frequent interim monitoring, offer high likelihood of early trial termination, and as such enhance enrollment feasibility. The termination and selection criteria have closed form solutions and are easy to compute with respect to any given set of error constraints. The proposed methods are applied to design a selection trial in which combinations of sorafenib and erlotinib are compared to a control group in patients with non-small-cell lung cancer using a continuous endpoint of change in tumor size. The operating characteristics of the proposed methods are compared to that of a single-stage design via simulations: The sample size requirement is reduced substantially and is feasible at an early stage of drug development.
II期癌症试验的主要目标是根据新方案在特定类型癌症中的抗肿瘤活性来评估其潜在疗效。由于肿瘤治疗学的进展以及患者群体的异质性，只有在存在积极标准治疗的前瞻性对照组的情况下，才能客观地解释这种评估。本文探讨了II期选择试验的设计问题，其中将几种实验方案与积极对照进行比较，目的是确定比对照更有效的实验组，或者在不存在这种治疗方法时宣布试验无效。当有许多候选方案时，进行多组随机选择试验是对实验治疗进行优先级排序以进行进一步测试的有用策略，但这种有积极对照的试验所需的样本量可能会引发可行性问题。在本研究中，我们将针对正态观测值的序贯概率比检验扩展到多组选择设置。所提出的方法允许频繁进行中期监测，具有较高的早期试验终止可能性，从而提高了入组可行性。终止和选择标准具有封闭形式的解，并且对于任何给定的误差约束集都易于计算。所提出的方法应用于设计一项选择试验，在非小细胞肺癌患者中，将索拉非尼和厄洛替尼的联合用药与对照组进行比较，使用肿瘤大小变化的连续终点指标。通过模拟将所提出方法的操作特征与单阶段设计的操作特征进行比较：样本量要求大幅降低，并且在药物开发的早期阶段是可行的。
