Bekele B Nebiyou, Shen Yu
Department of Biostatistics and Applied Mathematics, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Biometrics. 2005 Jun;61(2):343-54. doi: 10.1111/j.1541-0420.2005.00314.x.
In this article, we propose a Bayesian approach to phase I/II dose-finding oncology trials by jointly modeling a binary toxicity outcome and a continuous biomarker expression outcome. We apply our method to a clinical trial of a new gene therapy for bladder cancer patients. In this trial, the biomarker expression indicates biological activity of the new therapy. For ethical reasons, the trial is conducted sequentially, with the dose for each successive patient chosen using both toxicity and activity data from patients previously treated in the trial. The modeling framework that we use naturally incorporates correlation between the binary toxicity and continuous activity outcome via a latent Gaussian variable. The dose-escalation/de-escalation decision rules are based on the posterior distributions of both toxicity and activity. A flexible state-space model is used to relate the activity outcome and dose. Extensive simulation studies show that the design reliably chooses the preferred dose using both toxicity and expression outcomes under various clinical scenarios.
在本文中,我们提出了一种贝叶斯方法,用于肿瘤学I/II期剂量探索试验,通过联合对二元毒性结果和连续生物标志物表达结果进行建模。我们将我们的方法应用于一项针对膀胱癌患者的新基因疗法的临床试验。在该试验中,生物标志物表达表明了新疗法的生物活性。出于伦理原因,试验按顺序进行,根据试验中先前治疗患者的毒性和活性数据为每位连续患者选择剂量。我们使用的建模框架通过一个潜在高斯变量自然地纳入了二元毒性和连续活性结果之间的相关性。剂量递增/递减决策规则基于毒性和活性的后验分布。使用一个灵活的状态空间模型来关联活性结果和剂量。广泛的模拟研究表明,该设计在各种临床场景下,利用毒性和表达结果可靠地选择了优选剂量。