Biometric Research Branch, National Caner Institute, Executive Plaza North, Room 8124, 6130 Executive Boulevard, Rockville, MD 20852, USA.
Stat Med. 2011 Jul 30;30(17):2130-43. doi: 10.1002/sim.4255. Epub 2011 May 17.
The goal of phase I cancer trials is to determine the highest dose of a treatment regimen with an acceptable toxicity rate. Traditional designs for phase I trials, such as the Continual Reassessment Method (CRM) and the 3 + 3 design, require each patient or a cohort of patients to be fully evaluated for the dose-limiting toxicity (DLT) before new patients can be enrolled. As such, the trial duration may be prohibitively long. The Time-to-Event Continual Reassessment Method (TITE-CRM, Cheung and Chappell, 2000) circumvents this limitation by allowing staggered patient accrual without the need for complete DLT follow-up of previously treated patients. However, in the setting of fast patient accrual and late-onset toxicities, the TITE-CRM results in overly aggressive dose escalation and exposes a considerable number of patients to toxic doses. We examine a modification to the TITE-CRM proposed by the original TITE-CRM creator and propose an alternative approach useful in this setting by incorporating an accrual suspension rule. A simulation study designed based on a neuro-oncology trial indicates that the modified methods provide a much improved degree of safety than the TITE-CRM while maintaining desirable design accuracy. The practical aspects of the proposed designs are discussed. The modifications presented are useful when planning phase I trials involving chemoradiation therapy.
I 期癌症试验的目标是确定具有可接受毒性率的治疗方案的最高剂量。I 期试验的传统设计,如连续评估法(CRM)和 3+3 设计,要求每个患者或一组患者在新患者入组之前,对剂量限制毒性(DLT)进行全面评估。因此,试验持续时间可能会非常长。时间事件连续评估法(TITE-CRM,Cheung 和 Chappell,2000)通过允许分期患者入组,而无需对先前治疗的患者进行完整的 DLT 随访,从而规避了这一限制。然而,在患者快速入组和迟发性毒性的情况下,TITE-CRM 导致过度激进的剂量升级,并使相当数量的患者暴露于有毒剂量之下。我们检查了原始 TITE-CRM 提出者对 TITE-CRM 的修改,并通过纳入入组暂停规则,提出了一种在这种情况下有用的替代方法。基于神经肿瘤学试验设计的模拟研究表明,与 TITE-CRM 相比,修改后的方法提供了更高的安全性,同时保持了理想的设计准确性。讨论了所提出设计的实际方面。当计划涉及放化疗的 I 期试验时,所提出的修改是有用的。