Hansen Aaron R, Graham Donna M, Pond Gregory R, Siu Lillian L
Drug Development Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada M5G 2M9.
Cancer Control. 2014 Jul;21(3):200-8. doi: 10.1177/107327481402100304.
Concerns have been recognized about the operating characteristics of the standard 3 + 3 dose-escalation design. Various innovative phase 1 trial designs have been proposed to address the issues and new challenges posed by molecularly targeted agents. However, in spite of these proposals, the conventional design is still the most widely utilized.
A review of the literature of phase 1 trials and relevant statistical studies was performed.
Beyond statistical simulations, sparse clinical data exist to support or refute many of the shortcomings ascribed to the 3 + 3 rule method. Data from phase 1 trials demonstrate that traditional designs identified the correct dose and relevant toxicities with an acceptable level of precision in some instances; however, no single escalation method was proven superior in all circumstances.
Design selection should be guided by the principle of slow escalation in the face of toxicity and rapid dose increases in the setting of minimal or no adverse events. When the toxicity of a drug is uncertain or a narrow therapeutic window is suggested from preclinical testing, then a conservative 3 + 3 method is generally appropriate. However, if the therapeutic window is wide and the expected toxicity is low, then rapid escalation with a novel rule- or model-based design should be employed.
人们已经认识到对标准的3 + 3剂量递增设计的操作特性存在担忧。为了解决分子靶向药物带来的问题和新挑战，已经提出了各种创新的1期试验设计。然而，尽管有这些提议，传统设计仍然是使用最广泛的。
对1期试验的文献和相关统计研究进行了综述。
除了统计模拟之外，支持或反驳归因于3 + 3规则方法的许多缺点的临床数据很少。1期试验的数据表明，传统设计在某些情况下能够以可接受的精度确定正确的剂量和相关毒性；然而，没有一种单一的递增方法在所有情况下都被证明是优越的。
设计选择应以面对毒性时缓慢递增和在最小或无不良事件情况下快速增加剂量的原则为指导。当药物的毒性不确定或临床前测试表明治疗窗较窄时，那么保守的3 + 3方法通常是合适的。然而，如果治疗窗较宽且预期毒性较低，则应采用基于新规则或模型的设计进行快速递增。
