Hoering Antje, Crowley John
Cancer Research and Biostatistics, Seattle, WA 98195, USA.
Clin Adv Hematol Oncol. 2007 Apr;5(4):309-16.
The development of new anti-myeloma agents with different mechanisms of action from conventional chemotherapy has necessitated a new look at clinical trial design. We discuss design issues for cytostatic agents for phase I, II, and III clinical trials pertaining to myeloma. The success of phase I trials with cytotoxic agents is predicated on the dose toxicity curve being strictly monotone. With cytostatic agents, however, the shape of the dose toxicity curve is not necessarily monotone, and traditional phase I trial designs may no longer be applicable. The distinction between cytotoxic and cytostatic agents also highlights the importance of thinking of endpoints other than tumor response (or shrinkage) with agents whose success depends more on keeping the tumor stable. The appropriateness of different endpoints in phase II myeloma trials is discussed. The goal of phase III clinical trials for cytostatic agents is typically twofold: to determine efficacy of the new agent for all patients and for the subset of patients with a certain biomarker. We present different trial designs that can address both aims.
研发作用机制不同于传统化疗的新型抗骨髓瘤药物，使得人们有必要重新审视临床试验设计。我们讨论了用于骨髓瘤的I期、II期和III期临床试验的细胞生长抑制剂的设计问题。细胞毒性药物I期试验的成功取决于剂量毒性曲线严格单调。然而，对于细胞生长抑制剂，剂量毒性曲线的形状不一定是单调的，传统的I期试验设计可能不再适用。细胞毒性药物和细胞生长抑制剂之间的区别还凸显了对于那些成功更多取决于保持肿瘤稳定的药物，除了考虑肿瘤反应（或缩小）之外，思考其他终点的重要性。本文讨论了II期骨髓瘤试验中不同终点的适用性。细胞生长抑制剂III期临床试验的目标通常有两个：确定新药对所有患者以及对具有某种生物标志物的患者亚组的疗效。我们提出了能够实现这两个目标的不同试验设计。
