Stadler W M, Ratain M J
Department of Medicine, University of Chicago, IL 60637, USA.
Invest New Drugs. 2000 Feb;18(1):7-16. doi: 10.1023/a:1006371512390.
The elucidation of multiple potential targets in cancer cells and the development of multiple target-based antineoplastic agents provide unique challenges in clinical trial design. Many of these agents are predicted to have cytostatic as opposed to cytotoxic effects and thus the traditional surrogate endpoint of radiologic tumor shrinkage may be inadequate. The ethical and safety issues of obtaining multiple tumor biopsies further complicate the assessment of appropriate target inhibition in patients. We discuss specific issues that need to be addressed during preclinical, phase I, II, and III testing of these agents. We propose clinical trial designs, including a randomized discontinuation design during phase II evaluation, that may be particularly useful for cytostatic antineoplastic agents.
癌细胞中多个潜在靶点的阐明以及多种基于靶点的抗肿瘤药物的开发，给临床试验设计带来了独特的挑战。预计这些药物中的许多具有细胞抑制作用而非细胞毒性作用，因此传统的影像学肿瘤缩小替代终点可能并不充分。获取多次肿瘤活检的伦理和安全问题，进一步使患者体内适当靶点抑制的评估变得复杂。我们讨论了在这些药物的临床前、I期、II期和III期试验期间需要解决的具体问题。我们提出了临床试验设计，包括II期评估期间的随机停药设计，这可能对细胞抑制性抗肿瘤药物特别有用。
