Improving the design of phase II trials of cytostatic anticancer agents
Improving the design of phase II trials of cytostatic anticancer agents
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DOI：
10.1016/j.cct.2006.05.009
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发表时间：
2007-02-01
影响因子：
2.2
通讯作者：
Barge, Alan
中科院分区：
文献类型：
--
作者：
Stone, Andrew;Wheeler, Catherine;Barge, Alan
本文探讨了肿瘤学II期试验的设计，并建议脱离传统的非对照试验设计。进入II期临床评价是任何新癌症疗法开发的关键里程碑。随着新型分子靶向疗法的引入，其主要作用是减缓肿瘤的生长，确保临床试验设计将有效地捕获这些药物的任何临床益处将非常重要。II期试验的目标除了确定活性治疗外，还应扩展到确定那些可能在关键试验中成功的治疗。因此，有必要量化不正确地停止活性剂的发展或继续发展无效剂的可能性。我们认为，只有具有比较目的并包括并行活性对照的随机研究才能可靠地评估这些风险的显著性和把握度。鉴于II期研究的目的是确定有希望的治疗方法，重要的是不受传统显著性水平的限制。本文将回顾肿瘤学II期试验设计的各种方法，并为中等规模的完全随机试验提供一个框架。比如说，一项仅100例患者的随机试验可能导致90%的非活性药物的开发终止，而至少80%的无进展生存率有意义和现实增加的药物将被确定用于验证性研究。自由存活终点是确定新的细胞生长抑制剂的临床活性的最有效和最经济的方法。(c)2006年爱思唯尔公司All rights reserved.
This paper examines the design of phase II trials in oncology and recommends departing from the traditional uncontrolled trial design. Entrance into phase II clinical evaluation represents a key milestone in the development of any new cancer therapy. As novel molecular-targeted therapies are introduced, whose primary action is to slow the growth of tumors, it will be important to ensure that the clinical trial design will effectively capture any clinical benefit of these agents. The objective of a phase II trial should, in addition to identifying active therapies, be extended to identifying those that are likely to be successful in pivotal trials. It is therefore necessary to quantify the likelihood of either incorrectly halting the development of an active agent or continuing development of an ineffective agent. We believe only randomized studies with comparative intent and including a concurrent active control, can reliably assess these risks corresponding to significance and power. Given that the objective of phase II studies is to identify promising treatments, it is important not be constrained by conventional levels of significance. This paper will review the various approaches to phase II trial design in oncology and provide a framework for fully powered randomized trials of a moderate size. For example, a randomized trial of just 100 patients could lead to the termination of development of 90% of inactive agents whereas at least 80% of agents with a meaningful and realistic increase in progression-free survival would be identified for confirmatory study.We believe randomized studies with progression-free survival endpoints are the most powerful and economical method of determining the clinical activity of new cytostatic agents. (c) 2006 Elsevier Inc. All rights reserved.