Optimal and minimax three-stage designs for phase II oncology clinical trials
Optimal and minimax three-stage designs for phase II oncology clinical trials
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DOI：
10.1016/j.cct.2007.04.008
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发表时间：
2008-01-01
影响因子：
2.2
通讯作者：
Shan, Michael
中科院分区：
文献类型：
--
作者：
Chen, Kun;Shan, Michael
肿瘤学II期试验的共同目标是评估新药的抗肿瘤活性，并确定新药是否需要进一步研究。对于显著缩小肿瘤的癌症药物，缓解（CR和PR）率通常是癌症II期试验中检验H-0的主要终点：P = P-1，其中P-0和P-1是缓解率，考虑到假阳性（α）和假阴性（β）率，不需要或需要进一步研究。多个作者已经开发了包括两级和三级的多级设计。例如，Simon的最优两阶段设计[Simon R. II期临床试验的最佳两阶段设计。Control Clin Trials 1989; 10：1-10]，Ensign等人在第一阶段限制的最优三阶段设计[Ensign LG，Gehan EA，Kamen DS，Thall PF. Stat Med 1994;13：1727-1736]、无任何限制的Chen最优三阶段设计[Chen TT. II期临床试验的最佳三阶段设计。Stat Med 1997; 16：2701-2711]等。然而，所有上述设计仅由于缺乏研究药物的活性而提前终止试验。Fleming的多级设计[Fleming TR. If期临床试验的单样本多重检验程序。Biometrics 1982;38：143-151]允许因足够的活动或缺乏活动而提前停止。但他的设计并没有试图优化其效率。我们扩展了Chen的[Chen TT. Stat Med 1997; 16：2701-2711]设计并提出了三阶段癌症II期试验的最佳和极大极小设计，其允许在两种假设下提前停止。在P=P-0下，平均样本数最小化的意义上，该设计是最优的。极小极大设计使最大样本量（N）最小化，然后给定此N值使P=P-0下的平均样本数最小化。(C)2007年爱思唯尔公司All rights reserved.
The common objective of oncology phase II trials is to evaluate the anti-tumor activity of a new agent and to determine whether the new drug warrants further investigation. For cancer drugs that significantly shrink tumors, response (CR and PR) rate is usually the primary endpoint in cancer phase II trials for testing H-0: P = P-1, where P-0 and P-1 are response rates which does not or does warrant further investigation given the rate of false positive (alpha) and false negative (beta). Multiple-stage designs including two-stage and three-stage have been developed by several authors. For example, Simon's optimal two-stage design [Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1-10], Ensign et al. optimal three-stage design with restriction at the first stage [Ensign LG, Gehan EA, Kamen DS, Thall PF. An optimal three-stage design for phase II clinical trials. Stat Med 1994;13:1727-1736], Chen's optimal three-stage design without any restriction [Chen TT. Optimal three-stage designs for phase II clinical trials. Stat Med 1997; 16:2701-2711], etc. However, all the above designs only early terminate a trial due to lack of activity of the study drug. Fleming's multiple-stage design [Fleming TR. One-sample multiple testing procedure for phase If clinical trials. Biometrics 1982;38:143-151] allows early stopping for either sufficient activity or lack of activity. But his design does not attempt to optimize its efficiency.We extend Chen's [Chen TT. Optimal three-stage designs for phase II clinical trials Stat Med 1997; 16:2701-2711] design and propose an optimal and a minimax design for three-stage cancer phase II trials which allows early stopping under both hypotheses. The design is optimal in the sense that the average sample number (ASN) is minimized under P=P-0. The minimax design minimizes the maximal sample size (N) and then given this value of N minimizes the average sample number under P=P-0. (C) 2007 Elsevier Inc. All rights reserved.