Richard Kaplan, Angela Crook, David Fisher, Louise Brown, and Mahesh Parmar, Medical Research Council Clinical Trials Unit, London; Timothy Maughan, University of Oxford, Oxford; and Richard Wilson, Queen's University Belfast, Belfast, United Kingdom.
J Clin Oncol. 2013 Dec 20;31(36):4562-8. doi: 10.1200/JCO.2013.50.7905. Epub 2013 Nov 18.
There is a pressing need for more-efficient trial designs for biomarker-stratified clinical trials. We suggest a new approach to trial design that links novel treatment evaluation with the concurrent evaluation of a biomarker within a confirmatory phase II/III trial setting. We describe a new protocol using this approach in advanced colorectal cancer called FOCUS4. The protocol will ultimately answer three research questions for a number of treatments and biomarkers: (1) After a period of first-line chemotherapy, do targeted novel therapies provide signals of activity in different biomarker-defined populations? (2) If so, do these definitively improve outcomes? (3) Is evidence of activity restricted to the biomarker-defined groups? The protocol randomizes novel agents against placebo concurrently across a number of different biomarker-defined population-enriched cohorts: BRAF mutation; activated AKT pathway: PI3K mutation/absolute PTEN loss tumors; KRAS and NRAS mutations; and wild type at all the mentioned genes. Within each biomarker-defined population, the trial uses a multistaged approach with flexibility to adapt in response to planned interim analyses for lack of activity. FOCUS4 is the first test of a protocol that assigns all patients with metastatic colorectal cancer to one of a number of parallel population-enriched, biomarker-stratified randomized trials. Using this approach allows questions regarding efficacy and safety of multiple novel therapies to be answered in a relatively quick and efficient manner, while also allowing for the assessment of biomarkers to help target treatment.
目前迫切需要更有效的试验设计来进行基于生物标志物的临床试验。我们建议采用一种新的方法来设计临床试验，即将新的治疗方法的评估与在确证性 II/III 期临床试验中同时评估生物标志物结合起来。我们在晚期结直肠癌中描述了一种使用这种方法的新方案，称为 FOCUS4。该方案最终将为多种治疗方法和生物标志物回答三个研究问题：（1）在一线化疗后，靶向新型疗法在不同生物标志物定义的人群中是否具有活性信号？（2）如果是，这些疗法是否确实改善了结局？（3）活性证据是否仅限于生物标志物定义的群体？该方案将新型药物与安慰剂同时随机分配给多个不同的生物标志物定义的人群富集队列：BRAF 突变；激活 AKT 通路：PI3K 突变/绝对 PTEN 缺失肿瘤；KRAS 和 NRAS 突变；以及所有提到的基因均为野生型。在每个生物标志物定义的人群中，该试验采用多阶段方法，具有灵活性，可以根据计划的中期分析缺乏活性进行调整。FOCUS4 是首个测试方案的试验，该方案将所有转移性结直肠癌患者分配到多个平行的人群富集、生物标志物分层随机试验之一。使用这种方法可以快速有效地回答关于多种新型疗法的疗效和安全性的问题，同时还可以评估生物标志物以帮助确定治疗目标。
