CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London WC2B 6NH, UK.
Br J Cancer. 2014 Apr 29;110(9):2178-86. doi: 10.1038/bjc.2014.182. Epub 2014 Apr 17.
Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.
Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.
A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.
Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.
癌症的分子特征在个体之间存在差异。未来，大多数试验将需要评估生物标志物，以便将患者分配到目标治疗更有可能有效的富集人群中。MRC FOCUS3 试验是一项可行性研究，旨在评估此类研究规划中的关键要素。
2010 年 2 月至 2011 年 4 月，24 个中心注册了晚期结直肠癌患者。在获得患者同意后，分析其肿瘤样本的 KRAS/BRAF 致癌基因突变状态和拓扑异构酶 1（topo-1）免疫组织化学。然后，患者被分为四个分子亚组之一；在每个亚组内，患者被随机分配到两种假设驱动的实验性治疗之一或常见的对照组（FOLFIRI 化疗）。开发了一套 4 阶段的患者信息表（PIS），以避免患者负担过重。
共登记了 332 例患者，其中 244 例进行了随机分组。在随机分组的患者中，10 个工作日（w.d.）内提供了生物标志物结果的比例为 71%，15 w.d.为 91%，20 w.d.为 99%。两家实验室之间的 DNA 突变分析完全一致。超过 90%的参与者报告说对试验的所有方面都有极好的理解。在这种随机二期设置中，低 topo-1 组中省略伊立替康与增加反应率相关，而在 KRAS、BRAF 野生型队列中添加西妥昔单抗与无进展生存期延长相关。
可以在可行的时间框架内采集和分析患者样本，并获得可重复的突变结果。复杂的多臂设计可被患者接受，PIS 效果良好。每个队列内的随机分组提供了可用于指导临床实践的结果数据。
