Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer.
Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer.
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DOI：
10.1177/17407745211069879
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发表时间：
2022-04
期刊：
影响因子：
2.7
通讯作者：
Maughan, Timothy S.
中科院分区：
文献类型：
--
作者：
Brown, Louise C.;Graham, Janet;Fisher, David;Adams, Richard;Seligmann, Jenny;Seymour, Matthew;Kaplan, Richard;Yates, Emma;Parmar, Mahesh;Richman, Susan D.;Quirke, Philip;Butler, Rachel;Shiu, Kaikeen;Middleton, Gary;Samuel, Leslie;Wilson, Richard H.;Maughan, Timothy S.
关键词：
复杂的创新设计试验正变得越来越普遍，并提供了在更快的时间框架内改善患者结局的潜力。FOC 4是转移性结直肠癌的第一个分子分层试验，它仍然是全球启动的第一个伞式试验设计之一。在这里，我们的目的是描述从过去10年的审判中吸取的经验教训。FOC 4是一项II/III期分子分层伞式试验，旨在测试靶向治疗在转移性结直肠癌中的安全性和有效性。它使用适应性统计方法来决定哪些子试验应该提前关闭，并将新的治疗方法作为方案修订案添加。登记新诊断的转移性结直肠癌患者，并使用中心实验室检测将其肿瘤分层为分子亚型。一线治疗16周后，病情稳定或缓解的患者有资格随机分入分子分层子试验（FOX 4-B、C或D）或非分层FOX 4-N。所有研究的主要结局是比较干预与主动监测/安慰剂的无进展生存期。在审判结束时，通过调查和访谈从所有调查员那里获得反馈，并将其整合为一系列建议和经验教训，供今后进行类似审判之用。在2014年1月至2020年10月期间，来自88家英国医院的1434名患者注册。在平台试验中探索纳入的20种药物组合中，激活了三项分子靶向子试验：FOX 4-D（2014年2月至2016年3月）在BRAF-PIK 3CA-RAS野生型亚组中评价了AZD 8931; FOS 4-B（2016年2月-2018年7月）在PIK 3CA突变亚组中评价了阿司匹林，FOS 4-C（2017年6月-2020年10月）在RAS+ TP 53双突变亚组中评价了阿达沃塞B。FOC 14-N在整个过程中都是活性的，并评价了卡培他滨单药治疗与治疗中断。共有361例（25%）登记患者被随机分配至子试验。关于FOC 4交付经验的反馈可分为三个主要挑战领域：资金/基础设施、生物标志物检测程序和试验设计效率，其中总结了20项建议。适应性分层医学平台研究在常见癌症中是可行的，但存在挑战。我们的利益相关者反馈有助于告知这些试验设计如何成功并有效回答多个问题，前提是资源充足。
Complex innovative design trials are becoming increasingly common and offer potential for improving patient outcomes in a faster time frame. FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and it remains one of the first umbrella trial designs to be launched globally. Here, we aim to describe lessons learned from delivery of the trial over the last 10 years. FOCUS4 was a Phase II/III molecularly stratified umbrella trial testing the safety and efficacy of targeted therapies in metastatic colorectal cancer. It used adaptive statistical methodology to decide which sub-trial should close early, and new therapies were added as protocol amendments. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome for all studies was progression-free survival comparing the intervention with active monitoring/placebo. At the close of the trial, feedback was elicited from all investigators through surveys and interviews and consolidated into a series of recommendations and lessons learned for the delivery of similar future trials. Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014–March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4-B (February 2016–July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C (June 2017–October 2020) evaluated adavosertib in the RAS+TP53 double mutant subgroup. FOCUS4-N was active throughout and evaluated capecitabine monotherapy versus a treatment break. A total of 361 (25%) registered patients were randomised into a sub-trial. Feedback on the experiences of delivery of FOCUS4 could be grouped into three main areas of challenge: funding/infrastructure, biomarker testing procedures and trial design efficiencies within which 20 recommendations are summarised. Adaptive stratified medicine platform studies are feasible in common cancers but present challenges. Our stakeholder feedback has helped to inform how these trial designs can succeed and answer multiple questions efficiently, providing resource is adequate.
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影响因子：
2.5
作者：
Barthel FM;Parmar MK;Royston P
通讯作者：
Royston P
影响因子：
168.9
作者：
Maughan, TS;James, RD;Stephens, RJ
通讯作者：
Stephens, RJ
DOI：
10.1200/jco.21.01436
发表时间：
2021-11-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Adams RA;Fisher DJ;Graham J;Seligmann JF;Seymour M;Kaplan R;Yates E;Parmar M;Richman SD;Quirke P;Butler R;Brown E;Collinson F;Falk S;Wasan H;Shiu KK;Middleton G;Samuel L;Wilson RH;Brown LC;Maughan TS;FOCUS4 Trial Investigators
通讯作者：
FOCUS4 Trial Investigators
影响因子：
3.4
作者：
Richman, Susan D.;Adams, Richard;Jasani, Bharat
通讯作者：
Jasani, Bharat
影响因子：
2
作者：
Royston, P;Parmar, MKB;Qian, W
通讯作者：
Qian, W