Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer

Brown, L. C. et al. (2022) Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer. Clinical Trials, 19(2), pp. 146-157. (doi: 10.1177/17407745211069879) (PMID:35083924) (PMCID:PMC9036145)

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Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Item Type:Articles
Additional Information:FOCUS4 was co-funded by the Medical Research Council (MRC)/National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) Programme and Cancer Research UK (CRUK) in April 2013. A subsequent AstraZeneca educational grant in 2017 funded the translational aspects of FOCUS4-C. Supply and distribution of AZD8931 for FOCUS-D and AZD1775 for FOCUS4-C were provided by AstraZeneca Ltd. Supply and distribution of aspirin and placebo for FOCUS4-B were provided by Bayer. The MRC Clinical Trials Unit at UCL receives core funding from the MRC within UK Research and Innovation (UKRI) (Budget: MC_UU_12023/20).
Keywords:Pharmacology, General Medicine
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Wilson, Professor Richard and Graham, Dr Janet
Authors: Brown, L. C., Graham, J., Fisher, D., Adams, R., Seligmann, J., Seymour, M., Kaplan, R., Yates, E., Parmar, M., Richman, S. D., Quirke, P., Butler, R., Shiu, K., Middleton, G., Samuel, L., Wilson, R. H., and Maughan, T. S.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Research Group:On Behalf of the FOCUS4 Trial Investigators
Journal Name:Clinical Trials
Publisher:SAGE Publications
ISSN:1740-7745
ISSN (Online):1740-7753
Published Online:27 January 2022
Copyright Holders:Copyright © 2022 The Author(s)
First Published:First published in Clinical Trials 19(2): 146-157
Publisher Policy:Reproduced under a Creative Commons License

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