A full list of those involved in the study is available in Report Supplementary Material 2.
We acknowledge the expert contribution of Justina Orleans-Lindsay, specialist medical writer, for her assistance in drafting this final report.
An AstraZeneca Ltd educational grant in 2017 funded the translational aspects of FOCUS4-C. Supply and distribution of AZD8931 for FOCUS-D and AZD1775 for FOCUS4-C was provided by AstraZeneca Ltd. Supply and distribution of aspirin and placebo for FOCUS4-B was provided by Bayer AG (Leverkusen, Germany). The MRC Clinical Trials Unit at University College London receives core funding from the Medical Research Council within UKRI (budget: MC_UU_12023/20).
Trial Management Group
Maughan TS (chairperson), Wilson RH, Adams R, Seymour M, Seligmann JF, Graham J, Wasan H, Pope M, Pope J, Samuel L, Shiu K, Church D, Middleton G, Steward W, Twelves C, Wellman S, Hodgkinson E, Stoner N, Beety J, Duggleby K, Dutton G, MRC CTU team (see below) and laboratory staff (see below).
MRC CTU trial co-ordinating centre
Brown LC, Kaplan R, Parmar M, Fisher D, Campos M, Yates E, Santana S, Fiddament A, Harper L, Bara A, Pugh C, Bathia R, Letchemanan K, Przybył B, Bhogal S, Gopalakrishnan G, Purvis C, Diaz-Montana C, Mohamed F, Townsend S, Cragg W, Masters L, Van Looy N and Rauchenberger M.
Laboratories
Quirke P, Richman SD, Hemmings G, Davis J, Gallop N, Wilkinson L, Butler R, Roberts H, Jasani B, White R, Dodds R, James M and Morgan M.
Independent Data Monitoring Committee
Cameron D (chairperson), Souhami R, Peeters M, Billingham C, Griffiths G and Brown J.
Trial Steering Committee
Johnson P (chairperson), Rudd R, Whelan J and Russell A.
Ethics approval
FOCUS4 was approved by the UK National Ethics Committee Oxford – Panel C (reference 13/SC/0111) and by the relevant regulatory body, the Medicines and Healthcare products Regulatory Agency (MHRA) (CTA# 20363/0400/001 and EudraCT# 2012–005111–12) in May 2013. Subsequent amendments were also reviewed and approved by the UK National Ethics Committee Oxford – Panel C.
Contributions of authors
Louise C Brown (https://orcid.org/0000-0003-2827-6634) (Senior Statistician, MRC Trials Unit) was the project lead for FOCUS4 at the MRC CTU, designed the trial statistics and oversaw statistical analyses.
David Fisher (https://orcid.org/0000-0002-2512-2296) (Statistician, MRC Trials Unit) performed all statistical analyses.
Richard Adams (https://orcid.org/0000-0003-3915-7243) (Professor of Clinical Trials and Consultant Clinical Oncologist) was a core member of the TMG, and chief investigator of the FOCUS4-D and FOCUS4-N subtrials.
Jenny Seligmann (https://orcid.org/0000-0003-4379-6005) (Clinical Trial fellow and then Senior Lecturer in Medical Oncology) was a trial fellow and co-chief investigator of FOCUS4-C.
Matthew Seymour (https://orcid.org/0000-0002-2441-9629) (Professor of Gastrointestinal Cancer Medicine, National Cluster Lead for Cancer for NIHR CRN) was co-chief investigator for FOCUS4-C.
Richard Kaplan (https://orcid.org/0000-0002-0189-8348) (Professor of Medical Oncology) was programme lead at MRC Clinical Trials Unit and provided experienced triallist advice throughout.
Susan D Richman (https://orcid.org/0000-0003-3993-5041) (Senior Laboratory Scientist) oversaw the biomarker-testing laboratory in Leeds.
Philip Quirke (https://orcid.org/0000-0002-3597-5444) (Professor of Pathology) was the lead consultant pathologist with expertise in colorectal cancer and provided expert input for molecular diagnostics.
Rachel Butler (Head of Molecular Genetics Laboratory) provided expert leadership in genetic diagnostics.
Helen Roberts (https://orcid.org/0000-0001-5664-7151) (Head of Solid Tumour Services, Molecular Genetics Unit, Cardiff) provided expert analysis of NGS sequencing and TMG membership.
Janet Graham (https://orcid.org/0000-0002-2048-2698) (Consultant Medical Oncologist) was a member of the Trial Management Group.
Richard H Wilson (https://orcid.org/0000-0001-8018-7730) (Professor of Gastrointestinal Oncology) was co-chief investigator of FOCUS4 and CI of FOCUS4-B.
Timothy S Maughan (https://orcid.org/0000-0002-0580-5065) (Professor of Clinical Oncology) was co-chief investigator of FOCUS4, FOCUS4-C and FOCUS4-N, and was the chairperson of the TMG.
Publications
Adams RA, Fisher DJ, Graham J, Seligmann JF, Seymour M, Kaplan R, et al. Capecitabine versus active monitoring in stable or responding metastatic colorectal cancer after 16 weeks of first-line therapy: results of the randomised FOCUS4-N trial. J Clin Oncol 2021;39:3693–704. https://doi.org/10.1200/JCO.21.01436
Hague D, Townsend S, Masters L, Rauchenberger M, Van Looy N, Diaz-Montana C, et al. Changing platforms without stopping the train: experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons. Trials 2019;20:294. https://doi.org/10.1186/s13063-019-3322-7
Kaplan R, Maughan T, Crook A, Fisher D, Wilson R, Brown L, Parmar M. Evaluating many treatments and biomarkers in oncology: a new design. J Clin Oncol 2013;31:4562–8. https://doi.org/10.1200/JCO.2013.50.7905
Brown LC, Graham J, Fisher D, Adams R, Seligmann J, Seymour M, et al. Experiences of running a stratified medicine adaptive platform trial: challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer. Clin Trials 2022;19:146–57. https://doi.org/10.1177/17407745211069879
Morrell L, Hordern J, Brown L, Sydes MR, Amos CL, Kaplan RS, et al. Mind the gap? The platform trial as a working environment. Trials 2019;20:297. https://doi.org/10.1186/s13063-019-3377-5
Seligmann JF, Fisher DJ, Brown LC, Adams RA, Graham J, Quirke P, et al. Inhibition of WEE1 is effective in TP53- and RAS-mutant metastatic colorectal cancer: a randomised trial (FOCUS4-C) comparing adavosertib (AZD1775) with active monitoring. J Clin Oncol 2021;39:3705–15. https://doi.org/10.1200/JCO.21.01435
Adams R, Wilson R, Brown L, Maughan T. Reply to A. Kurreck et al and M.S. Copur et al. J Clin Oncol 2022;40:1263–4. https://doi.org/10.1200/JCO.21.02806
Richman SD, Hemmings G, Roberts H, Gallop N, Dodds R, Wilkinson L, et al. FOCUS4 biomarker laboratories: from the benefits to the practical and logistical issues faced during 6 years of centralised testing [published online ahead of print 7 March 2022]. J Clin Pathol 2022. https://doi.org/10.1136/jclinpath-2022-208233
Schiavone F, Bathia R, Letchemanan K, Masters L, Amos C, Bara A, et al. This is a platform alteration: a trial management perspective on the operational aspects of adaptive and platform and umbrella protocols. Trials 2019;20:264. https://doi.org/10.1186/s13063-019-3216-8
Data-sharing statement
FOCUS4 adopts a controlled access data sharing policy. Applications for use of the data can be made via the corresponding author for review by the MRC CTU data access committee.
Patient data
This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.
Disclaimers
This report presents independent research. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the MRC, the EME programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the EME programme or the Department of Health and Social Care.