Clinical trials in colorectal cancer

Lead Research Organisation: MRC Clinical Trials Unit

Abstract

The MRC-CTU colorectal team co-ordinate large controlled clinical trials aimed at progressively improving treatment outcomes in advanced colorectal cancer and early rectal cancer.||Four trials have tested chemotherapy and biological therapies in patients with advanced colorectal cancers. These are quite frequent tumours, but there have been major improvements, chemotherapy having increased survival from about 6 months to 10-12 months, and to between 16 20 months with addition of new agents. The COIN trial explores the addition of newer selective biological therapies hoping to further improve patients chances of living longer. COIN also tests the effectiveness of intermittent combination chemotherapy (giving patients holidays off chemotherapy). The COIN-B trial will provide further information on safety and effectiveness of adding biologics to intermittent chemotherapy. FOCUS3 is an initial test of molecular treatment selection based on characteristics of individual patients tumours. This is potentially a critical step in individualising therapy, selecting best options for each person and minimising use of agents that are unlikely to benefit him/her.||The team have also completed an important trial in early rectal cancer, which are likely to change the way patients with rectal cancer are treated both in the UK and worldwide by showing that the addition of a short course of radiotherapy prior to surgery results in a reduction in the likelihood of a rectal cancer returning.

Technical Summary

Colorectal cancer is the second most common site of cancer, with around 1 million cases diagnosed each year worldwide, accounting for about 9% of all new cancer cases. In the UK around 35,000 people are diagnosed with the disease, and 16,000 patients die each year (CR-UK Cancer Stats 2003). Most patients die of advanced disease. The colorectal team continues to run a series of large multicentre randomised trials, mainly aimed at optimising the treatment of patients with advanced disease. The team also manage follow-up of a trial in rectal cancer which completed accrual in 2005. FOCUS (CR08) commenced in May 2000 and recruited 2,135 patients by December 2003. The trial was a 5-arm randomised trial comparing the use of irinotecan and oxaliplatin in combination with 5FU either given as first-line treatment or held in reserve as second-line treatment after the failure of 5FU alone. The control arm was the UK standard treatment of 5FU followed on progression by single-agent irinotecan. All four of the research arms gave longer overall survival than the control arm. Most of the differences did not reach the predetermined 1% significance level for superiority, the comparison between the first-line combination of Irinotecan and 5FU and the control arm was the most promising (HR 0.84 (0.73-0.96; p=0.01)). The main results from the trial were published in the Lancet in 2007 (Seymour et al., Lancet 2007; 370:143-152.). Furthermore, all patients in FOCUS were asked at the time of randomisation for consent to retrieve surplus stored pathology material for molecular study. Thus FOCUS provided an excellent resource for studying the relationship between molecular variables and treatment effect. Preliminary results were presented at the American Society of Clinical Oncology (ASCO) annual meetings in 2004 and 2006. Several papers on this work have been published, while another was recently submitted for publication. This tumour tissue resource has been further expanded in the sequence of trials that followed and represents an increasingly valuable asset for biomarker and translational research. FOCUS2 (CR09) opened in January 2004 and closed in July 2006 following the recruitment of 459 patients. FOCUS2 was designed to assess lower-dose treatment for patients with advanced colorectal cancer who were ineligible or unsuitable for trials of full-dose combination chemotherapy because of poor general health status, advanced age or both. Patients were randomised in a 2x2 fashion to receive one of the four following chemotherapy treatment plans: 1st-line: 5FU/FA (MdG) 1st-line: capecitabine (Cap) 2nd-line: Oxaliplatin(Ox)MdG 2nd-line: OxMdG 1st-line: OxMdG 1st-line: OxCap Chemotherapy was started at 80% of standard dose with the option of increasing to 100% at 6 weeks if well-tolerated. The principal outcome measures were progression free survival for the addition of oxaliplatin (Ox) comparison and quality of life for the MdG/Capecitabine (Cap) comparison. Preliminary results have been presented in the form of a poster presentation at ASCO 2007 and the National Cancer Research Institute (NCRI) meeting in 2007. An oral presentation was given at the European CanCer Organisation (ECCO) meeting in 2007. Ox containing regimens showed a slightly longer progression free survival (PFS) however, these differences did not reach the pre-defined significance level of 5%. The addition of Ox did show an improvement in patients reported quality of life (QL) at 12 weeks (62% vs. 49%, p=0.04). There was no impact on the overall survival (OS) despite the significantly improved response rates (15% vs. 41%, p<0.001). There was some evidence that the addition of oxaliplatin reduced the ability to dose increase at the 6 week time point despite there being no difference in the grade 33 toxicity rates. The substitution of MdG with Cap had no effect on PFS, OS or the QL at 12 weeks, however there was a statistically significant increase in overall grade 33 toxicity (2

Publications


10 25 50
Braun MS (2009) Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Braun MS (2008) Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology
 
Description CR07 - RCPath Minimum Dataset
Geographic Reach UK 
Policy Influence Type Influenced training of practitioners or researchers
Impact Following on from the findings of the MRC CR07 trial the Plane of surgery is now a core item in the RCPath minimum dataset and is now a part of routine grading and reporting of rectal cancer surgery.
 
Guideline Title NCCN Guidelines Version 2.2015 Colon Cancer
Description Colorectal Anti-EGFR SR (PMID:22118887) NCCN guideline 2015
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact "A recent meta-analysis concluded there was a clear benefit to the use of EGFR inhibitors in patients with KRAS-wild-type metastatic colorectal cancer", based on our systematic review and meta-analysis of summary data (PMID: 22118887)
 
Description FOCUS data: NICE Technology Assessment TA93
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a national consultation
Impact FOCUS data was submitted to NICE for use in their apparisal of the use of irinotecan and oxaliplatin for the treatment of advanced colorectal cancer. NICE made the following recommendation: Irinotecan and oxaliplatin, within their licensed indications, are recommended as treatment options for people with advanced colorectal cancer as follows: • irinotecan in combination with 5-fluorouracil and folinic acid as first-line therapy, or irinotecan alone in subsequent therapy • oxaliplatin in combination with 5-fluorouracil and folinic acid as first-line or subsequent therapy.
 
Description Lack of benefit of cetuximab therapy in first-line treatment of colorectal cancer
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact The COIN trial demonstrated that anti-EGFR antibody therapy with cetuximab does not improve progression-free survival outcome along with initial chemotherapy, even within the presumed most responsive subset of patients.
 
Description intermittent chemotherapy as standard practice for first-line treatment of colorectal cancer
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact The MRC COIN trial confirmed in 2011 what data from the earlier MRC FOCUS trial had suggested, that for most patients having colorectal cancer chemotherapy, a break in the chemotherapy did not compromise survival. This approach began to be widely adopted as a standard in the UK even before completion of the COIN trial, which was very widely activated across the UK. This approach is now standard in the UK and influencing standards in other countries. It not only has quality of life and economic benefits but also serves as the platform for the next generation of chemotherapy trials.
 
Description Add-Aspirin trial - CRUK (CTAAC) grant
Amount £3,598,674 (GBP)
Funding ID C471/A15015 
Organisation Cancer Research UK (CRUK) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2013 
End 12/2023
 
Description CRUK funding (CTAAC - FOCUS-2)
Amount £403,460 (GBP)
Organisation Cancer Research UK (CRUK) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2006 
End 08/2006
 
Description CRUK funding (CTAAC-COIN)
Amount £444,766 (GBP)
Organisation Cancer Research UK (CRUK) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2006 
End 04/2010
 
Description FOCUS4 trial programme
Amount £3,938,399 (GBP)
Organisation Medical Research Council (MRC) 
Department Efficacy and Mechanism Evaluation (EME) Programme
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2013 
End 01/2020
 
Description FOCUS4 trial programme
Amount £3,525,623 (GBP)
Funding ID 11/100/50 
Organisation NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2013 
End 03/2020
 
Description MRC FOCUS3
Amount £425,908 (GBP)
Funding ID G0701770 
Organisation MRC-UK 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2008 
End 09/2010
 
Description MRC IES Platform (FOCUS3)
Amount £425,892 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 11/2008 
End 10/2011
 
Description NIHR (HTA) funding for Add-Aspirin trial
Amount £3,124,812 (GBP)
Funding ID 12/01/38 
Organisation National Institute for Health Research (NIHR) 
Department Health Technology Assessment Programme (HTA)
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 05/2014 
End 04/2023
 
Description S-CORT MRC-CRUK consortium: Stratification in COloRectal cancer: from biology to Treatment prediction
Amount £6,137,601 (GBP)
Funding ID MR/M016587/1 
Organisation MRC-UK 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2015 
End 03/2020
 
Title Colorectal Trials: Tumour Samples for Translational Research 
Description Formalin-fixed paraffin-embedded blocks of tumour and normal tissue from patients in the MRC FOCUS (approx. 1600 patient samples), FOCUS-2 (approx. 400 patient samples), COIN (approx. 2100 patient samples), COIN-B (approx. 200 samples) and FOCUS 3 (200 samples) trials have been collected and banked at the University of Leeds and the Wales Cancer Bank. In addition samples of whole blood have also been collected from patients participating in the FOCUS-2, COIN and COIN-B trials. 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2009 
Provided To Others? Yes  
Impact The number of research projects carried out using these samples is now more than 25, with results from several of these translational studies presented at national and international scientific meetings and published (PMID references: 18509181, 19884549, 19858398, 22118887, 22634755) . KRAS mutational status (obtained from testing tumour tissue) ended up being a key componenet of the primary analysis of the COIN trial results and a feature of the design of the FOCUS4 trial programme. 
URL http://europepmc.org/abstract/MED/18509181
 
Title Combined FOCUS, FOCUS2, COIN, FOCUS3, and FOCUS4 specimen collection 
Description A pooled set of specimens plus complete corresponding clinical data, including outcome data from a series of colorectal cancer trials 
Type Of Material Biological samples 
Year Produced 2009 
Provided To Others? Yes  
Impact Multiple use in piloting and quality assuring assays for biomarker and other translational studies, as well as serving as a resource for more definitive translational research 
 
Title New trial design for stratified medicine clinical trials 
Description A new clinical trials design intended to be much more efficient than most trials in stratified medicine have been thus far 
Type Of Material Improvements to research infrastructure 
Year Produced 2013 
Provided To Others? Yes  
Impact Other trials actively being developed, using this design 
URL http://jco.ascopubs.org/content/31/36/4562.full?sid=64cfcd5a-26c6-4690-bf24-e36aaf012852
 
Title Add-Aspirin trial database 
Description A secure database with built in checks/validations, as well as functionality for producing reports, has been developed in-house to record all data collected in the trial. 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Due to the size and scope of the planned trial (;10,000 participants with four different tumour types), the database is expected to provide a rich resource of information for use in future research beyond the original trial question. The data will be made available to other researchers via an application process. 
 
Title Colorectal trial specimen collection and outcomes database 
Description A stored collection of specimens (tumour and blood) from patients on a series of colorectal cancer therapeutic trials including FOCUS, FOCUS2, COIN, FOCUS3 and FOCUS4, along with anonymised demographic and outcome data 
Type Of Material Database/Collection of data 
Year Produced 2009 
Provided To Others? Yes  
Impact At least 20 translational projects underway and many exploratory or pilot projects. Publications listed as specific outputs. 
 
Description ALMAC biomarker validation 
Organisation Almac Group
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution COIN trial samples are being provided to ALMAC (under Merck funding) for measuring epiregulin, amphiregulin and other EGFR ligands, and other biomarkers, to confirm a possible role as predictive biomarkers for response to anti-EGFR antibodies
Collaborator Contribution In collaboration with funding from Merck, has made possible the assessment of role of EGFR ligands on outcome of COIN trial, and helps with planning of successor colorectal trials
Impact analyses pending
Start Year 2010
 
Description ARCAD Database Project 
Organisation ARCAD Foundation
Country France, French Republic 
Sector Charity/Non Profit 
PI Contribution Data from FOCUS and COIN, and ultimately other colorectal trials contributing to large multi-national, multi-trial, database in which non-trioal specific questions can be explored
Collaborator Contribution Jointly investigating the utility and validity of intermediate endpoints such as PFS to longer term endpoints, particularly overall survival
Impact pending
Start Year 2010
 
Description Add-Aspirin - Tata Memorial Hospital 
Organisation Tata Memorial Hospital
Country India, Republic of 
Sector Hospitals 
PI Contribution Leading the Add-Aspirin trial; management of the trial in the UK; oversight and mentoring of the research group at the Tata Memorial Hospital who will manage Indian participation in the trial.
Collaborator Contribution Management and oversight of the Add-Aspirin trial in India.
Impact In terms of the Add-Aspirin trial, the collaboration will speed up delivery of the research and enable demonstration of the health intervention in a range of settings, increasing the potential global impact of the results. Additionally, the work is facilitating development of a cancer research network in India and will pave the way for future collaborative projects.
Start Year 2013
 
Description Add-Aspirin Trial 
Organisation Cancer Research UK (CRUK)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution application for Add-Aspirin trial funding
Collaborator Contribution funding from CRUK for Add-Aspirin Trial
Impact trial in setup phase
Start Year 2013
 
Description Add-Aspirin trial - Bayer Pharmaceuticals PLC 
Organisation Bayer
Department Bayer HealthCare
Country Germany, Federal Republic of 
Sector Private 
PI Contribution We approached Bayer to supply the drugs for the Add-Aspirin trial.
Collaborator Contribution Bayer Pharmaceuticals are supplying the Add-Aspirin trial medication (100mg aspirin tablets, 300mg aspirin tablets and matched placebos) free of charge.
Impact Contract signed, no output to date. The trial is currently in set-up.
Start Year 2014
 
Description COIN Merck Collaboration 
Organisation Merck & Co. Inc. (MSD)
Country United States of America 
Sector Private 
PI Contribution MRC CTU have been responsible for the design, co-ordination, management and analysis of the MRC COIN and COIN-B trials.
Collaborator Contribution Merck have provided free cetuximab for use in the MRC COIN and COIN-B trials and will provide free cetuximab for the future FOCUS-3 feasibility trial
Impact The COIN trial recently completed accrual and the first results were presented at the ESMO/ECCO international congress in Sept 2009 and at the NCRI annual meeting in October 2009. Manuscripts describing the trials and the results are in preparation. One publication has also resulted from this trial to date: PMID 19165196. Main results have been submitted for publication in 3 manuscripts.
 
Description COIN Sanofi-Aventis Collaboration 
Organisation Sanofi
Department Sanofi-Aventis
Country United States of America 
Sector Private 
PI Contribution MRC CTU have been responsible for the design, co-ordination, management and analysis of the MRC COIN trial.
Collaborator Contribution Sanofi-Aventis provided free oxaliplatin for patients in Arm B of the COIN trial until oxaliplatin was approved for the treatment of patients with advanced colorectal cancer in the UK (NICE approval)
Impact The COIN trial recently completed accrual and the first results were presented at the ESMO/ECCO international congress in Sept 2009 and at the NCRI annual meeting in October 2009. Manuscripts describing the trials and the results are in preparation. One publication has also resulted from this trial to date: PMID 19165196 Main trial results have been submitted for publication in 3 manuscripts.
 
Description COIN-ICORG 
Organisation Irish Clinical Oncology Research Group (ICORG)
Country Ireland, Republic of 
Sector Charity/Non Profit 
PI Contribution MRC CTU have been responsible for the design, co-ordination, management and analysis of the MRC COIN trial.
Collaborator Contribution ICORG co-ordinated the participation of 10 sites in the Republic of Ireland in the COIN trial; 49 patients were recruited from these 10 sites.
Impact The COIN trial recently completed accrual and the first results were presented at the ESMO/ECCO international congress in Sept 2009 and at the NCRI annual meeting in October 2009. Manuscripts describing the trials and the results are in preparation. One publication has also resulted from this trial to date: PMID 19165196
Start Year 2007
 
Description Collaboration with AstraZenca 
Organisation AstraZeneca
Department Oncology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution Agreement to collaboratively explore a new agent (AZD8931) in colorectal cancer, in the FOCUS4 trial
Collaborator Contribution Extensive discussion by company and MRC teams of the agent's mechanism of action and safety in preparation for its selection for FOCUS4
Impact For MRC CTU, the provision of this agent has helped get the FOCUS4 trial launched quickly. For AstraZeneca, this is an important test of an agent that otherwise might not have a pathway to market.
Start Year 2011
 
Description Collaboration with GSK and Novartis for FOCUS4 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Provision of the FOCUS4 trial as a framework for investigation of multiple GSK agents, and combinations, in defined molecular subtypes of colorectal cancer. The original arrangement is being modified to accommodate the agreements between GSK and Novartis relevant to their portfolio of oncology products.
Collaborator Contribution Planned supply of agents, placebos and costs of distribution to multiple participating sites, + modest additional financial support to the overall trial
Impact None as yet
Start Year 2013
 
Description Collaboration with GSK and Novartis for FOCUS4 
Organisation Novartis
Country Global 
Sector Private 
PI Contribution Provision of the FOCUS4 trial as a framework for investigation of multiple GSK agents, and combinations, in defined molecular subtypes of colorectal cancer. The original arrangement is being modified to accommodate the agreements between GSK and Novartis relevant to their portfolio of oncology products.
Collaborator Contribution Planned supply of agents, placebos and costs of distribution to multiple participating sites, + modest additional financial support to the overall trial
Impact None as yet
Start Year 2013
 
Description Colorectal Trial Collaborators - Participating Sites 
Organisation National Cancer Research Institute (NCRI)
Department National Cancer Research Network (NCRN)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution MRC CTU have been responsible for the design, co-ordination, management and analysis of the MRC CR07 (1350 patients), FOCUS (2135 patients), FOCUS-2 (460 patients), COIN (2445 patients) and COIN-B (target 158 patients with KRAS wild-type tumours) trials. Subsequently, the MRC-funded pilot FOCUS-3 trial was completed and the massive, co-funded (EME + CRUK) molecularly stratified FOCUS4 trial is set to launch in Dec 2013.
Collaborator Contribution This collaboration includes research staff at each of the roughly 120 clinical sites that have participated in the colorectal clinical trials. Each site identified patients potentially suitable for the trial, sought informed consent, treated and followed-up patients within the trial and provided data through completion and return of case record forms.
Impact Results from the MRC CR07 trial have been presented at national and international scientific meetings. Primary trial publications: 19269519 and 19269520 Results from the MRC FOCUS trial have been presented at national and international scientific meetings. Primary trial publication: 17630037 Results from the MRC FOCUS2 trial have been presented at national and international scientific meetings. A manuscript presenting the trial results is currently in preparation. The COIN trial completed accrual, was presented at the ESMO/ECCO international congress in Sept 2009 and at the NCRI annual meeting in October 2009 and was published by a pair of reports in Lancet and Lancet Oncology. A manuscript describing the outcome of FOCUS-3 is in preparation. In addition, a comprehensive colorectal specimen bank was developed from the COIN, COIN-B, and FOCUS-3 trials (and will also involve specimens from FOCUS4). From this repository a large number of translational projects have been launched and several have now been published (see references).
 
Description Colorectal Trials - Baxter Collaboration 
Organisation Baxter
Department Baxter Healthcare
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution MRC CTU have been responsible for the design, co-ordination, management and analysis of the MRC FOCUS , FOCUS-2, COIN and COIN-B trials.
Collaborator Contribution Baxter provided reduced price ambulatory pumps to FOCUS/FOCUS2/COIN/COINB trial sites for adminstration of trial chemotherapy.
Impact Results from the MRC FOCUS trial have been presented at national and international scientific meetings. Primary trial publication: 17630037 Results from the MRC FOCUS2 trial have been presented at national and international scientific meetings. A manuscript presenting the trial results is currently in preparation. The COIN trial recently completed accrual and the first results were presented at the ESMO/ECCO international congress in Sept 2009 and at the NCRI annual meeting in October 2009. Manuscripts describing the trials and the results are in preparation. One publication has also resulted from this trial to date: PMID 19165196
 
Description Colorectal Trials - Immatics 
Organisation Immatics Biotechnologies GmbH
Country Germany, Federal Republic of 
Sector Private 
PI Contribution The MRC team have provided clinical data and tumour samples from patients randomised to Arm C of the MRC COIN trial.
Collaborator Contribution Immatics are conducting a clinical trial, the primary objective of which is to determine whether IMA910 as single agent with GM-CSF as adjuvant following pre-treatment with low-dose cyclophosphamide is safe and shows sufficient anti-tumour effectiveness in patients with advanced CRC to warrant further development. Using the arm C data of the COIN trial for matched pair analysis with the data generated in the trial will allow a more solid and adequate assessment of effectiveness of IMA910 with respect to disease control rate and overall survival.
Impact No data has been published to date.
Start Year 2011
 
Description Colorectal Trials - Queen's University 
Organisation School of Medicine, Dentistry and Biomedical Sciences
Department Centre for Cancer Research and Cell Biology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution MRC have provided tumour samples from patients enrolled in the MRC COIN/COIN-B trials together with some clinical data.
Collaborator Contribution This QUB team will investigate the significance of the pro-angiogenic CXC-chemokine interleukin-8 (IL-8) within the tumour microenvironment of CRC in modulating the response to FOLFOX chemotherapy.
Impact No outputs to date.
Start Year 2009
 
Description Colorectal Trials - Roche 
Organisation Roche
Department Roche Diagnostics
Country Global 
Sector Private 
PI Contribution Roche are collaborating with the MRC colorectal team on the MRC FOCUS3 trial which is co-ordinated by the MRC CTU
Collaborator Contribution Roche are providing financial support for the MRC Colorectal Porgramme.
Impact Th e FOCUS3 trial has completed accrual. A manuscript is being prepared.
Start Year 2010
 
Description Colorectal Trials - University of Cardiff 
Organisation Cardiff University
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution The colorectal team at the MRC CTU work closely with the translational research teams at the University of Cardiff to ensure the success of the translational studies attached to the colorectal clinical trials.
Collaborator Contribution The translational research components of the MRC COIN and COIN-B trials and part of the translational research component of the FOCUS-3 trial were carried out or are currently being carried out by research teams at the University of Cardiff
Impact The translational research associated with the COIN, COIN-B and FOCUS3 trials is all currently ongoing or due to begin in 2010. Because of evidence that KRAS mutational status in patients' tumours is a key predictor of response to agents such as cetuximab the translational reesearch component of the trial was key to analysis of the trial's primary clinical outcome measure of overall survival in patients with KRAS wild-type colorectal cancer.
 
Description Colorectal Trials - University of Leeds 
Organisation University of Leeds
Department Faculty of Medicine and Health
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution The colorectal team at the MRC CTU work closely with the translational research teams at the University of Leeds to ensure the success of the translational studies attached to the colorectal clinical trials.
Collaborator Contribution The translational research components of the MRC CR07, FOCUS, FOCUS-2 trials and part of the translational research component of the FOCUS-3 trial were carried out or are currently being carried out by research teams at the University of Leeds
Impact Results from the translational studies associated with the FOCUS and FOCUS-2 trials have been presented at national and international scientific meetings. PMID references: 18509181, 19884549 and 19858398 The translational research associated with the CR07 and FOCUS3 trials is due to begin in 2010.
 
Description Colorectal Trials - Wyeth Collaboration 
Organisation Pfizer Ltd
Department Wyeth Pharmaceuticals
Country United States of America 
Sector Private 
PI Contribution MRC CTU have been responsible for the design, co-ordination, management and analysis of the MRC FOCUS , FOCUS-2, COIN and COIN-B trials.
Collaborator Contribution Wyeth have produced reduced price L-folinic acid for use in the MRC FOCUS, FOCUS-2 and COIN trials
Impact Results from the MRC FOCUS trial have been presented at national and international scientific meetings. Primary trial publication: 17630037 Results from the MRC FOCUS2 trial have been presented at national and international scientific meetings. A manuscript presenting the trial results is currently in preparation. The COIN trial recently completed accrual and the first results were presented at the ESMO/ECCO international congress in Sept 2009 and at the NCRI annual meeting in October 2009. Manuscripts describing the trials and the results are in preparation. One publication has also resulted from this trial to date: PMID 19165196
 
Description Colorectal trials - NCRI Colorectal Clinical Studies Group 
Organisation National Cancer Research Institute (NCRI)
Department NCRI Colorectal Cancer CSG
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution MRC CTU have been responsible for the design, co-ordination, management and analysis of the MRC CR07, FOCUS , FOCUS-2, COIN and COIN-B trials.
Collaborator Contribution All of the MRC CTU colorectal trials are run in collaboration with the NCRI colorectal cancer CSG which as a group discusses trial design and encourages national participation in the trial
Impact Results from the MRC CR07 trial have been presented at national and international scientific meetings. Primary trial publications: 19269519 and 19269520 Results from the MRC FOCUS trial have been presented at national and international scientific meetings. Primary trial publication: 17630037 Results from the MRC FOCUS2 trial have been presented at national and international scientific meetings. A manuscript presenting the trial results is currently in preparation. The COIN trial recently completed accrual and the first results were presented at the ESMO/ECCO international congress in Sept 2009 and at the NCRI annual meeting in October 2009. Manuscripts describing the trials and the results are in preparation. One publication has also resulted from this trial to date: PMID 19165196. Main trial results have been submitted for publication in 3 manuscripts.
 
Description Colorectal trials - NCRN 
Organisation National Cancer Research Institute (NCRI)
Department National Cancer Research Network (NCRN)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution MRC CTU have been responsible for the design, co-ordination, management and analysis of the MRC CR07, FOCUS , FOCUS-2, COIN and COIN-B trials.
Collaborator Contribution The NCRN (a component of NIHR and funded by the English Dept of Health) and corresponding networks in the other UK nations provide the infrastructure in which the trial was run at participating hospitals. In particular, it supports local research nurses and data managers who are responsible for collecting and returning trial data to the CTU.
Impact Results from the MRC CR07 trial have been presented at national and international scientific meetings. Primary trial publications: 19269519 and 19269520 Results from the MRC FOCUS trial have been presented at national and international scientific meetings. Primary trial publication: 17630037 Results from the MRC FOCUS2 trial have been presented at national and international scientific meetings. A manuscript presenting the trial results is currently in preparation. The COIN trial recently completed accrual and the first results were presented at the ESMO/ECCO international congress in Sept 2009 and at the NCRI annual meeting in October 2009. Manuscripts describing the trials and the results are in preparation. One publication has also resulted from this trial to date: PMID 19165196. Main trial results have been submitted for publication in 3 manuscripts.
 
Description Colorectal trials Pfizer 
Organisation Pfizer Ltd
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution Developing new colorectal cancer trials that incorporate molecular stratification on the basis of putative biomarker predictors of response.
Impact FOCUS3 trial initiated and FOCUS 4 trial in planning stages
Start Year 2009
 
Description FOCUS Aventis Collaboration 
Organisation Sanofi
Department Aventis
Country France, French Republic 
Sector Private 
PI Contribution MRC CTU have been responsible for the design, co-ordination, management and analysis of the MRC FOCUS trial.
Collaborator Contribution Sanofi-Synthelabo provided free oxaliplatin for patients in Arm E of the MRC FOCUS trial
Impact Results from the MRC FOCUS trial have been presented at national and international scientific meetings. Primary trial publication: 17630037
 
Description FOCUS Sanofi-Synthalebo Collaboration 
Organisation Sanofi
Department Sanofi-Aventis
Country United States of America 
Sector Private 
PI Contribution MRC CTU have been responsible for the design, co-ordination, management and analysis of the MRC FOCUS trial.
Collaborator Contribution Sanofi-Synthelabo provided free oxaliplatin for patients in Arm E of the MRC FOCUS trial
Impact Results from the MRC FOCUS trial have been presented at national and international scientific meetings. Primary trial publication: 17630037
 
Description Oxford University 
Organisation Medical Research Council (MRC)
Department CRUK/MRC Oxford Institute for Radiation Oncology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Major collaboration in developing, and jointly applying for funding for a stratified medicine trial
Collaborator Contribution Hosting CI and one or more research fellows in support of major new colorectal cancer trial
Impact none yet
Start Year 2011
 
Description Pharma collaboration(s) with AstraZeneca on FOCUS4 
Organisation AstraZeneca
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution The FOCUS4 trial as a framework for studying the effect of AZD8931 in all-wild-type (non-mutated) colorectal cancer. In 2016, this will be expanded to include the testing of AZ's WEE1 inhibitor in various marker cohorts expected to be vulnerable to a mechanism of synthetic lethality.
Collaborator Contribution Provision of the agent and placebo as well as the mechanism of distribution to about 20 sites
Impact none as yet
Start Year 2013
 
Description S-CORT MRC-CRUK Consortium 
Organisation Cardiff University
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We serve as the central link between the clinical and outcome data of thousands of patients, access to their tumour and blood samples, and the data from an array of translational laboratory studies carried out by the consortium as a whole. We also provide statistical design advice.
Collaborator Contribution The development of a portal for entry and curation of large scale biological data (Oxford); the performance of translational laboratory studies (all the other partners)
Impact Some preliminary publications, but main outputs are yet to come
Start Year 2015
 
Description S-CORT MRC-CRUK Consortium 
Organisation Queen's University of Belfast
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We serve as the central link between the clinical and outcome data of thousands of patients, access to their tumour and blood samples, and the data from an array of translational laboratory studies carried out by the consortium as a whole. We also provide statistical design advice.
Collaborator Contribution The development of a portal for entry and curation of large scale biological data (Oxford); the performance of translational laboratory studies (all the other partners)
Impact Some preliminary publications, but main outputs are yet to come
Start Year 2015
 
Description S-CORT MRC-CRUK Consortium 
Organisation University of Birmingham
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We serve as the central link between the clinical and outcome data of thousands of patients, access to their tumour and blood samples, and the data from an array of translational laboratory studies carried out by the consortium as a whole. We also provide statistical design advice.
Collaborator Contribution The development of a portal for entry and curation of large scale biological data (Oxford); the performance of translational laboratory studies (all the other partners)
Impact Some preliminary publications, but main outputs are yet to come
Start Year 2015
 
Description S-CORT MRC-CRUK Consortium 
Organisation University of Leeds
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We serve as the central link between the clinical and outcome data of thousands of patients, access to their tumour and blood samples, and the data from an array of translational laboratory studies carried out by the consortium as a whole. We also provide statistical design advice.
Collaborator Contribution The development of a portal for entry and curation of large scale biological data (Oxford); the performance of translational laboratory studies (all the other partners)
Impact Some preliminary publications, but main outputs are yet to come
Start Year 2015
 
Description S-CORT MRC-CRUK Consortium 
Organisation University of Oxford
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We serve as the central link between the clinical and outcome data of thousands of patients, access to their tumour and blood samples, and the data from an array of translational laboratory studies carried out by the consortium as a whole. We also provide statistical design advice.
Collaborator Contribution The development of a portal for entry and curation of large scale biological data (Oxford); the performance of translational laboratory studies (all the other partners)
Impact Some preliminary publications, but main outputs are yet to come
Start Year 2015
 
Description S-CORT MRC-CRUK Consortium 
Organisation Wellcome Trust Sanger Institute
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution We serve as the central link between the clinical and outcome data of thousands of patients, access to their tumour and blood samples, and the data from an array of translational laboratory studies carried out by the consortium as a whole. We also provide statistical design advice.
Collaborator Contribution The development of a portal for entry and curation of large scale biological data (Oxford); the performance of translational laboratory studies (all the other partners)
Impact Some preliminary publications, but main outputs are yet to come
Start Year 2015
 
Title Add-Aspirin 
Description Add-Aspirin is a phase III, double-blind, placebo-controlled randomised trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common non-metastatic solid tumours. It is currently in the set-up phase and funding has been secured from CRUK. Further funding applications are ongoing. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2013
Development Status Actively seeking support
Impact under development. Novel methodology proposed including 4 individually powered trials integrated into one over-arching trial 
 
Title COIN-B 
Description MRC COIN-B is an open-label, multi-centre, randomised, 2-arm, phase II trial of how Cetuximab might safely and effectively be added to an intermittent chemotherapy (ICT) maintenance strategy, in the first-line treatment of advanced colorectal cancer (ACRC). 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2007
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier ISRCTN38375681
Impact In COIN-B, cetuximab was safely incorporated in two planned novel first line ICT strategies. Cetuximab maintenance was associated with a longer CFI and longer time to progression/death. This promising strategy of biological maintenance monotherapy in molecularly selected cohorts needs validation in phase III trials. 
URL http://www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s=11
 
Title COIN: Demonstration that cetuximab therapy does not improve outcome in combination with 1st-line chemotherapy for colorectal cancer 
Description Cetuximab is a monoclonal antibody that is licensed in colorectal cancer, but the COIN trial demonstrated that its addition to 1st-line FOLFOX chemotherapy did not extend survival, even in patients without KRAS mutations. As the COIN trial participation was very broad among UK oncologists, this observation will prevent unnecessary toxicity and reduce costs throughout the country. Funding from Cancer Research UK, MRC and Merck-Serono 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2011
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier ISRCTN 27286448
Impact The COIN trial assists in rationalising the use of an important but expensive cancer treatment. 
URL http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=1314
 
Title COIN: Established intermittent chemotherapy as standard practice for first line colorectal cancer 
Description The COIN trial established the use of intermittent chemotherapy, incorporating treatment breaks, as non-inferior standard treatment for colorectal cancer, except for patients with elevated platelet counts. Funding from Cancer Research UK, MRC and Merck-Serono. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Wide-scale adoption
Year Development Stage Completed 2011
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier ISRCTN 27286448
Impact Intermittent, rather than continuous chemotherapy for colorectal cancer has been studied for some years, including in earlier MRC trials in this programme, but the COIN trial developed large scale evidence for this approach. Also, the COIN trial was so widely supported across the UK that intermittent therapy has become a new and widely adopted standard of care. This approach saves toxicity for patients and chemotherapy expense for the NHS. 
URL http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=1314
 
Title FOCUS3 
Description A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS 3): A paradigm for randomised controlled trials in the era of personalised medicine? 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2012
Development Status Closed
Clinical Trial? Yes
UKCRN/ISCTN Identifier ISRCTN83171665
Impact The FOCUS 3 trial was a feasibility study designed to address the challenges of patient acceptability, technical logistics, and to test a novel design for examining the predictive role of biomarkers for 1st-line therapy of ACRC. We have shown that such studies are feasible and very well received by particpants. The central trial design concepts have been taken forward into a major UK trial programme FOCUS4 - molecular selection of therapy in CRC: a molecularly stratified RCT programme which will be launched in 2013. 
URL http://www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s=52
 
Title FOCUS4 
Description FOCUS4 - Molecular selection of therapy in colorectal cancer: a molecularly-stratified randomised controlled trial programme. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier ISRCTN90061546
Impact A new trial design using stratified medicine and adaptive methods to test novel agents in colorectal cancer. 
URL http://www.controlled-trials.com/ISRCTN90061546/
 
Title Add-Aspirin Drug Supply Management System 
Description A drug supply management system tailored to the trial requirements has been developed in-house to provide a secure system for coordinating all aspects of the drug supply process in the study. The drug packaging and distribution team, as well as research staff and pharmacists at participating sites will have web-based access to the system, and it will allow close oversight of the whole process by the Trials Unit team. Input from all of the relevant parties has been sought in developing the system and it has been designed in such a way that it can subsequently be adapted for use in future trials conducted at the unit. 
Type Of Technology Software 
Year Produced 2014 
Impact This in-house system may replace the need to out-source the management of drug supply processes, and so will have cost-saving implications both within Add-Aspirin and for future trials. 
 
Description Add-Aspirin oral presentation at ESMO world congress on Gastrointestinal Cancer Conference 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Oral presentation and poster presentation entitled "Are the Benefits of Aspirin in Colorectal Cancer Limited to PIK3CA Mutated Cancers?" at an international conference. The talk promoted discussion and raised awareness of the Add-Aspirin trial.

Promoted discussion
Year(s) Of Engagement Activity 2014
URL http://annonc.oxfordjournals.org/content/25/suppl_2/ii109.3.short
 
Description Add-Aspirin trial launch meeting at NCRI conference Liverpool 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Add-Aspirin trial launch meeting- Trial promotion and training for research nurses and doctors hoping to participate in the trial at their site.

Increased requests for further information from sites interested in participating in the trial.
Year(s) Of Engagement Activity 2014
 
Description COIN Trial Results 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact A press release explaining the primary COIN trials results was released.

the story was picked up by a number of media sources.
Year(s) Of Engagement Activity 2009
 
Description Lay Summary of CR07 trial results 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact We have provided a lay summary of the CR07 trial results to all participating centres in the trial for dissemination to patients who participated in the trial.

Lay summary was only recently circulated but from experience reports like this are appreciated by patients.
Year(s) Of Engagement Activity 2009