Contact information
Type
Scientific
Primary contact
Dr Angela Meade
ORCID ID
Contact details
MRC Clinical Trials Unit
222 Euston Road
London
NW1 2DA
United Kingdom
+44 (0)207 6704700
amm@ctu.mrc.ac.uk
Additional identifiers
EudraCT number
ClinicalTrials.gov number
NCT00008060
Protocol/serial number
E164/3; CR08
Study information
Scientific title
A randomised trial assessing the role of two new agents in the management of advanced colorectal cancer
Acronym
MRC FOCUS (Fluorouracil, Oxaliplatin, CPT-11, Use and Sequencing)
Study hypothesis
1. The principal objective is to determine whether there is an advantage for patients for the use of combination chemotherapy for colorectal cancer compared with the standard approach of sequential single-agent therapies.
2. In addition the trial will determine whether combination therapy is best used in first-line management of advanced disease, or reserved for second-line treatment following standard first-line single-agent modified de Gramont (MdG).
3. Finally, the trial will compare the efficacy and toxicity of an irinotecan-containing combination versus the equivalent oxaliplatin-containing combination.
Ethics approval
Added 17/07/2007: Northern and Yorkshire Medical Research Ethics Committee, approval given on 12/11/1999.
Study design
Randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Not specified
Trial type
Treatment
Patient information sheet
Condition
Colorectal cancer
Intervention
This is a five-arm trial in which patients will be randomly allocated to one of five 'treatment plans'. These plans comprise first-line and, in some cases, a second-line chemotherapy treatment plan. The five plans are:
Plan A: First-line Modified de Gramont (MdG) regimen. In the event of radiological or clinical disease progression, MdG will be stopped, and, if appropriate, patients will receive second-line therapy with single-agent irinotecan.
Plan B: First-line MdG. In the event of radiological or clinical progression patients will, if appropriate, receive second-line therapy with MdG-plus-Irinotecan (IrMdG).
Plan C: First-line treatment with IrMdG.
Plan D: First-line MdG. In the event of radiological or clinical progression patients will, if appropriate, receive second-line therapy with MdG-plus-Oxaliplatin (OxMdG).
Plan E: First-line treatment with OxMdG.
The chemotherapy schedules employed in the plans are as follows:
MdG: l-folinic acid 175 mg iv infusion over two hours
5-fluorouracil 400 mg/m^2 intravenous bolus over five minutes
5-fluorouracil 2800 mg/m^2 intravenous infusion over 46 hours
Cycle repeat: 14 days
Irinotecan (single agent):
Irinotecan 300-350 mg/m^2 intravenous infusion over 30 minutes
Cycle repeat: 21 days
IrMdG: Irinotecan 180 mg/m^2 intravenous infusion over 30 minutes
l-folinic acid 175 mg/m^2 intravenous infusion over two hours
5-fluorouracil 400 mg/m^2 intravenous bolus over five minutes
5-fluorouracil 2400 mg/m^2 intravenous infusion over 46 hours
Cycle repeat: 14 days
OxMdG:Oxaliplatin 80 mg/m^2 intravenous infusion over two hours concurrent with
l-folinic acid 175 mg intravenous infusion over two hours
5-fluorouracil 400 mg/m^2 intravenous bolus over five minutes
5-fluorouracil 2400 mg/m^2 intravenous infusion over 46 hours
Cycle repeat: 14 days
In every case, chemotherapy schedules are continued for at least 24 weeks unless disease progression or unacceptable toxicity occurs. Dose reductions or delays for toxicity are defined in the full protocol.
Intervention type
Drug
Phase
Not Specified
Drug names
Fluorouracil, Oxaliplatin, CPT-11
Primary outcome measure
Survival from randomisation
Secondary outcome measures
1. Time to failure of first-line treatment
2. Time to failure of protocol treatment plan
3. Objective response rate
4. Patient assessment of quality of life and acceptability of treatment, health economics
Overall trial start date
12/05/2000
Overall trial end date
31/12/2003
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Histologically confirmed adenocarcinoma of the colon or rectum
2. Inoperable disease (either locally advanced, recurrent or metastatic and not suitable for curative surgery or radiotherapy)
3. Measurable or evaluable disease
4. World Health Organization (WHO) performance status zero to two
5. Fit, able and willing to undergo any of the possible trial treatments and to comply with the quality of life questionnaires
Participant type
Patient
Age group
Not Specified
Gender
Not Specified
Target number of participants
700 in arm one and 350 each in other arms
Participant exclusion criteria
1. White Blood Cells (WBC) less than 4 x 10^9/l
2. Platelets less than 150 x 10^9/l
3. Bilirubin more than 1.25 x Upper Limit of Normal (ULN)
4. Alkaline phosphatase more than 3 x ULN
5. Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) more than 3 x ULN
6. Renal impairment (calculated Creatinine Clearance [CrCl] less than 60 ml/min, or measured Glomerular Filtration Rate [GFR] below normal range)
7. Serious uncontrolled medical co-morbidity
Recruitment start date
12/05/2000
Recruitment end date
31/12/2003
Locations
Countries of recruitment
United Kingdom
Trial participating centre
MRC Clinical Trials Unit
London
NW1 2DA
United Kingdom
Sponsor information
Organisation
Medical Research Council (MRC) Clinical Trials Unit (UK)
Sponsor details
222 Euston Road
London
NW1 2DA
United Kingdom
+44 (0)207 670 4700
enquiries@ctu.mrc.ac.uk
Sponsor type
Research council
Website
Funders
Funder type
Research council
Funder name
Medical Research Council (MRC) (UK)
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
1. 2005 ASCO Annual Meeting Proceedings abstract in http://meeting.ascopubs.org/cgi/content/abstract/23/16_suppl/3518
2. 2007 results in http://www.ncbi.nlm.nih.gov/pubmed/17630037
3. 2008 results in http://www.ncbi.nlm.nih.gov/pubmed/18509181
4. 2009 results on the association of molecular markers with toxicity outcomes in http://www.ncbi.nlm.nih.gov/pubmed/19858398
5. 2009 results on the effect of KRAS and BRAF mutations on efficacy of treatment agents in http://www.ncbi.nlm.nih.gov/pubmed/19884549
Publication citations
-
Results
Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ, , , Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial., Lancet, 2007, 370, 9582, 143-152, doi: 10.1016/S0140-6736(07)61087-3.
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Results
Braun MS, Richman SD, Quirke P, Daly C, Adlard JW, Elliott F, Barrett JH, Selby P, Meade AM, Stephens RJ, Parmar MK, Seymour MT, Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial., J. Clin. Oncol., 2008, 26, 16, 2690-2698, doi: 10.1200/JCO.2007.15.5580.
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Results on the association of molecular markers with toxicity outcomes
Braun MS, Richman SD, Thompson L, Daly CL, Meade AM, Adlard JW, Allan JM, Parmar MK, Quirke P, Seymour MT, Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial., J. Clin. Oncol., 2009, 27, 33, 5519-5528, doi: 10.1200/JCO.2008.21.6283.
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Results on the effect of KRAS and BRAF mutations on efficacy of treatment agents
Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P, KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial., J. Clin. Oncol., 2009, 27, 35, 5931-5937, doi: 10.1200/JCO.2009.22.4295.