title: A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?
abstract: BACKGROUND
  Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.
  
  
  METHODS
  Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.
  
  
  RESULTS
  A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.
  
  
  CONCLUSIONS
  Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: T S
authors.initials: TS
authors.lastname: Maughan
authors.affiliation: MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London WC2B 6NH, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Meade
authors.affiliation: Cardiff University and Velindre Cancer Centre, Cardiff, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Adams
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: S D
authors.initials: SD
authors.lastname: Richman
authors.affiliation: University Hospital of Wales, Cardiff CF14 4XW, UK.
authors.forename: R
authors.initials: R
authors.lastname: Butler
authors.affiliation: MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London WC2B 6NH, UK.
authors.forename: D
authors.initials: D
authors.lastname: Fisher
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7AE, UK.
authors.forename: R H
authors.initials: RH
authors.lastname: Wilson
authors.affiliation: Institute of Cancer and Genetics, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: B
authors.initials: B
authors.lastname: Jasani
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: G R
authors.initials: GR
authors.lastname: Taylor
authors.affiliation: Institute of Cancer and Genetics, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: G T
authors.initials: GT
authors.lastname: Williams
authors.affiliation: Institute of Cancer and Genetics, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Sampson
authors.affiliation: St James's Institute of Oncology, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: M T
authors.initials: MT
authors.lastname: Seymour
authors.affiliation: MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London WC2B 6NH, UK.
authors.forename: L L
authors.initials: LL
authors.lastname: Nichols
authors.affiliation: MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London WC2B 6NH, UK.
authors.forename: S L
authors.initials: SL
authors.lastname: Kenny
authors.affiliation: Wales Cancer Trials Unit, Cardiff University, Cardiff CF14 4YS, UK.
authors.forename: A
authors.initials: A
authors.lastname: Nelson
authors.affiliation: Wales Cancer Trials Unit, Cardiff University, Cardiff CF14 4YS, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Sampson
authors.affiliation: Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S5 7AU, UK.
authors.forename: E
authors.initials: E
authors.lastname: Hodgkinson
authors.affiliation: UCL Cancer Institute, London WC1E 6BT, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Bridgewater
authors.affiliation: Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S5 7AU, UK.
authors.forename: D L
authors.initials: DL
authors.lastname: Furniss
authors.affiliation: Department of Oncology, Castle Hill Hospital, East Riding of Yorkshire HU16 5JQ, UK.
authors.forename: R
authors.initials: R
authors.lastname: Roy
authors.affiliation: MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London WC2B 6NH, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Pope
authors.affiliation: MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London WC2B 6NH, UK.
authors.forename: J K
authors.initials: JK
authors.lastname: Pope
authors.affiliation: MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London WC2B 6NH, UK.
authors.forename: M
authors.initials: M
authors.lastname: Parmar
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: P
authors.initials: P
authors.lastname: Quirke
authors.affiliation: MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London WC2B 6NH, UK.
authors.forename: R
authors.initials: R
authors.lastname: Kaplan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D057285:Precision Medicine; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
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