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?

T. S. Maughan, A. M. Meade, R. A. Adams, S. D. Richman, R. Butler, D. Fisher, R. H. Wilson, B. Jasani, G. R. Taylor, G. T. Williams, J. R. Sampson, M. T. Seymour, L. L. Nichols, S. L. Kenny, A. Nelson, C. M. Sampson, E. Hodgkinson, J. A. Bridgewater, D. L. Furniss, R. Roy & 5 others M. J. Pope, J. K. Pope, M. Parmar, P. Quirke, R. Kaplan

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.Patients and 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.

Original languageEnglish
Pages (from-to)2178-2186
Number of pages9
JournalBritish Journal of Cancer
Volume110
Issue number9
DOIs
Publication statusPublished - Apr 29 2014
Externally publishedYes

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Precision Medicine
Feasibility Studies
Colorectal Neoplasms
Randomized Controlled Trials
irinotecan
Mutation
Biomarkers
Investigational Therapies
Random Allocation
Oncogenes
Disease-Free Survival
Neoplasms

Keywords

  • biomarkers
  • colorectal cancer
  • multi-arm trials
  • personalised medicine

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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? / Maughan, T. S.; Meade, A. M.; Adams, R. A.; Richman, S. D.; Butler, R.; Fisher, D.; Wilson, R. H.; Jasani, B.; Taylor, G. R.; Williams, G. T.; Sampson, J. R.; Seymour, M. T.; Nichols, L. L.; Kenny, S. L.; Nelson, A.; Sampson, C. M.; Hodgkinson, E.; Bridgewater, J. A.; Furniss, D. L.; Roy, R.; Pope, M. J.; Pope, J. K.; Parmar, M.; Quirke, P.; Kaplan, R.

In: British Journal of Cancer, Vol. 110, No. 9, 29.04.2014, p. 2178-2186.

Research output: Contribution to journalArticle

Maughan, TS, Meade, AM, Adams, RA, Richman, SD, Butler, R, Fisher, D, Wilson, RH, Jasani, B, Taylor, GR, Williams, GT, Sampson, JR, Seymour, MT, Nichols, LL, Kenny, SL, Nelson, A, Sampson, CM, Hodgkinson, E, Bridgewater, JA, Furniss, DL, Roy, R, Pope, MJ, Pope, JK, Parmar, M, Quirke, P & Kaplan, R 2014, '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?', British Journal of Cancer, vol. 110, no. 9, pp. 2178-2186. https://doi.org/10.1038/bjc.2014.182
Maughan, T. S. ; Meade, A. M. ; Adams, R. A. ; Richman, S. D. ; Butler, R. ; Fisher, D. ; Wilson, R. H. ; Jasani, B. ; Taylor, G. R. ; Williams, G. T. ; Sampson, J. R. ; Seymour, M. T. ; Nichols, L. L. ; Kenny, S. L. ; Nelson, A. ; Sampson, C. M. ; Hodgkinson, E. ; Bridgewater, J. A. ; Furniss, D. L. ; Roy, R. ; Pope, M. J. ; Pope, J. K. ; Parmar, M. ; Quirke, P. ; Kaplan, R. / 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?. In: British Journal of Cancer. 2014 ; Vol. 110, No. 9. pp. 2178-2186.
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T2 - A model for randomised controlled trials in the era of personalised medicine?

AU - Maughan, T. S.

AU - Meade, A. M.

AU - Adams, R. A.

AU - Richman, S. D.

AU - Butler, R.

AU - Fisher, D.

AU - Wilson, R. H.

AU - Jasani, B.

AU - Taylor, G. R.

AU - Williams, G. T.

AU - Sampson, J. R.

AU - Seymour, M. T.

AU - Nichols, L. L.

AU - Kenny, S. L.

AU - Nelson, A.

AU - Sampson, C. M.

AU - Hodgkinson, E.

AU - Bridgewater, J. A.

AU - Furniss, D. L.

AU - Roy, R.

AU - Pope, M. J.

AU - Pope, J. K.

AU - Parmar, M.

AU - Quirke, P.

AU - Kaplan, R.

PY - 2014/4/29

Y1 - 2014/4/29

N2 - 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.Patients and 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.

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