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?

• Published in: British journal of cancer Vol. 110; no. 9; pp. 2178 - 2186
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.04.2014; Nature Publishing Group
• Subjects: 631/208/212/2166; 692/308/2779/109; 692/699/67/1504/1885; Aged; Aged, 80 and over; Biological and medical sciences; Biomarkers; Biomarkers, Tumor - analysis; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Chemotherapy; Clinical Study; Clinical trials; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Consent; Disease-Free Survival; DNA Mutational Analysis; Drug Resistance; Epidemiology; Feasibility Studies; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Hypotheses; Male; Medical prognosis; Medical research; Medical sciences; Middle Aged; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Oncology; Patients; Precision Medicine; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Treatment Outcome; Tumors; United Kingdom > UK; personalised medicine; colorectal cancer; multi-arm trials; biomarkers; Rectal disease; Prognosis; Colorectal cancer; Biological marker; Malignant tumor; Medical screening; Randomized controlled trial; Hypothesis; Colonic disease; Medicine; Cancerology; Phase II trial; Digestive diseases; Intestinal disease; Clinical trial; Evolution; Advanced stage; Feasibility; Models; Arm; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.182

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.