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Background:\ud \ud 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.\ud \ud \ud Patients and Methods:\ud \ud 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.\ud \ud \ud Results:\ud \ud 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.\ud \ud \ud Conclusions:\ud \ud 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.

It is likely that future trials for many solid tumours will be stratified by predictive/prognostic biomarkers in order to a) derive more homogeneous patient cohorts; b) "personalize" treatment interventions in relation to tumour (or host) phenotype; and c) improve the likelihood of discovering a beneficial effect, in at least a subset of patients with the disease. In some settings there are likely to be multiple relevant biomarkers and treatments to be tested. For logistical reasons it would be efficient to combine these into single trials. Moreover, the inclusion of overlapping or common treatment arms could serve to further validate the use of a given biomarker for selection and support retrospective testing of other biomarker selection algorithms that may arise during the course of a trial’s enrolment period. These requirements present significant challenges both for creating efficient designs and for making these comprehensible for prospective subjects. Methods: FOCUS 3 is a feasibility study designed to address these issues and test a novel design for examining the predictive role of biomarkers (KRAS/BRAF mutations and topo-1 expression) for 1st-line therapy of aCRC. It employs an unusual design in which the two biomarkers defined four possible cohorts. Specific treatment questions were relevant to each marker and, because each cohort was defined by 2 markers, there were 2 relevant experimental arms for each cohort, plus 1 common control arm for all cohorts (FOLFIRI). The study thus incorporates 5 treatment regimens, but only 3 possibilities for each patient, defined by marker phenotype. We will complete recruitment of 240 patients by April 2011. Paraffin blocks from 24 sites were obtained for central biomarker analysis and aim to feedback results within 10 working days. A 4 stage suite of patient information sheets (PIS) was designed to avoid patient overload and we are assessing patients’ comprehension in a qualitative study. Conclusion: Patient samples can be collected and analysed centrally within acceptable time constraints. Complex, stratified, multi arm designs can be made acceptable to patients through good PIS design, ensured by patient and carer input into their design.