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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 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 - Br. J. Cancer (2014)

Bottom Line: 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%.Complex multi-arm designs are acceptable to patients with good PIS.Randomisation within each cohort provides outcome data that can inform clinical practice.

View Article: PubMed Central - PubMed

Affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.

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.

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Related in: MedlinePlus

Diagram in patient information sheet 1 – given to patients to explain the tests carried out on their tumour sample.
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fig2: Diagram in patient information sheet 1 – given to patients to explain the tests carried out on their tumour sample.

Mentions: Patients were randomised centrally by the MRC CTU via telephone using minimisation and allocated in a 1 : 1 : 1 ratio to the control arm (A) common to each of the four subgroups or one of two experimental regimens (Figures 1 and 2). If either molecular test failed, patients could still be randomised in a 1 : 1 ratio based on the results available (Figure 1). Treatment allocation was not masked. Randomisation was stratified by standard clinical prognostic factors.


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 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 - Br. J. Cancer (2014)

Diagram in patient information sheet 1 – given to patients to explain the tests carried out on their tumour sample.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4007241&req=5

fig2: Diagram in patient information sheet 1 – given to patients to explain the tests carried out on their tumour sample.
Mentions: Patients were randomised centrally by the MRC CTU via telephone using minimisation and allocated in a 1 : 1 : 1 ratio to the control arm (A) common to each of the four subgroups or one of two experimental regimens (Figures 1 and 2). If either molecular test failed, patients could still be randomised in a 1 : 1 ratio based on the results available (Figure 1). Treatment allocation was not masked. Randomisation was stratified by standard clinical prognostic factors.

Bottom Line: 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%.Complex multi-arm designs are acceptable to patients with good PIS.Randomisation within each cohort provides outcome data that can inform clinical practice.

View Article: PubMed Central - PubMed

Affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.

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.

Show MeSH
Related in: MedlinePlus