A single tumour biopsy taken after 16 weeks of first-line chemotherapy will determine which experimental drug combination a patient with advanced bowel cancer receives next. This matters because metastatic colorectal cancer is not a single disease—different patients’ tumours harbour different genetic mutations, yet standard treatment still treats them all the same. FOCUS 4 is the first large-scale trial programme to test whether matching therapy to a tumour’s molecular profile improves outcomes, using a multi-arm, multi-stage adaptive design that can drop ineffective drugs mid-trial and replace them with new candidates. If successful, the programme could shift the standard of care from one-size-fits-all chemotherapy to a molecularly stratified approach, where treatment decisions are guided by a patient’s specific tumour genetics. The adaptive trial design also means fewer patients are exposed to futile therapies, and promising drugs can be identified more quickly. The study will recruit 2,400 patients to randomise 1,536 across five biomarker-defined cohorts, with progression-free survival as the primary endpoint.
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FOCUS 4 - Molecular selection of therapy in colorectal cancer: a molecularly-stratified randomised controlled trials programme. Study Population: Adult patients with inoperable advanced or metastatic colorectal cancer (CRC) who are suitable for intermittent chemotherapy. Patients will be asked to consent to biomarker testing on a sample of their tumour, whilst they receive 16 weeks of first-line chemotherapy. On receipt of the biomarker test results, the patients who have responding or stable disease at the end of their 16 weeks of chemotherapy will be offered randomisation into a clinical trial designed for their molecular biomarker cohort. Study Interventions: 5 study cohorts: i)BRAF mutation: dual placebo v specific BRAF mutated kinase inhibitor in combination with panitumumab (an EGFR targeted monoclonal antibody) with or without MEK inhibitor ii) PIK3CA mutant tumours and/or loss of PTEN function: dual placebo v dual PIK3 / mTOR inhibitor monotherapy with or without MEK inhibitor iii) KRAS/NRAS mutation: dual placebo v dual AKT inhibitor and MEK inhibitor iv) EGFR Dependent (wildtype for all the above mutations): placebo v HER1, 2 and 3 inhibitor (AZD8931) v) Non-classified: capecitabine v active monitoring. Outcome measures: The primary endpoint is progression free survival (PFS) with a potential additional primary endpoint of overall survival (OS) Secondary endpoints: Toxicity, safety, tumour shrinkage and quality of life. Assessment follow up: Patients will be assessed for toxicity and safety at intervals deemed appropriate for the agent being tested. CT scans will be required at 8-week intervals until progression has occurred. After progression, patients will be followed at 3 months and then 6 monthly until death. Proposed Sample Size: 2400 patients registered and biomarker tested to enable randomisation of 1536 patients into the clinical trials Statistical analysis: The trials in the molecular cohorts will be adaptive in design and utilise a Multi-Arm, Multi-Stage (MAMS) approach with pre-specified interim analyses to identify therapies that appear to be having a strong or weak treatment effect. Treatments that do not demonstrate a sufficiently strong effect will be dropped and alternative therapies will replace them for that cohort. Project timetables: Recruitment is expected to commence in August 2013 with 4-5 years of recruitment followed by 2 years of follow-up.
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