Title: Molecular selection of therapy in metastatic colorectal cancer: a molecularly stratified randomised controlled trial programme (FOCUS 4)
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: Tests that can be done on tumour samples from patients with advanced stage bowel cancer may help select the best treatment for an individual patient. There are a number of new cancer drugs that may be more beneficial in one subtype of bowel cancer than another. The FOCUS4 Trials Programme aims to recruit over 1500 patients at centres across the UK to evaluate how well these new cancer drugs work in different subtypes of bowel cancer. Patients diagnosed with bowel cancer which is not removable by surgery or has spread to elsewhere in their body will be invited to join this programme of trials. Patients who decide to join will be started on a course of chemotherapy (a form of drug treatment aimed to kill the cancer cells) for up to 16 weeks. During this time a piece of the patient’s tumour will be analysed to find out more about the molecular make up of their particular tumour. Two sorts of tests will be performed on the tumour. The first test looks at some of the genes which are often altered in colorectal cancer (the genes are called RAS, BRAF and PIK3CA). The second test detects complex molecules that the cancer is producing, including some proteins. The results of these tests will be used to classify an individual into the following subtypes of colorectal cancer: A- BRAF subtype: an abnormal (mutated) version of the BRAF gene in the cancer. B- PIK3CA subtype: an abnormal (mutated) version of the PIK3CA gene or loss of a protein (PTEN) in the cancer C- RAS subtype: an abnormal (mutated) version of the KRAS or NRAS genes in the cancer. D- No mutation subtype: no change (mutation) in the BRAF, PIK3CA, KRAS and NRAS genes in the cancer. N – Non-classified: the tests fail to work so it is not possible to classify the tumour as any one of the specific subtypes above. Patients will be assessed after the 16 weeks of chemotherapy to see how the tumour is responding to standard treatment. If the cancer has shrunk or at least not grown, patients will be eligible to enter a clinical trial testing a particular treatment in their subtype of cancer. Within each of the 5 cancer subtype trials, patients will be allocated randomly to receive either a new treatment or a placebo (dummy treatment). In some subtypes the new treatment may be given as 2 new treatments in combination which in previous studies appears to work well together. This randomly allocated treatment will continue unless there is evidence that the cancer has grown or the patient or doctor decides to stop it due to side effects. The researchers will compare the performance of each drug against the placebo to see if it is better.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS