FOCUS4 Aims and Objectives

The primary research objectives fall into 3 main categories:

CLINICAL BENEFIT

In the interval following standard first-line chemotherapy, do the proposed interventions improve progression-free survival and overall survival compared with placebo in the biomarker-defined cohorts?

TRIAL DESIGN IMPROVEMENT

FOCUS4 is an adaptive, molecularly stratified trial which aims to improve the efficiency with which new novel agents can be tested in the colorectal cancer setting. Patients will be registered with newly-diagnosed advanced or metastatic disease from colorectal cancer, undertake a centralised molecular analysis of their tumour and be offered entry into the most appropriate trial based on the results of the molecular tests. Some trials will adapt over time and use a Multi-Stage design that analyses the trial data at pre-specified timepoints to determine whether the new agent is having a strong treatment effect.

Multi-Arm, Multi-Stage (MAMS) design

There are a number of advantages to the FOCUS4 design (see Trial Schema):

• It uses molecularly enriched cohorts to maximise the possibility of detecting promising new treatments or rejecting unsuccessful ones
• It uses multi-stage trial design with analyses at pre-specified time points for early detection of sufficient activity
• It tests more than one treatment at the same time, each against its own placebo control
• It moves seamlessly from phase 2 to 3
• It tests whether activity is specific to the biomarker positive subgroup
• It takes advantage of the chemo break that patients appreciate and UK clinicians like to employ in patients who are stable or responding to 1st line chemotherapy
• It tests the clinical efficacy of novel agents with biological rationale in patients before resistance to standard agents occurs
• Its efficient 'Umbrella' structure provides a potential biomarker trial for all patients

BIOMARKER RESEARCH

In addition to assessment of any clinical benefit from new agents, FOCUS4 also aims to move with the developing field of biomarkers.

1. Biomarker development programme for EGFR dependent cohort: What is the optimal algorithm for stratification of the EGFR dependent cohort, (AREG, EREG, DUSP4, DUSP6 mRNA expression) and what optimal cut points should be used? What is the impact of mutation or amplification in HER2 or over-expression of HER3?
2. Fresh tumour biopsies before randomisation and on progression: Does detailed molecular analysis of biopsies from unresected primary tumour or metastases following initial chemotherapy (prior to interval) result in better selection of therapy than the targeted biomarker analysis on diagnostic material taken before initial chemotherapy? Do such analyses comparing biopsies on progression with those taken at randomisation reveal mechanisms of resistance to therapy?
3. Circulating tumour DNA analysis: Does sequential assessment of circulating tumour DNA from plasma for the presence of somatic mutation provide early information on resistance and/or document specific mechansims of resistance to the investigational therapies?
4. Sequencing of genes in candidate pathways from FFPE: Does a more detailed genetic analysis of archival tumour result in an ability to provide more detailed and accurate molecular stratification?
5. Pharmacogenomic sub-studies: Germline DNA will be collected.
6. Pharmacodynamic sub-studies (for given cohorts): Further details will be provided in specific trial protocols.