FOCUS4 Summary

Long Title of Trials Programme Molecular selection of therapy in colorectal cancer: a molecularly stratified randomised controlled trial programme
Note This protocol is the FOCUS4 Master Protocol. Patients will be registered into the FOCUS4 Trial Programme and subsequently randomised into a trial available for their molecular cohort. These protocols will have the acronyms of FOCUS4-A, FOCUS4-B etc., and are provided as separate protocol documents.
ISRCTN # Application in progress
EudraCT # 2012-005111-12
CTA # 00316/0245/001-0001
REC # 13/SC/0097
Type of Participants to be Studied Adult patients with inoperable advanced or metastatic colorectal cancer (CRC) who are suitable for intermittent chemotherapy.
Study Design The FOCUS4 Master Protocol describes the registration period - identification of patients, biomarker testing and initial 16 weeks of standard therapy prior to entry into FOCUS4.

Patients undergoing 16 weeks of first-line chemotherapy for CRC will be registered and asked for consent to send their tumour block sample for biomarker panel assessment. The results of this assessment will be used to classify patient into one of several possible molecular cohorts. Patients are offered entry into the trial available for their molecular cohort.

Each trial within these patient molecular cohorts will aim to be double blind and compare an intervention with a placebo control and have its own dedicated protocol. FOCUS4-N will run concurrently for patients whose biomarker panel results are unclassifiable; for those whose molecular cohort is temporarily not open for recruitment, and for any patients unable or unwilling to travel. (For safety reasons, agents for some cohorts will initially be available only at a limited number of trial sites). FOCUS4-N will answer a conventional (not molecularly stratified) chemotherapy question comparing capecitabine against no treatment; unlike the other trials, this chemotherapy comparison will not be blinded or placebo controlled.

FOCUS4 is a rolling trial programme that utilises the MAMS design. A maximum of 4 staged interim analyses are proposed for each trial: Stage I (safety), Stage II (lack of sufficient activity), Stage III (efficacy for PFS) and Stage IV (efficacy for OS). Stages I and II would be regarded as equivalent to a conventional phase 2 study and Stages III and IV a phase 3 study. Results at each stage will be reviewed confidentially by an Independent Data Monitoring Committee (IDMC) but results at the end of stage II (phase 2) may be released by the IDMC to allow an open decision to be made on whether to proceed to stage III (phase 3). In addition, if the novel agent is showing sufficiently strong activity, it may be tested in patients who are not selected for that molecular cohort to ascertain whether the action of the novel agent is specific to that biomarker classification.

The four molecular cohorts are organised into a hierarchy of classification (see Trial Schema and explanation above) and are described below along with FOCUS4-N. Specific agent(s) are detailed separately in each of the protocols. The trials listed below are the current trials planned for each molecular cohorts at the time of writing of this Master Protocol:

Cohort: BRAF mutant tumours
Comparison: FOCUS4-A
Intervention(s): Specific BRAF mu tated kinase inhibitor in combination with panitumumab (an EGFR targeted monoclonal antibody) with or without MEK inhibitor.
Control: Dual placebo

Cohort: PIK3CA mutant tumours
Comparison: FOCUS4-B
Intervention(s): Aspirin
Control: Placebo

Cohort: KRAS or NRAS mutant tumours
Comparison: FOCUS4-C
Intervention(s): Dual pathway inhibition using an AKT inhibitor and MEK inhibitor
Control: Dual Placebo

Cohort: EGFR dependent (BRAF, PIK3CA, KRAS, NRAS wild type)
Comparison: FOCUS4-D
Intervention(s): HER1, 2 and 3 inhibitor
Control: Placebo

Cohort: Non-stratified (patients whose biomarker panel results are unclassifiable or who are unable or unwilling to enter the trial available in their molecular cohort or the trial for their molecular cohort is not open to recruitment at that time). 
Comparison: FOCUS4-N
Intervention(s): Capecitabine
Control: Active monitoring (treatment break)
Study Hypothesis The primary objectives are to test:
1) In the interval following standard first-line chemotherapy, does the proposed intervention improve PFS compared with the control group in the biomarker-defined cohort?
2) Do the biomarkers used identify one or more patient cohorts with greater responsiveness to therapy than an unselected group?
Primary Outcome Measure(s) There are no primary outcome measures for the registration period as no interventions are being compared during this period.

The primary outcome measure for the subsequent trials that commence at the end of the registration period will be progression -free survival (PFS) which includes death from any cause as well as CT scan evidence that there is disease progression according to RECIST criteria. Analysis will be timed from randomisation with the baseline CT scan performed just prior to randomisation.

An additional primary outcome of overall survival may be evaluated for trials that progress to Stage III.
Secondary Outcome Measure(s) 1) Safety, toxicity, response, tumour shrinkage.
2) Quality of life (QL) may be assessed in any molecularly stratified trial where the release of interim results at the end of stage II leads to a decision to continue the trial to stage III. However, QL data may be collected at other stages if it is deemed to be important for that specific trial. QL will be assessed throughout FOCUS4-N from randomisation onwards.

Randomisation into any trial will not occur until the end of the 16 week registration period. Minimisation with a random element will be used for patient allocation and the randomisation ratio will be defined within each protocol. Generally this will be 2:1 in favour of the novel therapy (unless agent supply is limited or there is a 3-way randomisation).

Number of Patients to be Studied FOCUS4 is a rolling trials programme that utilises the MAMS design. The following numbers indicate the cumulative number of patients required to evaluate the current intervention up to the end of each interim analysis stage. Actual sample sizes may vary for each trial within these cohorts and are detailed in the specific protocols:
  • BRAF mutant = 61 (stage I), 97 (II), 139 (III), 301 (IV)
  • PIK3CA mutant/PTEN loss = 170 (I),264 (II), 373 (III), 264 (IV)
  • KRAS/NRAS mutant = 177 (I), 273 (II), 378(III), 574 (IV)
  • EGFR dependant (wildtype) = 180 (I), 275 (II), 381(III), 547 (IV)
  • FOCUS4-N: Target up to 643 patients.
Duration 7 years (4 to 5 years recruitment)
Ancillary Studies/Substudies 1) Biomarker development studies for mRNA based stratification in the all-wildtype cohort
2) Fresh tumour biopsies at randomisation and on progression from patients giving consent and with accessible tumour
3) Circulating Tumour DNA analysis
4) Sequencing of genes in candidate pathways from FFPE
5) Pharmacogenomic sub-studies
6) Pharmacodynamic sub-studies (for given cohorts)
Sponsor Medical Research Council
Funder NIHR/MRC EME programme and Cancer Research UK
Chief Investigators Overall: Professor Tim Maughan and Dr Richard Wilson

Each individual trial:

FOCUS4-A: Professor Gary Middleton
FOCUS4-B: Professor Richard Wilson/Dr David Church
FOCUS4-C: Professor Richard Wilson
FOCUS4-D: Dr Richard Adams
FOCUS4-N: Professor Tim Maughan