Condition category
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status
No longer recruiting
Publication status

Contact information



Primary contact

Dr Cheryl Pugh


Contact details

Aviation House
125 Kingsway
United Kingdom

Additional identifiers

EudraCT number

2012-005111-12 number

Protocol/serial number


Study information

Scientific title

Molecular selection of therapy in colorectal cancer: a molecularly stratified randomised controlled trial programme



Study hypothesis

FOCUS4 is an umbrella, or platform, for testing novel agents in biomarker-defined subpopulations of first-line advanced disease colorectal cancer patients who are not considered candidates for potentially curative surgery. It is also a trial of a new strategy for testing stratified approaches to therapy in any biologically complex tumour type. See Trial Schema in the Trial Protocol.
The backbone of the platform is 16 weeks of treatment with any standard first line colorectal cancer treatment, after which, as is frequently standard practice in the UK and Europe, there is a programmed treatment break for responding and stable patients. During that break, either new agent(s) or placebo is administered. The primary outcome measure for assessing the activity of the new treatment is progression free survival in the interval (time to death or progression requiring resumption of chemotherapy).
At present, four coherent biomarker-stratified groups can be identified and trials will be established in each of these cohorts as follows:
- BRAF mutant
- PIK3CA mutation or complete loss of PTEN on IHC
- KRAS or NRAS mutant
- All wild type (no mutations of BRAF, PIK3CA, KRAS or NRAS)
- Unclassified biomarker results
For each of these subgroups, a relevant novel agent or combination is to be tested in an adaptive double blind randomised trial design with multiple interim analyses for early termination if there is no strong evidence of worthwhile activity (the principles are derived from the Multi-Arm, Multi-Stage (MAMS) design).

FOCUS4 will open with one molecularly stratified trial (FOCUS4-D) testing AZD8931 (a HER 1,2 3 inhibitor) against placebo in patients stratified into the All wild-type cohort. In addition, a non-stratified trial (FOCUS4-N) will be open for patients whose biomarker results are unclassified or who are unable or unwilling to participate in the molecular trial available to them. The molecularly stratified trials for the BRAF, PIK3CA, KRAS/NRAS mutant cohorts are still in development and will be updated on this site when they open. Target recruitment levels will also be adjusted at that time.

Ethics approval

MREC; 10/05/2013; 13/SC/0111

Study design

Randomised; Interventional; Design type: Treatment

Primary study design


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet


Topic: National Cancer Research Network; Subtopic: Colorectal Cancer; Disease: Colon, Rectum


AZD8931 (for FOCUS4-D), HER 1,2 3 Inhibitor; Capecitabine (FOCUS4-N), Oral 5FU pro drug
Randomisation is performed using minimisation with a random element. Minimisation factors are based upon known prognostic factors for outcome.

For FOCUS4-D: The trial medication is orally administered twice daily over a continuous 28 day cycle. Patients are followed up every 4 weeks for symptoms and toxicity when they also collect their double-blind placebo controlled prescription from hospital pharmacy. CT scans are performed every 8 weeks to determine progression status of the tumour.

For FOCUS4-N: Capecitabine is an oral administration taken twice daily for 14 days followed by a 7 day break before recommencing the 21 day cycle. All patients from both arms are required to attend an outpatients appointment every 3-4 weeks to assess symptoms and toxicity and for those in the capecitabine arm, they need to collect their next prescription. All patients have a CT scan every 8 weeks to determine progression status of the tumour.

Intervention type



Not Applicable

Drug names


Primary outcome measure

Progression free survival, determined by multi-stage design of each molecular trial

Secondary outcome measures

Overall survival: becomes a joint primary outcome if the trial continues to the final stage analysis

Overall trial start date


Overall trial end date


Reason abandoned (if study stopped)


Participant inclusion criteria

Registration inclusion criteria (please refer to the protocol for eligibility for randomisation)
1. Male/female patients at least 18 years old
2. Formalin fixed paraffin embedded (FFPE) tumour block taken prior to the commencement of standard chemotherapy and available for biomarker analysis
3. Histologically confirmed adenocarcinoma of the colon/rectum
4. Inoperable metastatic or locoregional disease (synchronous or metachronous)
5. WHO performance status 0, 1 or 2
6. Unidimensionally measurable disease RECIST 1.1 classification
7. Have had an electronically accessible CT scan performed within 4 weeks prior to start of standard chemotherapy
8. Platelet count < 400 x 109/L prior to start of standard chemotherapy
9. For women of childbearing potential, a negative pregnancy test and acceptable contraceptive precautions
10. Effective contraception for male patients if the risk of conception exists
11. Consent for screening of an archival FFPE tumour block for biomarker analysis (PIS1 & CF1)
13. Patients should have sufficient capacity for informed consent and provided signed informed consent

Participant type


Age group




Target number of participants

Planned Sample Size (based upon FOCUS4-D and FOCUS4-N being open): 384; UK Sample Size: 384; Recruitment will be updated as other trials open

Participant exclusion criteria

Registration exclusion criteria (please refer to the protocol for eligibility for randomisation)
1. Previous systemic palliative chemotherapy using a different regimen for established advanced or metastatic disease
2. Adjuvant chemotherapy given in the last 6 months
3. Patients with brain metastases
4. Pregnant and lactating women

Recruitment start date


Recruitment end date



Countries of recruitment

United Kingdom

Trial participating centre

United Kingdom

Sponsor information


The Medical Research Council (MRC) (UK)

Sponsor details

The Medical Research Council Clinical Trials Unit at UCL
Institute of Clinical Trials & Methodology
Aviation House
125 Kingsway
United Kingdom

Sponsor type

Research council



Funder type


Funder name

Cancer Research UK (UK)

Alternative name(s)


Funding Body Type

private sector organisation

Funding Body Subtype

Other non-profit organizations


United Kingdom

Funder name

Efficacy and Mechanism Evaluation Programme; Grant Codes: 11/100/50

Alternative name(s)

NIHR Efficacy and Mechanism Evaluation Programme, EME

Funding Body Type

government organisation

Funding Body Subtype

National government


United Kingdom

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Basic results (scientific)

Publication list

2015 pre-trial inter-laboratory analytical validation results in:
2017 FOCUS4-D results in:

Publication citations

Additional files

Editorial Notes

15/02/2018: Publication reference added.