FOCUS4: Molecular selection of therapy in colorectal cancer

ISRCTN	ISRCTN90061546
DOI	https://doi.org/10.1186/ISRCTN90061546
EudraCT/CTIS number	2012-005111-12
Secondary identifying numbers	14893

Submission date: 16/10/2013
Registration date: 16/10/2013
Last edited: 26/04/2023

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-treatments-for-different-types-of-bowel-cancer-focus4

Study website

Contact information

Dr Cheryl Pugh
Scientific

MRC CTU
Aviation House
125 Kingsway
London
WC2B 6NH
United Kingdom

Email	mrcctu.focus4@ucl.ac.uk

Study information

Study design	Randomised; Interventional; Design type: Treatment
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	http://www.focus4trial.org/informationforpatients/furtherinformation
Scientific title	Molecular selection of therapy in colorectal cancer: a molecularly stratified randomised controlled trial programme
Study acronym	FOCUS4
Study objectives	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(s)	MREC; 10/05/2013; 13/SC/0111
Health condition(s) or problem(s) studied	Topic: National Cancer Research Network; Subtopic: Colorectal Cancer; Disease: Colon, Rectum
Intervention	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	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Capecitabine, sapitinib (AZD8931), adavosertib (AZD1775)
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 study start date	01/12/2013
Completion date	30/10/2020

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
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
Key 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
Key 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
Date of first enrolment	01/12/2013
Date of final enrolment	30/11/2017

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

MRC CTU

London
WC2B 6NH
United Kingdom

Sponsor information

The Medical Research Council (MRC) (UK)
Research council

The Medical Research Council Clinical Trials Unit at UCL
Institute of Clinical Trials & Methodology
Aviation House
125 Kingsway
London
WC2B 6NH
United Kingdom

"ROR"	https://ror.org/03x94j517

Funders

Funder type

Government

Cancer Research UK (UK)
Private sector organisation / Other non-profit organizations

Alternative name(s): CR_UK, Cancer Research UK - London, CRUK
Location: United Kingdom

Efficacy and Mechanism Evaluation Programme; Grant Codes: 11/100/50
Government organisation / National government

Alternative name(s): NIHR Efficacy and Mechanism Evaluation Programme, EME
Location: United Kingdom

Results and Publications

Intention to publish date	13/09/2021
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	The results from the primary analysis were published in September 2021 in the Journal of Clinical Oncology.
IPD sharing plan	The datasets generated during and/or analysed during the current study are/will be available upon request. All requests will be reviewed by the Data Sharing Committee at the MRC CTU at UCL and by the FOCUS4 Trial Management Group.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	pre-trial inter-laboratory analytical validation results	01/01/2016		Yes	No
Results article	FOCUS4-D results	01/03/2018		Yes	No
Results article	FOCUS4-C (adavosertib) results	20/09/2021	20/09/2021	Yes	No
Results article	FOCUS4-N results for capecitabine	13/09/2021	20/09/2021	Yes	No
Other publications	editorial discussing the evidence for treatment breaks following FOCUS4-N results	13/09/2021	26/01/2022	Yes	No
HRA research summary			28/06/2023	No	No

Editorial Notes

26/04/2023: Cancer Research UK plain English summary link updated in the plain English summary field.
26/01/2022: The following changes have been made:
1. Publication reference added.
2. The overall trial end date has been changed from 30/11/2017 to 31/10/2020.
3. The intention to publish date has been added.
4. The publication and dissemination plan has been added.
5. The individual participant data (IPD) sharing statement and the IPD sharing summary have been added.
30/12/2021: Internal review.
27/09/2021: Internal review.
20/09/2021: The following changes have been made:
1. Publication references added.
2. Adavosertib (AZD1775) and sapitinib (AZD8931) were added to the drug names.
3. The trial phase has been added.
15/02/2018: Publication reference added.