FEASIBILITY of IBIS 3. An International Breast Intervention Study investigating prevention of late recurrence in ER+ breast cancer survivors following 5 years of adjuvant treatment

ISRCTN	ISRCTN93764730
DOI	https://doi.org/10.1186/ISRCTN93764730
EudraCT/CTIS number	2014-004430-26

Submission date: 21/11/2014
Registration date: 11/12/2014
Last edited: 18/06/2020

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

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-extended-treatment-following-5-years-hormone-therapy-breast-cancer-ibis-3-feasibility

Study website

Contact information

Prof Jack Cuzick
Public

Centre for Cancer Prevention
Wolfson Institute of Preventive Medicine
Charterhouse Square
London
EC1M 6BQ
United Kingdom

Phone	+44 (0)20 7882 3518
Email	j.cuzick@qmul.ac.uk

Dr Mangesh Thorat
Scientific

Centre for Cancer Prevention
Wolfson Institute of Preventive Medicine
Barts & The London School of Medicine and Dentistry
Queen Mary University of London
London
EC1M 6BQ
United Kingdom

ORCID ID	0000-0001-8673-5320
Phone	+44 (0)20 7882 3890 (fax)
Email	m.thorat@qmul.ac.uk

Study information

Study design	Interventional multi-centre CTIMP RCT 2x2x2 factorial design
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	FEASIBILITY of IBIS 3. An International Breast Intervention Study investigating prevention of late recurrence in ER+ breast cancer survivors following 5 years of adjuvant treatment
Study acronym	IBIS 3 (Feasibility)
Study objectives	IBIS 3 is designed to continue the work of IBIS-I and IBIS-II in determining whether a chemo-preventive strategy towards breast cancer is effective. Late recurrence of oestrogen receptor positive (ER+) breast cancer is a well-known problem, with high recurrence rates being seen for at least 20 years after diagnosis. In fact, over half of all recurrences in ER+ breast cancer occur more than 5 years after the primary tumour diagnosis. These include true recurrences and new primary tumours. Although reduced from about 2.5%/year with tamoxifen to 2%/year with 5 years of an aromatase inhibitor in the ATAC trial, the 10 year recurrence rate does not fall below 2%/year (Cuzick et al, 2010). The ATAC trial indicates that ER, PgR and HER2 do not provide substantial prognostic information in the post 5-year treatment period. It shows that Ki-67 has a minimal effect whereas baseline nodal status and tumour size (≥ 2cm) continue to have prognostic value (Sestak et al, 2013). Late re-treatment of breast cancer is an important approach for dealing with the problem of late recurrence. Diminished endocrine control is well documented and other new or synergistic approaches are likely to be more effective. This approach will also inform on the preventive action of these agents both alone and in combination not only on elimination of metastases but also on new primary tumours. Because a substantial number of late recurrences are in fact new tumours, this approach will also inform on the preventive action of these agents both alone and in combination. The main IBIS 3 trial will directly address the issue of late recurrence in breast cancer survivors. The main goal will be to reduce late recurrence with the combination of three different drug therapies. Specifically, it will evaluate the impact of metformin and/or an aromatase inhibitor (anastrozole or letrozole or exemestane) and/or zoledronic acid in a 2x2x2 factorial trial. Of particular interest will be any positive detection of any synergism between these agents. The main trial will explore mechanisms of drug action and identify which patients are at greatest risk of late recurrence, including both local, regional and distant metastases of the primary tumour as well as new tumours (mostly contralateral), using a range of tests which may include circulating tumour DNA, IHC4, PAM50, and tumour methylation profiles. This feasibility study will look at the viability of recruiting to the main trial; assess recruitment rates, inform on number of sites required for the main trial, treatment adherence and the use of recruiting through GP surgeries local to sites via the PCRN/LCRN. The study will also determine the feasibility of the use of email for data collection of PROs from patients and assess the acceptability of investigations, such as providing blood samples and questionnaires required for the main trial. The decision rule for moving to the main trial will be recruitment of at least 80 patients within a year and that at least 20% of eligible patients approached agree to join the trial.
Ethics approval(s)	Hampstead Ethics Committee, 08/06/2015, ref: 15/LO/0833
Health condition(s) or problem(s) studied	Hormone receptor positive breast cancer recurrence
Intervention	Metformin and zoledronic acid will be evaluated when combined with an aromatase inhibitor (anastrozole, letrozole or examestane) in a 2x2x2 factorial design.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase III
Drug / device / biological / vaccine name(s)	Aromatase inhibitor (anastrozole, letrozole or examestane), metformin, zoledronic acid
Primary outcome measure	Primary objective is to determine acceptability and feasibility of recruitment, recruitment rate and number of sites required for main trial. Primary endpoint is the recruitment of 100 patients within 12 months. Assessment method is recruitment numbers via randomisation figures and screening logs.
Secondary outcome measures	Secondary objectives are: 1. To determine reasons for non-participation/drop-outs and address these for main trial (endpoint: recruitment and follow-up of 100 patients; assessment method: analysis of screening logs to understand reasons for non-participation) 2. To evaluate treatment adherence and reasons for stopping (endpoint: 6 monthly follow-up; assessment method: data collected on CRFs, PROs [FACT-ES, EQ5DL], Kaplan Meier curves) 3. To determine reasons for non-adherence and address for main trial (endpoint: 6 monthly follow-up; assessment method: data collected on CRFs, PROs [FACT-ES, EQ5DL]) 4. To assess the use of referral through GP surgeries as PICs local to sites via the PCRN/LCRN (endpoint: the recruitment of 100 patients; assessment method: recruitment method captured by CRF and assessment of referral letters) 5. To investigate feasibility of the use of email for data collection of PROs from patients (enpoint: at baseline + asked again at 12 and 24 months to see if email use increases with time; assessment method: comparison of numbers of patients providing data by email or by post and quality and completeness of that data) 6. To assess acceptability of investigations for main trial (endpoint: at 12 months and ongoing until trial ends; assessment method: number of patients providing blood samples [data on CRF], PRO data [FACT-ES, EQ5DL])
Overall study start date	01/01/2014
Completion date	26/03/2018
Reason abandoned (if study stopped)	Participant recruitment issue

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Female
Target number of participants	300
Total final enrolment	89
Key inclusion criteria	Current inclusion criteria as of 30/03/2017: 1. Informed Consent 2. ≤ 75 years 3. Post-menopausal women confirmed by previous AI use only 4. Previous ER+ breast cancer treated by endocrine therapy. ER+ is equivalent to an Allred/Quick score of 3 or above. Additional treatment with trastuzumab (if Her2+) and chemotherapy are allowed. 5. Surgery for breast cancer plus 5 years adjuvant endocrine therapy (at least 4 years with AI completed within the last 6 years; therefore 5-11 years from diagnosis) 6. Breast cancer must have been node positive AND/OR ≥2cm in size (measurement based on invasive tumour) 7. A bilateral mammogram (unless unilateral mastectomy in which case unilateral mammogram) must have been taken within the last year and not show any evidence of breast cancer. Women who have had a bilateral mastectomy, where contralateral mastectomy was either prophylactic or was performed to treat breast cancers diagnosed at the same time, are eligible and a mammogram is not required in this case. 8. A baseline bone mineral density (BMD) scan within the last year; DXA must include hip (femoral neck or proximal femur) AND lumbar spine and can include forearm. 9. Low BMD (where T-score is -4.0 ≤T≤ -2.0) women are eligible for metformin and aromatase inhibitor treatments. This must be managed in accordance with local clinical procedures for treatment of osteoporosis i.e., take bisphosphonate treatment and have regular DXA scans Previous inclusion criteria: 1. Informed consent 2. ≤ 75 years old 3. Post-menopausal women (defined as at least 12 months since last period) 4. Previous ER+ (or PR+) breast cancer treated by endocrine therapy. ER+ is equivalent to an Allred/Quick score of 3 or above. Additional trastuzumab (if Her2+) and chemotherapy are allowed. 5. Surgery for breast cancer plus 4-6 years adjuvant endocrine therapy (at least 4 years with AI completed within the last 3 years; therefore maximum of 9 years from diagnosis) 6. Breast cancer must have been node positive (macrometastases) AND/OR ≥2cm 7. A bilateral mammogram (unless unilateral mastectomy in which case unilateral mammogram) must have been taken within the last year and not show any evidence of breast cancer. Women who have had a bilateral mastectomy are eligible and a mammogram is not required in this case. 8. A baseline bone mineral density scan within the last year; DXA must include hip (femoral neck or proximal femur) AND lumbar spine and can include forearm. 9. Low BMD (where T-score is -4.0 ≤T≤ -2.0) and no more than one known low trauma vertebral fracture AND/OR high FRAX score (http://www.shef.ac.uk/FRAX/tool.aspx) are eligible for metformin and aromatase inhibitor treatments. This must be managed in accordance with local clinical procedures for treatment of osteoporosis i.e., take bisphosphonate treatment and have regular DXA scans.
Key exclusion criteria	Current exclusion criteria as of 30/03/2017: 1. Any recurrence or clinical suspicion of active breast cancer (including DCIS) 2. Any other previous cancer (apart from original breast cancer) (except non-melanoma skin cancer or in situ cancer of the cervix). 3. Current (or intended) use of oestrogen-based hormone replacement therapy (HRT) 4. Type I diabetes 5. Type II diabetes AND osteoporosis 6. T-scores of less than minus four, or two or more known low trauma vertebral fractures 7. Abnormal renal function as classified as eGFR < 45mls/min. – If possible the CKD-EP1 equation should be used to calculate eGFR but the Cockroft-Gault formula is acceptable. See Appendix 3 for formulae and dose reduction schedule. 8. Any severe concomitant disease, e.g congestive cardiac failure, that would, at the discretion of the investigator, put patient at unusual risk or confounds the results of the study. Reference should be made to the appropriate Summary of Product Characteristics (SmPC) of each study drug 9. Current continual treatment with glucocorticoids for 4 weeks or more 10. Any medical condition that would significantly interfere with the ability to accept the study drugs. 11. Psychologically and physically unsuitable for two years of drug therapy. 12. Treatment with an unlicensed or experimental drug during 30 days before randomisation. Excluded from metformin randomisation only 13. Type II diabetics (or those with baseline fasting glucose > 7.0 mmol/L) but must be on antidiabetic medication 14. Known hypersensitivity or intolerance to metformin 15. Currently taking meglitinides, sulfonylureas, thiazolidinediones (glitazones) or insulin 16. History of acidosis of any type 17. Habitual intake of 3 or more units of alcohol per day Excluded from zoledronic randomisation only 18. Low BMD (where T-score is -4.0 ≤T≤ -2.0). This must be managed in accordance with local clinical procedures for treatment of osteoporosis i.e., take bisphosphonate treatment and have regular DXA scans. See Appendix 4 for definitions. Excluded from AI randomisation only 19. Currently being treated by extended AI 20. Current use (or intention to use) raloxifene, tamoxifen or any other SERM Previous exclusion criteria: 1. Any recurrence or clinical suspicion of active breast cancer (including DCIS) 2. Any other previous cancer (apart from original breast cancer) in the past 5 years (except non-melanoma skin cancer or in situ cancer of the cervix) 3. Current treatment (or intended use) of oestrogen-based hormone replacement therapy (HRT) 4. Type I diabetes 5. Diabetes (Types I and II) AND osteoporosis 6. T-scores of less than minus four, or two or more known low trauma vertebral fractures 7. Abnormal renal function as classified as eGFR < 40ml/min. If possible the CKD-EP1 equation should be used to calculate eGFR but the Cockroft-Gault formula is acceptable 8. Any severe concomitant disease, e.g. congestive cardiac failure, that would, at the discretion of the investigator, put patient at unusual risk or confounds the results of the study. Reference should be made to the appropriate Summary of Product Characteristics (SmPC) of each study drug 9. Current continual treatment with glucocorticoids for 4 weeks or more 10. Any medical condition that would significantly interfere with the ability to accept the study drugs 11. Psychologically and physically unsuitable for two years of drug therapy 12. Treatment with an unlicensed or experimental drug during 30 days before randomisation Excluded from metformin randomisation only: 1. Type II diabetics (or those with baseline fasting glucose > 7.0 mmol/L) but must be on antidiabetic medication 2. Known hypersensitivity or intolerance to metformin 3. Currently taking meglitinides, sulfonylureas, thiazolidinediones (glitazones) or insulin 4. History of acidosis of any type 5. Habitual intake of three or more units of alcohol per day Excluded from zoledronic randomisation only: 1. Low BMD (where T-score is -4.0 ≤T≤ -2.0) and no more than one known low trauma vertebral fracture AND/OR high FRAX score (http://www.shef.ac.uk/FRAX/tool.aspx) Excluded from AI randomisation only: 1. Currently being treated by extended AI 2. Current use (or intention to use) raloxifene, tamoxifen or any other SERM
Date of first enrolment	26/09/2016
Date of final enrolment	26/09/2017

Locations

Countries of recruitment

England
Scotland
United Kingdom
Wales

Study participating centres

Borders General Hospital

Melrose
TD6 9BS
United Kingdom

Weston Park Hospital

Sheffield
S10 2SJ
United Kingdom

Christie NHS Foundation Trust

Manchester
M20 4BX
United Kingdom

Cardiff University Hospital NHS Trust

Cardiff
CF14 4XW
United Kingdom

St Bartholomew's Hospital

London
EC1A 7BE
United Kingdom

Ninewells Hospital

Dundee
DD1 9SY
United Kingdom

Imperial College Healthcare NHS Trust

Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom

Doncaster Royal Infirmary

Armthorpe Road
Doncaster
DN2 5LT
United Kingdom

Macclesfield District General Hospital

Victoria Road
Macclesfield
SK10 3BL
United Kingdom

North Tyneside General Hospital

Rake Lane
North Shields
NE29 8NH
United Kingdom

Pinderfields Hospital

Aberford Road
Wakefield
WF1 4DG
United Kingdom

Western General Hospital

Crewe Road
Edinburgh
EH4 2XU
United Kingdom

Poole Hospital NHS Foundation Trust

Longfleet Road
Poole
BH15 2JB
United Kingdom

Sponsor information

Queen Mary University of London
University/education

The Joint Research Management Office
Queen Mary, University of London
Queen Mary Innovation Centre
Lower Ground Floor
5 Walden Street
London
E1 2EF
England
United Kingdom

Phone	+44 (0)20 7882 7260
Email	gerry.leonard@bartshealth.nhs.uk
"ROR"	https://ror.org/026zzn846

Funders

Funder type

Charity

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

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

Australia and New Zealand Breast Cancer Trials Group (ANZBCTG)

No information available

Results and Publications

Intention to publish date	31/12/2020
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Planned publication in a high-impact peer reviewed journal.
IPD sharing plan	The datasets generated during and/or analysed during the current study are/will be available upon request from ibis3@qmul.ac.uk

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Plain English results				No	Yes
Basic results			11/06/2020	No	No
Abstract results	barriers to recruitment presented at 4th International Clinical Trials Methodology Conference (ICTMC) and the 38th Annual Meeting of the Society for Clinical Trials	01/05/2017	16/06/2020	No	No
HRA research summary			28/06/2023	No	No

Editorial Notes

18/06/2020: A scientific contact has been added.
16/06/2020: The following changes have been made:
1. Publication reference added.
2. The Overall trial status has been changed to "Stopped" as the trial was stopped early due to participant recruitment issues.
11/06/2020: The following changes have been made:
1. The link to the basic results of this trial have been added.
2. The total final enrolment number has been added.
11/06/2020: Contact details updated. The intention to publish date was changed from 31/12/2019 to 31/12/2020.
03/09/2019: Cancer Research UK lay results summary link added to Results (plain English).
15/03/2019: Internal review.
11/03/2019: The public contact was updated.
11/12/2018: The overall trial end date was changed from 31/12/2018 to 26/03/2018.
13/11/2017: Recruitment end date has been updated from 25/09/2018 to 26/09/2017.
30/03/2017: Total target enrollment has changed from 100 to 300. Recruitment dates changed from 01/05/2016 - 30/06/2016 to 26/09/2016 - 25/09/2018. Overall trial end date changed from 31/08/2017 to 31/12/2018. Removed North Bristol NHS Trust, Royal Marsden and Aberdeen Royal Infirmary as trial participating centres. Added Borders General Hospital, Imperial College Healthcare NHS Trust Charing Cross Hospital, Doncaster Royal Infirmary, Macclesfield District General Hospital, North Tyneside General Hospital, Pinderfields Hospital, Western General Hospital, Poole Hospital NHS Foundation Trust as trial participating centres. Added participant level data sharing plan and intention to publish date.
04/11/2017: Cancer Help UK lay summary link added to plain English summary field.
29/03/2016: Ethics approval information added.