Contact information
Type
Public
Primary contact
Miss Jill Knox
ORCID ID
Contact details
Centre for Cancer Prevention
Wolfson Institute of Preventive Medicine
Charterhouse Square
London
EC1M 6BQ
United Kingdom
+44 (0)20 7882 3510
j.knox@qmul.ac.uk
Additional identifiers
EudraCT number
2014-004430-26
ClinicalTrials.gov number
Protocol/serial number
N/A
Study information
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
Acronym
IBIS 3 (Feasibility)
Study hypothesis
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
Hampstead Ethics Committee, 08/06/2015, ref: 15/LO/0833
Study design
Interventional multi-centre CTIMP RCT 2x2x2 factorial design
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
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
Phase
Phase III
Drug names
Aromatase inhibitor (anastrozole, letrozole or examestane), metformin, zoledronic acid
Primary outcome measures
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 trial start date
01/01/2014
Overall trial end date
31/12/2018
Reason abandoned
Eligibility
Participant 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.
Participant type
Patient
Age group
Adult
Gender
Female
Target number of participants
300
Participant 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
Recruitment start date
26/09/2016
Recruitment end date
25/09/2018
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Borders General Hospital
Melrose
TD6 9BS
United Kingdom
Trial participating centre
Weston Park Hospital
Sheffield
S10 2SJ
United Kingdom
Trial participating centre
Christie NHS Foundation Trust
Manchester
M20 4BX
United Kingdom
Trial participating centre
Cardiff University Hospital NHS Trust
Cardiff
CF14 4XW
United Kingdom
Trial participating centre
St Bartholomew's Hospital
London
EC1A 7BE
United Kingdom
Trial participating centre
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom
Trial participating centre
Imperial College Healthcare NHS Trust
Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom
Trial participating centre
Doncaster Royal Infirmary
Armthorpe Road
Doncaster
DN2 5LT
United Kingdom
Trial participating centre
Macclesfield District General Hospital
Victoria Road
Macclesfield
SK10 3BL
United Kingdom
Trial participating centre
North Tyneside General Hospital
Rake Lane
North Shields
NE29 8NH
United Kingdom
Trial participating centre
Pinderfields Hospital
Aberford Road
Wakefield
WF1 4DG
United Kingdom
Trial participating centre
Western General Hospital
Crewe Road
Edinburgh
EH4 2XU
United Kingdom
Trial participating centre
Poole Hospital NHS Foundation Trust
Longfleet Road
Poole
BH15 2JB
United Kingdom
Sponsor information
Organisation
Queen Mary University of London
Sponsor details
The Joint Research Management Office
Queen Mary
University of London
Queen Mary Innovation Centre
Lower Ground Floor
5 Walden Street
London
E1 2EF
United Kingdom
+44 (0)20 7882 7260
gerry.leonard@bartshealth.nhs.uk
Sponsor type
University/education
Website
Funders
Funder type
Charity
Funder name
Cancer Research UK
Alternative name(s)
Funding Body Type
private sector organisation
Funding Body Subtype
other non-profit
Location
United Kingdom
Funder name
Australia and New Zealand Breast Cancer Trials Group (ANZBCTG)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
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
Intention to publish date
31/12/2019
Participant level data
Not provided at time of registration
Results - basic reporting
Publication summary