Study to determine the preventive effect of denosumab on breast cancer in women carrying a BRCA1 germline mutation
| ISRCTN | ISRCTN77394655 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN77394655 |
| EudraCT/CTIS number | 2017-002505-35 |
| IRAS number | 1005699 |
| ClinicalTrials.gov number | NCT05382286 |
| Secondary identifying numbers | B00782, IRAS 1005699, CPMS 54435 |
- Submission date
- 14/09/2022
- Registration date
- 09/11/2022
- Last edited
- 12/02/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Plain English summary of protocol
https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-denosumab-and-the-risk-of-breast-cancer-in-women-with-changes-to-the-brca1-gene
Background and study aims
This is a preventional later-stage clinical trial in patients with breast cancer. The primary aim is to establish if there is a reduction in the risk of any invasive or ductal carcinoma in situ (occurring inside a milk duct of the breast) breast cancer in women with a germline BRCA1 mutation, a harmful gene variant that can be inherited from either parent when they are treated with the cancer drug denosumab compared to a dummy control drug (placebo).
Who can participate?
Women aged between 25 and 55 years old with a confirmed BRCA 1 germline deletion or likely deletion mutation
What does the study involve?
The study duration is projected to be a total of 12 years, comprising a 2-year enrolment phase, a 5-year treatment phase and a 5-year follow-up phase. The target recruitment is 2918 participants. Once consented, participants will be randomised in a 1:1 ratio using an interactive voice and/or web-based response system. Arm A will be treated with: Denosumab 120 mg by injection under the skin, every 6 months for a duration of 5 years. Arm B will be treated with the placebo comparator with the same routine.
Participation in the study will involve a screening/consent visit followed by treatment visits every 6 months for a duration of 5 years. Participants will then be followed up every 12 months for 5 years after the point that the last investigation product is administered.
What are the possible benefits and risks of participating?
The blood tests could cause pain and bruising. Only nurses experienced in phlebotomy will take blood samples in this study.
Denosumab may cause side effects which are listed in the PIS as follows:
Very Common side effects (which may affect more than 1 person in 10):
1. Low blood calcium
2. Shortness of breath
3. Muscle and bone pain
Common side effects (which may affect between 1 and 10 people in every 100):
1. Decreased phosphorus in the blood
2. Osteonecrosis of the jaw
3. Hair loss (alopecia)
Uncommon effects (which may affect between 1 and 10 people in every 1,000):
1. High blood calcium in patients with Giant Cell Tumor of Bone (GCTB) after stopping denosumab
2. Unusual thigh bone fracture (atypical femoral fracture
3. Rash that may occur on the skin or sores in the mouth (lichenoid drug eruption)
Rare side effects (which may affect between 1 and 10 people in every 10,000):
1. Allergic reaction (drug hypersensitivity)
2. Broken bones in your spine after stopping Denosumab
Where is the study run from?
Manchester University Hospital NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
June 2022 to June 2032
Who is funding the study?
1. Austrian Breast and Colorectal Cancer Study Group (ABCSG) (Austria)
2. Amgen (USA)
3. US Department of Defense (USA)
Who is the main contact?
Oncology Research Team, MFT.OncologyResearch@nhs.net (UK)
Contact information
Principal Investigator
Cobbet House
Oxford Road
Manchester
M13 9WL
United Kingdom
| Phone | +44 (0)161 291 4408 |
|---|---|
| gareth.evans9@nhs.net |
Scientific
Oglesby Cancer Research Building
Wilmslow Road
Manchester
M204BX
United Kingdom
 ORCID ID |
0000-0001-8141-6515 |
|---|---|
| Phone | +44 (0)161 291 4408 |
| Sacha.howell@nhs.net |
Public
Clinical Trials Management Office Research & Innovation
Wythenshawe Hospital
Southmoor Road
Manchester
M23 9QZ
United Kingdom
| Phone | +44 (0)161 291 4962 |
|---|---|
| karen.rhodes@mft.nhs.uk |
Study information
| Study design | Randomized placebo-controlled double-blind multi-centre prospective study |
|---|---|
| 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 to request a participant information sheet |
| Scientific title | BRCA-P: A randomized, double-blind, placebo-controlled, multi-center, international phase III Study to determine the preventive effect of denosumab on breast cancer in women carrying a BRCA1 germline mutation |
| Study acronym | BRCA-P |
| Study objectives | To evaluate the reduction in the risk of any breast cancer (invasive or DCIS) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo To determine the reduction in the risk of invasive breast cancer in women with germline BRCA1 mutation who are treated with denosumab compared to placebo To determine the reduction in the risk of invasive triple negative breast cancer (TNBC) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo To determine the reduction in risk of ovarian, fallopian and peritoneal cancers (in women who have not undergone PBSO) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo To determine the reduction in risk of other (i.e. non-breast and non-ovarian) malignancies, including those known to be associated with BRCA1 germline mutations in women with germline BRCA1 mutation who are treated with denosumab compared to placebo To determine the reduction in the risk of clinical fractures in pre- and postmenopausal women with germline BRCA1 mutation who are treated with denosumab compared to placebo |
| Ethics approval(s) | Approved 13/09/2022, Health and Care Research Wales (Address: not available; Tel: not available; HCRW.approvals@wales.nhs.uk, approvals@hra.nhs.uk), ref: 22/WA/0204 |
| Health condition(s) or problem(s) studied | Breast cancer |
| Intervention | Arm A (Experimental): Denosumab 120 mg subcutaneously, every 6 months (q6m) for 5 years. (Daily supplements, containing 500 mg elemental calcium and at least 400 I.U. vitamin D are highly recommended throughout the study treatment). Arm B (Placebo Comparator): Placebo sc, q6m for 5 years (Daily supplements, containing 500 mg elemental calcium and at least 400 I.U. vitamin D are highly recommended throughout study treatment). |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Denosumab |
| Primary outcome measure | Follow-up visits should be performed either as a clinic visit, telephone contact, email or other means of communication yearly. 1. Quality of Life measured using the self-reported questionnaires SF-12, Cancer Worry Scale, Impact of Events Scale (IES) and the Greene Climacteric Scale, (provided to perimenopausal/postmenopausal participants only), as well as a BRCA-P questionnaire provided to the participant at the following treatment visits: 6 months, 12 months, and every 12 months after that 2. Adverse events, fractures, oncologic events and oral events (ONJ) should be collected either by clinic visit, telephone contact, email or other means of communication at the end of treatment visit/contact, 6 months after the participant received the last dose of IP 3. Occurrence of new oncological events obtained from the participant and recorded in study records at each yearly follow-up visit/contact |
| Secondary outcome measures | 1. Occurrence of new clinical fractures and whether a diagnostic x-ray was performed obtained from the participant and recorded in study records at each yearly follow-up visit/contact 2. Atypical Femur Fracture occurrence proactively assessed during each clinical visit, phone or email contact and recorded in the participant’s study records 3. Osteonecrosis of the Jaw Assessment (ONJ) proactively assessed during each clinical visit, phone or email contact and recorded in the participant’s study records 4. Osteonecrosis of the external auditory canal proactively assessed during each clinical visit, phone or email contact and recorded in the participant’s study records |
| Overall study start date | 24/06/2022 |
| Completion date | 01/06/2032 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 25 Years |
| Upper age limit | 55 Years |
| Sex | Female |
| Target number of participants | 2918 |
| Total final enrolment | 3 |
| Key inclusion criteria | 1. Women with a confirmed deleterious or likely deleterious BRCA 1 germline mutation (Variant class 4 or 5) 2. Age ≥25 years and ≤55 years at randomization 3. No evidence of breast cancer by MRI or MG and clinical breast examination within the last 6 months prior to randomization 4. No clinical evidence of ovarian cancer at randomization 5. Negative pregnancy test at randomization for women of childbearing potential 6. Documentation that preventive breast surgery has been discussed as a potential treatment but is not planned at the time of randomization 7. Women for whom preventive medications (tamoxifen, raloxifene or aromatase inhibitors) are not indicated as the standard of care, or who have an intolerance of or opt not to take these drugs. 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 9. Written informed consent before any study-specific procedure is performed All individuals will be considered for inclusion in this study regardless of disability, marriage and civil partnership, maternity, race, religion and belief, and sexual orientation. |
| Key exclusion criteria | 1. Prior bilateral mastectomy 2. History of ovarian cancer (including fallopian tube and primary peritoneal cancer) 3. History of breast cancer 4. History of invasive cancer except for basal cell or squamous cell skin cancer. History of the following are also allowed: carcinoma in situ of the cervix, stage 1 papillary or follicular thyroid cancer, atypical hyperplasia or LCIS (Lobular Carcinoma In Situ) 5. Pregnant or lactating women (within the last 2 months prior to randomization) 6. Unwillingness to use highly effective contraception method during and within at least 5 months after cessation of denosumab/placebo therapy in women of childbearing potential. Clinically relevant hypocalcaemia (history and current condition), or serum calcium <2.0 mmol/L (<8.0 mg/dL) Hypocalcemia defined by calcium below the normal range (a single value below the normal range does not necessarily constitute hypocalcemia, but should be ‘corrected’ before dosing the participant). Monitoring of calcium level in regular intervals (usually prior to IP administration) is highly recommended 7. Tamoxifen, raloxifene or aromatase inhibitor use during the last 3 months prior to randomization or for a duration of more than 3 years in total (current and prior HRT is permitted) 8. Prior use of denosumab 9. Participant has a known prior history or current evidence of osteonecrosis or osteomyelitis of the jaw, or an active dental/jaw condition which requires oral surgery including tooth extraction within 3 months of enrollment 10. Concurrent treatment with a bisphosphonate or an anti-angiogenic agent 11. Any major medical or psychiatric condition that may prevent the participant from completing the study 12. Hepatic impairment (defined as known chronic liver disease such as alcoholic cirrhosis or chronic autoimmune hepatitis or transaminases (aspartate aminotransferase or alanine aminotransferase) >1.5x upper limit of the laboratory normal range. 13. Known active infection with Hepatitis B virus or Hepatitis C virus 14. Known infection with human immunodeficiency virus (HIV)Use of any other investigational product (current or prior Aspirin or NSAIDs are permitted) 15. Hypersensitivity to the active substance or to any of the excipients 16. Known rare hereditary problems of fructose intolerance |
| Date of first enrolment | 20/11/2022 |
| Date of final enrolment | 31/12/2024 |
Locations
Countries of recruitment
- Australia
- Austria
- Germany
- Israel
- Spain
- United Kingdom
Study participating centre
Manchester
M13 9WL
United Kingdom
Sponsor information
Other
1st Floor Nowgen
Grafton street
Manchester
M13 9WU
England
United Kingdom
| Phone | +44 (0)161 2766206 6206 |
|---|---|
| lynne.webster@mft.nhs.uk | |
| Website | https://mft.nhs.uk/ |
"ROR" |
https://ror.org/00he80998 |
Funders
Funder type
Other
No information available
Government organisation / For-profit companies (industry)
- Alternative name(s)
- Amgen Inc., Applied Molecular Genetics Inc.
- Location
- United States of America
Government organisation / National government
- Alternative name(s)
- United States Department of Defense, Department of Defense, U.S. Dept of Defense, US Department of Defense, DOD, USDOD
- Location
- United States of America
Results and Publications
| Intention to publish date | 01/06/2033 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | 1. Peer reviewed scientific journals 2. Conference presentation 3. Publication on website 4. Personal data would never be used for data analysis or presentation/publication. A data file would be generated which would not contain any patient identifiable information. This data file would be shared with appropriate researchers who have relevant approvals to use the data. Participants of this trial are asked to review and consent to their data being used for future research |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 1.0 | 01/04/2022 | 06/10/2022 | No | No |
| HRA research summary | 28/06/2023 | No | No |
Additional files
Editorial Notes
12/02/2025: A contact email was updated.
16/01/2025: Total final enrolment added.
20/11/2024: The recruitment end date was changed from 07/11/2024 to 31/12/2024.
04/04/2024: Contact details updated.
16/03/2023: Cancer Research UK plain English summary link added to plain English summary field.
02/12/2022: Internal review.
21/09/2022: ISRCTN received notification of combined HRA/MHRA approval for this trial on 21/09/2022
14/09/2022: Trial’s existence confirmed by the HRA.
