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Trial registered on ANZCTR


Trial ID
ACTRN12614000694617
Ethics application status
Approved
Date submitted
26/06/2014
Date registered
2/07/2014
Date last updated
28/06/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
BRCA-D, a pilot study evaluating a new breast cancer prevention strategy for BRCA1 and BRCA2 mutation carriers and high risk, non-BRCA carriers.
Scientific title
A pre-operative window study evaluating the biological effects of the RANK-Ligand (RANKL) inhibitor Denosumab on normal breast tissue from BRCA1 and BRCA2 mutation carriers and high risk, non-BRCA carriers.
Secondary ID [1] 284864 0
Nil known
Universal Trial Number (UTN)
Trial acronym
BRCA-D
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast cancer 292266 0
Condition category
Condition code
Cancer 292621 292621 0 0
Breast
Human Genetics and Inherited Disorders 292622 292622 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Denosumab 120 mg monthly subcutaneous injections for 3 months
Intervention code [1] 289670 0
Prevention
Intervention code [2] 289698 0
Treatment: Drugs
Comparator / control treatment
No control
Control group
Uncontrolled

Outcomes
Primary outcome [1] 292460 0
Change in Ki67 expression assessed by immunohistochemistry in breast epithelium of BRCA1 mutation carriers.
Timepoint [1] 292460 0
Between baseline and after 3 months of denosumab
Secondary outcome [1] 309011 0
Safety and tolerability of denosumab. Measurements to evaluate this will include vital signs, clinical laboratory tests (haematology, hepatic, renal functions and assessment of albumin-adjusted calcium). Adverse events and project-specific adverse events (osteonecrosis of the jaw, hypocalccemia, wound complications and infections during related to surgery) will also be recorded.
Timepoint [1] 309011 0
Adverse events will be assessed up to 1 month after the last administration of denosumab. Project specific adverse events will also be recorded up to 3 months after the last administration of denosumab.
Secondary outcome [2] 309013 0
Change in c-KIT, ALDH1 and RANK immunostaining
Timepoint [2] 309013 0
Up to 42 days post-final dose of denosumab
Secondary outcome [3] 309014 0
Change in RANK and RANKL expression in epithelial and stromal cells assessed by immunohistochemistry and gene expression profile
Timepoint [3] 309014 0
Up to 42 days post-final dose of denosumab
Secondary outcome [4] 309015 0
Change in ER and PR expression and associated genes (e.g. BCL-2) using immunohistochemistry and gene expression profiling.
Timepoint [4] 309015 0
Up to 42 days post-final dose of denosumab
Secondary outcome [5] 309017 0
Change in luminal cell expression of CK5/6 using immunohistochemistry
Timepoint [5] 309017 0
Up to 42 days post-final dose of denosumab
Secondary outcome [6] 309018 0
Decrease in C-terminal telepeptide (CTX), calcium and free calcium levels using serum assay
Timepoint [6] 309018 0
Up to 42 days post-final dose of denosumab
Secondary outcome [7] 309019 0
Change in breast tissue parenchymal enhancement using BIRADS score on MRI scan
Timepoint [7] 309019 0
Up to 42 days post-final dose of denosumab

Eligibility
Key inclusion criteria
1. Documented BRCA1 or BRCA2 mutation, or high risk, non-BRCA carriers according to NBOCC guidelines
2. ECOG 0-1
3. Premenopausal status
4. Serum calcium or albumin adjusted calcium >2.0mmol/L and <2.9 mmol/L
5. Must agree to take Calcium and Vitamin D supplementation
6. Subjects with reproductive potential must be willing to use acceptable methods of effective contraception (with the exception of hormonal contraception)
Minimum age
18 Years
Maximum age
50 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. BRCA1 or BRCA2 variants that are considered to be non detrimental or where pathogenicity is unknown
2. Active breast cancer
3. Previous irradiation of the breast to be studied
4. Previous bilateral oophorectomy
5. Pregnancy and lactation
6. Hormonal contraception (Mirena IUD is allowed) with a washout period of at least 3 months prior to first dose of study drug
7. Endocrine therapy use in the last 6 months for the purpose of risk reduction
7. History of non-breast malignancies within the last 5 years, except cervical carcinoma in-situ, melanoma in-situ, skin BCC or SCC or Stage 1 thyroid cancer
8. Prior history or current evidence of osteonecrosis of the jaw
9. Active dental/jaw condition requiring oral surgery including tooth extraction
10. Previous treatment with denosumab

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 289479 0
Commercial sector/Industry
Name [1] 289479 0
Amgen
Address [1] 289479 0
115 Cotham Road, Kew, Victoria 3101
Country [1] 289479 0
Australia
Primary sponsor type
Hospital
Name
Melbourne Health
Address
The Royal Melbourne Hospital, 300 Grattan Street, Parkville, VIC 3050
Country
Australia
Secondary sponsor category [1] 288164 0
None
Name [1] 288164 0
Address [1] 288164 0
Country [1] 288164 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291236 0
Melbourne Health HREC Committee
Ethics committee address [1] 291236 0
The Royal Melbourne Hospital
300 Grattan Street
Parkville, Victoria, 3050
Ethics committee country [1] 291236 0
Australia
Date submitted for ethics approval [1] 291236 0
Approval date [1] 291236 0
17/03/2014
Ethics approval number [1] 291236 0
2014.015

Summary
Brief summary
This study will determine the effects of Denosumab on normal breast tissue in women with BRCA1 and BRCA2 mutations, as well as in women without BRCA mutations but who are at high risk of developing breast cancer based on family history.

Who is it for?
You may be eligible to join this study if you are a pre-menopausal woman aged between 18 years to 50 years and have documented BRCA1 or BRCA2 mutation considering prophylactic mastectomy, OR willing to undergo two breast biopsies on separate occasions. You may also be eligible if you are not known to carry a BRCA mutation, but meet certain criteria that would deem you to be at high risk of developing breast cancer due to your family history.

Study details
This is a proof-of-concept pilot study to determine if short-term treatment with Denosumab is a feasible chemoprevention option against breast cancer for BRCA1 and BRCA2 mutation carriers, as well as high risk, non-BRCA carriers. All women participating in the study will receive 3 doses of 120mg per dose of Denosumab subcutaneously (injected into the skin) monthly for three months. Women will then proceed to their surgery as planned, or have their second breast biopsy. Participants will be followed up for up to 3 months after the last treatment dose.

The change in the number of doses of Denosumab (from 4 to 3) was implemented in September 2015, after 6 patients had been enrolled.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 49446 0
Prof Geoffrey Lindeman
Address 49446 0
Department of Medical Oncology
The Royal Melbourne Hospital
300 Grattan Street
Parkville, 3050 Victoria
Country 49446 0
Australia
Phone 49446 0
+61-3-93427151
Fax 49446 0
Email 49446 0
lindeman@wehi.edu.au
Contact person for public queries
Name 49447 0
Ms Kylie Shackleton
Address 49447 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville, VIC 3052
Country 49447 0
Australia
Phone 49447 0
+61-3-9345-2805
Fax 49447 0
Email 49447 0
shackleton@wehi.edu.au
Contact person for scientific queries
Name 49448 0
Dr Sheau Wen Lok
Address 49448 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville, VIC 3052
Country 49448 0
Australia
Phone 49448 0
+61-3-9345-2805
Fax 49448 0
Email 49448 0
sheau.lok@mh.org.au