A Randomized, Double-Blind, Placebo-Controlled, Multi-Center, International Phase 3 Study to Determine the Preventive Effect of Denosumab on Breast Cancer in Women Carrying a BRCA1 Germline Mutation

Protocol # :
BRCA1 Mutation
Breast Cancer
Breast Diseases
Breast Neoplasms
Breast Carcinoma
Disease Sites
Principal Investigator
Garber, Judy, E

Trial Description

This phase III trial compares denosumab to placebo for the prevention of breast cancer in
women with a BRCA1 germline mutation. A germline mutation is an inherited gene change which,
in the BRCA1 gene, is associated with an increased risk of breast and other cancers.
Denosumab is a monoclonal antibody that is used to treat bone loss in order to reduce the
risk of bone fractures in healthy people, and to reduce new bone growths in cancer patients
whose cancer has spread to their bones. Research has shown that denosumab may also reduce the
risk of developing breast cancer in women carrying a BRCA1 germline mutation.

Eligibility Requirements

Inclusion Criteria:

- Women with a confirmed deleterious or likely deleterious BRCA 1 germline mutation
(variant class 4 or 5)

- Age >= 25 years and =< 55 years at randomization

- No evidence of breast cancer by MRI or mammography (MG) and clinical breast
examination within the last 6 months prior to randomization

- No clinical evidence of ovarian cancer at randomization

- Negative pregnancy test at randomization for women of childbearing potential

- No preventive breast surgery planned at time of randomization

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Written informed consent before any study-specific procedure is performed

Exclusion Criteria:

- Prior bilateral mastectomy

- History of ovarian cancer (including fallopian and peritoneal cancer)

- History of breast cancer

- History of invasive cancer except for basal cell or squamous cell skin cancer or
carcinoma in situ of the cervix, stage 1 papillary or follicular thyroid cancer,
atypical hyperplasia or LCIS (lobular carcinoma in situ)

- Pregnant or lactating women (within the last 2 months prior to randomization)

- 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. (Note: Women of childbearing potential should be monitored for pregnancy
prior to each denosumab/placebo injection)

- Clinically relevant hypocalcemia (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 subject). Monitoring of calcium level in regular intervals (usually
prior to investigational product [IP] administration) is highly recommended

- 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
hormone replacement therapy [HRT] is permitted)

- Prior use of denosumab

- Subject 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

- Concurrent treatment with a bisphosphonate or an anti-angiogenic agent

- Any major medical or psychiatric condition that may prevent the subject from
completing the study

- Known active infection with hepatitis B virus or hepatitis C virus

- Known infection with human immunodeficiency virus (HIV)

- Use of any other investigational product (current or prior aspirin or non-steroidal
anti-inflammatory drugs [NSAIDs] are permitted)