Studying the Effect of Denosumab on Preventing Breast Cancer in Women with a BRCA1 Germline Mutation, the BRCA-P Trial
This phase III trial compares denosumab to usual care for the prevention of breast cancer in women with a BRCA1 germline mutation. A germline mutation is gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; germline mutations are passed on from parents to offspring. Denosumab is a monoclonal antibody that is used to treat bone loss in people who are at risk for bone fractures and for cancer patients whose cancer has spread to their bones. Denosumab may also decrease or prevent the risk of developing breast cancer in women carrying a BRCA1 germline mutation.
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 tube and primary peritoneal cancer)
- History of breast cancer
- 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 lobular carcinoma in situ (LCIS)
- 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
- Clinically relevant hypocalcemia (history and current condition), or serum calcium < 2.0 mmol/L (< 8.0 mg/dL) or corrected calcium (< 2.1 mmol/L) * 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 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)
- Any prior use of denosumab
- 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 =< 3 months prior enrollment
- Concurrent treatment with a bisphosphonate or an anti-angiogenic agent (washout period for bisphosphonates [e.g. Zoledronic Acid] is up to 6 months, therefore these medications need to be stopped >= 6 months before first IP administration the latest)
- Concurrent therapy with other Investigational Products (at enrollment or during trial treatment)
- Any major medical or psychiatric condition that may prevent the participant from completing the study
- Known active infection with hepatitis B virus or hepatitis C virus
- Known infection with human immunodeficiency virus (HIV)
- Hypersensitivity to the active substance or to any of the excipients
- Known rare hereditary problems of fructose intolerance
Additional locations may be listed on ClinicalTrials.gov for NCT04711109.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. To evaluate the reduction in the risk of any breast cancer (invasive or ductal carcinoma in situ [DCIS]) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.
SECONDARY OBJECTIVES:
I. 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.
II. 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.
III. To determine the reduction in risk of ovarian, fallopian tube cancers (in women who have not undergone prophylactic bilateral salpingo-oophorectomy [PBSO]) and primary peritoneal cancers in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.
IV. 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.
V. 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.
VI. To compare rates of breast biopsies and rate of benign breast lesions in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.
SAFETY OBJECTIVE:
I. To determine the safety profile of denosumab delivered at the study dose compared to placebo in pre- and postmenopausal women with germline BRCA1 mutation.
EXPLORATORY OBJECTIVES:
I. To determine the reduction in the risk of osteopenia and osteoporosis in pre- and postmenopausal women with germline BRCA1 mutation during denosumab treatment compared to placebo at sites/ countries where dual X-ray absorptiometry (DXA) is standard of care (SoC) or funded.
II. To identify serological and other markers that allow early diagnosis of breast cancer in BRCA1 mutation carriers.
III. To study the genetic, epigenetic, and phenotypic characteristics of cancers that occur during denosumab/placebo treatment.
IV. To study changes in bone turnover markers in pre- and postmenopausal women during denosumab/placebo treatment.
V. To study changes in hormone biomarkers including RANKL, OPG, LH, FSH, E2 and progesterone.
VI. To study changes in breast mammographic density, or breast background parenchymal enhancement on magnetic resonance imaging (MRI) using a Breast Imaging Reporting and Data System (BIRADs) score.
VII. To evaluate single nucleotide polymorphisms (SNPs) that have been associated with altered breast cancer risk, mammographic density, bone mineral density and any relationship to treatment effect.
VIII. To study the incidence of serous tubal in situ carcinoma (STIC), other precursor lesions and occult neoplasia in women who undergo risk-reducing bilateral salpingo-oophorectomy during the clinical trial.
IX. To study differences in arms in quality of life in all subjects, as well as menopausal symptoms in perimenopausal and postmenopausal subjects through questionnaires.
X. To study additional research questions / to perform additional analyses from biological material and / or clinical data that have been collected within this trial (upon decision of the steering committee and in alignment with the national study sponsors).
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive denosumab subcutaneously (SC) every 6 months (q6m) for up to 5 years in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples throughout the trial and may also undergo DXA throughout the trial.
ARM B: Patients receive placebo SC q6m for up to 5 years in the absence of disease progression. Patients also undergo collection of blood samples throughout the trial and may also undergo DXA throughout the trial.
After completion of study treatment, patients are followed up every 12 months for 5 years.
Trial PhasePhase III
Trial Typeprevention
Lead OrganizationAlliance for Clinical Trials in Oncology
Principal InvestigatorJudy Ellen Garber
- Primary IDA211801
- Secondary IDsNCI-2020-11358
- ClinicalTrials.gov IDNCT04711109