Studying the Effect of Denosumab on Preventing Breast Cancer in Women With a BRCA1 Germline Mutation
- Conditions
- BRCA1 MutationBreast CancerBreast DiseasesBreast NeoplasmsBreast CarcinomaNeoplasms
- Interventions
- Registration Number
- NCT04711109
- Lead Sponsor
- Alliance for Clinical Trials in Oncology
- Brief Summary
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.
- Detailed Description
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 and peritoneal cancers (in women who have not undergone prophylactic bilateral salpingo-oophorectomy \[PBSO\]) 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 nonovarian) 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.
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 the development of breast cancer or unacceptable toxicity.
ARM B: Patients receive placebo SC q6m for up to 5 years in the absence of the development of breast cancer.
After completion of study treatment, patients are followed up every 12 months for 5 years.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Female
- Target Recruitment
- 300
- 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
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Prior bilateral mastectomy
-
History of ovarian cancer (including fallopian and peritoneal cancer)
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History of breast cancer
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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)
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Pregnant or lactating women (within the last 2 months prior to randomization)
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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)
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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
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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)
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Prior use of denosumab
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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
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Concurrent treatment with a bisphosphonate or an anti-angiogenic agent
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Any major medical or psychiatric condition that may prevent the subject from completing the study
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Known active infection with hepatitis B virus or hepatitis C virus
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Known infection with human immunodeficiency virus (HIV)
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Use of any other investigational product (current or prior aspirin or non-steroidal anti-inflammatory drugs [NSAIDs] are permitted)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A (denosumab) Quality-of-Life Assessment Patients receive denosumab SC q6m for up to 5 years in the absence of disease progression or unacceptable toxicity. Arm B (placebo) Placebo Patients receive placebo SC q6m for up to 5 years in the absence of disease progression. Arm B (placebo) Quality-of-Life Assessment Patients receive placebo SC q6m for up to 5 years in the absence of disease progression. Arm A (denosumab) Denosumab Patients receive denosumab SC q6m for up to 5 years in the absence of disease progression or unacceptable toxicity.
- Primary Outcome Measures
Name Time Method Time to the occurrence of any breast cancer (invasive or ductal carcinoma in situ [DCIS]) From randomization to the occurrence of breast cancer (invasive or DCIS), assessed up to 5 years Time to breast cancer (invasive or DCIS) will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.
- Secondary Outcome Measures
Name Time Method Time to ovarian, fallopian and peritoneal cancer (in women who have not undergone prophylactic bilateral salpingo-oophorectomy) Up to 5 years post treatment Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model. Time to ovarian cancer will be analyzed in the overall group and in different strata (oral contraceptive use, hormone replacement therapy use, and menopausal status).
Time to invasive breast cancer Up to 5 years post treatment Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.
Time to invasive triple negative breast cancer Up to 5 years post treatment Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.
Time to other (nonbreast or ovarian cancer) malignancies, including those known to be associated with BRCA1 mutations Up to 5 years post treatment Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.
Time to clinical fractures in pre- and postmenopausal women Up to 5 years post treatment Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.
Frequency of breast biopsies Up to 5 years post treatment May be recommended as part of care based on a finding on mammogram, MRI, ultrasound or physical exam performed as part of monitoring for breast cancer. Will be compared between the two treatment arms via chi-square analysis.
Frequency of benign breast lesions Up to 5 years post treatment May be recommended as part of care based on a finding on mammogram, MRI, ultrasound or physical exam performed as part of monitoring for breast cancer. Will be compared between the two treatment arms via chi-square analysis.
Assess incidence, nature and severity of adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 Up to 5 years post treatment Overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment will be reported per treatment arm.
Trial Locations
- Locations (47)
USC / Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
UCSF Medical Center-Mount Zion
🇺🇸San Francisco, California, United States
Rocky Mountain Cancer Centers-Aurora
🇺🇸Aurora, Colorado, United States
UCHealth University of Colorado Hospital
🇺🇸Aurora, Colorado, United States
Rocky Mountain Cancer Centers-Boulder
🇺🇸Boulder, Colorado, United States
Rocky Mountain Cancer Centers - Centennial
🇺🇸Centennial, Colorado, United States
Rocky Mountain Cancer Centers-Midtown
🇺🇸Denver, Colorado, United States
Rocky Mountain Cancer Centers-Rose
🇺🇸Denver, Colorado, United States
Mountain Blue Cancer Care Center - Swedish
🇺🇸Englewood, Colorado, United States
Rocky Mountain Cancer Centers - Swedish
🇺🇸Englewood, Colorado, United States
Rocky Mountain Cancer Centers-Littleton
🇺🇸Littleton, Colorado, United States
Rocky Mountain Cancer Centers-Sky Ridge
🇺🇸Lone Tree, Colorado, United States
MedStar Georgetown University Hospital
🇺🇸Washington, District of Columbia, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸Chicago, Illinois, United States
NorthShore University HealthSystem-Evanston Hospital
🇺🇸Evanston, Illinois, United States
NorthShore University HealthSystem-Highland Park Hospital
🇺🇸Highland Park, Illinois, United States
Carle Cancer Center
🇺🇸Urbana, Illinois, United States
University of Kansas Hospital-Indian Creek Campus
🇺🇸Overland Park, Kansas, United States
University of Kansas Hospital-Westwood Cancer Center
🇺🇸Westwood, Kansas, United States
Maine Medical Center- Scarborough Campus
🇺🇸Scarborough, Maine, United States
Maine Medical Partners - South Portland
🇺🇸South Portland, Maine, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸Baltimore, Maryland, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
University of Michigan Comprehensive Cancer Center
🇺🇸Ann Arbor, Michigan, United States
Corewell Health Grand Rapids Hospitals - Butterworth Hospital
🇺🇸Grand Rapids, Michigan, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, United States
Regions Hospital
🇺🇸Saint Paul, Minnesota, United States
OptumCare Cancer Care at Fort Apache
🇺🇸Las Vegas, Nevada, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Novant Health Presbyterian Medical Center
🇺🇸Charlotte, North Carolina, United States
Novant Health Breast Surgery - Greensboro
🇺🇸Greensboro, North Carolina, United States
Novant Health Cancer Institute - Kernersville
🇺🇸Kernersville, North Carolina, United States
Novant Health Cancer Institute - Mount Airy
🇺🇸Mount Airy, North Carolina, United States
Novant Health Cancer Institute - Thomasville
🇺🇸Thomasville, North Carolina, United States
Novant Health Forsyth Medical Center
🇺🇸Winston-Salem, North Carolina, United States
Sanford Roger Maris Cancer Center
🇺🇸Fargo, North Dakota, United States
Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
University of Pennsylvania/Abramson Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
University of Pittsburgh Cancer Institute (UPCI)
🇺🇸Pittsburgh, Pennsylvania, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸Dallas, Texas, United States
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States
Huntsman Cancer Institute/University of Utah
🇺🇸Salt Lake City, Utah, United States
University of Vermont Medical Center
🇺🇸Burlington, Vermont, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸Richmond, Virginia, United States