Studying the Effect of Denosumab on Preventing Breast Cancer in Women With a BRCA1 Germline Mutation

Breast Cancer Clinical Trial

— BRCA-P  

Official title:

BRCA-P: 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04711109
• Other study ID #: A211801
• Secondary ID: NCI-2020-11358UG
• Status: Recruiting
• Phase: Phase 3
• Start date: February 14, 2023
• Est. completion date: December 2033

Study information

• Verified date: May 2024
• Source: Alliance for Clinical Trials in Oncology
• Contact: Judy E. Garber, MD, MPH
• Phone: (617) 632-5961
• Email: judy_garber[@]dfci.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: December 2033
• Est. primary completion date: July 2027
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 25 Years to 55 Years

Eligibility

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)

Related Conditions & MeSH terms

• BRCA1 Mutation
• Breast Cancer
• Breast Carcinoma
• Breast Diseases
• Breast Neoplasms
• Neoplasms

Intervention

Drug:
• Denosumab
Given SC
• Placebo
Given SC

Other:
• Quality-of-Life Assessment
Ancillary studies

Locations

Country	Name	City	State
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Rocky Mountain Cancer Centers-Aurora	Aurora	Colorado
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado
United States	University of Vermont Medical Center	Burlington	Vermont
United States	Rocky Mountain Cancer Centers - Centennial	Centennial	Colorado
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
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	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Corewell Health Grand Rapids Hospitals - Butterworth Hospital	Grand Rapids	Michigan
United States	Novant Health Breast Surgery - Greensboro	Greensboro	North Carolina
United States	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois
United States	M D Anderson Cancer Center	Houston	Texas
United States	Novant Health Cancer Institute - Kernersville	Kernersville	North Carolina
United States	OptumCare Cancer Care at Fort Apache	Las Vegas	Nevada
United States	Rocky Mountain Cancer Centers-Littleton	Littleton	Colorado
United States	Rocky Mountain Cancer Centers-Sky Ridge	Lone Tree	Colorado
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Novant Health Cancer Institute - Mount Airy	Mount Airy	North Carolina
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	University of Kansas Hospital-Indian Creek Campus	Overland Park	Kansas
United States	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	UCSF Medical Center-Mount Zion	San Francisco	California
United States	Maine Medical Partners - South Portland	South Portland	Maine
United States	Novant Health Cancer Institute - Thomasville	Thomasville	North Carolina
United States	Carle Cancer Center	Urbana	Illinois
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Novant Health Forsyth Medical Center	Winston-Salem	North Carolina

Sponsors (3)

Lead Sponsor	Collaborator
Alliance for Clinical Trials in Oncology	Austrian Breast & Colorectal Cancer Study Group (ABCSG), National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to the occurrence of any breast cancer (invasive or ductal carcinoma in situ [DCIS])	Time to breast cancer (invasive or DCIS) will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.	From randomization to the occurrence of breast cancer (invasive or DCIS), assessed up to 5 years
Secondary	Time to invasive breast cancer	Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.	Up to 5 years post treatment
Secondary	Time to invasive triple negative breast cancer	Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.	Up to 5 years post treatment
Secondary	Time to ovarian, fallopian and peritoneal cancer (in women who have not undergone prophylactic bilateral salpingo-oophorectomy)	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).	Up to 5 years post treatment
Secondary	Time to other (nonbreast or ovarian cancer) malignancies, including those known to be associated with BRCA1 mutations	Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.	Up to 5 years post treatment
Secondary	Time to clinical fractures in pre- and postmenopausal women	Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.	Up to 5 years post treatment
Secondary	Frequency of breast biopsies	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.	Up to 5 years post treatment
Secondary	Frequency of benign breast lesions	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.	Up to 5 years post treatment
Secondary	Assess incidence, nature and severity of adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0	Overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment will be reported per treatment arm.	Up to 5 years post treatment