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

Sponsor

Alliance for Clinical Trials in Oncology (Other)

Overall Status

Recruiting

CT.gov ID

NCT04711109

Collaborator

National Cancer Institute (NCI) (NIH), Austrian Breast & Colorectal Cancer Study Group (ABCSG) (Other)

300

Enrollment

Locations

Arms

141.2

Anticipated Duration (Months)

23.1

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
BRCA1 Mutation Breast Cancer Breast Diseases Breast Neoplasms Breast Carcinoma Neoplasms	Drug: Denosumab Drug: Placebo Other: Quality-of-Life Assessment	Phase 3

Detailed Description

PRIMARY OBJECTIVE:

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:

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.
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.
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.
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.
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.
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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Prevention

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

Actual Study Start Date :

Feb 23, 2022

Anticipated Primary Completion Date :

Jul 1, 2027

Anticipated Study Completion Date :

Dec 1, 2033

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (denosumab) Patients receive denosumab SC q6m for up to 5 years in the absence of disease progression or unacceptable toxicity.	Drug: Denosumab Given SC Other: Quality-of-Life Assessment Ancillary studies
Placebo Comparator: Arm B (placebo) Patients receive placebo SC q6m for up to 5 years in the absence of disease progression.	Drug: Placebo Given SC Other: Quality-of-Life Assessment Ancillary studies

Arm

Intervention/Treatment

Experimental: Arm A (denosumab)

Patients receive denosumab SC q6m for up to 5 years in the absence of disease progression or unacceptable toxicity.

Drug: Denosumab

Given SC

Other: Quality-of-Life Assessment

Ancillary studies

Placebo Comparator: Arm B (placebo)

Patients receive placebo SC q6m for up to 5 years in the absence of disease progression.

Drug: Placebo

Given SC

Other: Quality-of-Life Assessment

Ancillary studies

Outcome Measures

Primary Outcome Measures

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

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 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 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

25 Years to 55 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rocky Mountain Cancer Centers-Aurora	Aurora	Colorado	United States	80012
2	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado	United States	80304
3	Rocky Mountain Cancer Centers - Centennial	Centennial	Colorado	United States	80112
4	Rocky Mountain Cancer Centers-Midtown	Denver	Colorado	United States	80218
5	Rocky Mountain Cancer Centers-Rose	Denver	Colorado	United States	80220
6	Mountain Blue Cancer Care Center - Swedish	Englewood	Colorado	United States	80113
7	Rocky Mountain Cancer Centers - Swedish	Englewood	Colorado	United States	80113
8	Rocky Mountain Cancer Centers-Littleton	Littleton	Colorado	United States	80120
9	Rocky Mountain Cancer Centers-Sky Ridge	Lone Tree	Colorado	United States	80124
10	Carle Cancer Center	Urbana	Illinois	United States	61801
11	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
12	Sanford Roger Maris Cancer Center	Fargo	North Dakota	United States	58122
13	M D Anderson Cancer Center	Houston	Texas	United States	77030