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

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ClinicalTrials.gov Identifier: NCT04711109
Recruitment Status : Recruiting
First Posted : January 15, 2021
Last Update Posted : November 1, 2023
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Austrian Breast & Colorectal Cancer Study Group (ABCSG)
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Study Description
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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:

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated 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 : February 23, 2022
Estimated Primary Completion Date : July 2027
Estimated Study Completion Date : December 2033

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Denosumab

Arms and Interventions
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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
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Primary Outcome Measures :
  1. Time to the occurrence of any breast cancer (invasive or ductal carcinoma in situ [DCIS]) [ Time Frame: 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 :
  1. Time to invasive breast cancer [ Time Frame: Up to 5 years post treatment ]
    Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.

  2. Time to invasive triple negative breast cancer [ Time Frame: Up to 5 years post treatment ]
    Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.

  3. Time to ovarian, fallopian and peritoneal cancer (in women who have not undergone prophylactic bilateral salpingo-oophorectomy) [ Time Frame: 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).

  4. Time to other (nonbreast or ovarian cancer) malignancies, including those known to be associated with BRCA1 mutations [ Time Frame: Up to 5 years post treatment ]
    Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.

  5. Time to clinical fractures in pre- and postmenopausal women [ Time Frame: Up to 5 years post treatment ]
    Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.

  6. Frequency of breast biopsies [ Time Frame: 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.

  7. Frequency of benign breast lesions [ Time Frame: 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.

  8. Assess incidence, nature and severity of adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: 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
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Ages Eligible for Study:   25 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04711109


Contacts
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Contact: Judy E. Garber, MD, MPH (617) 632-5961 judy_garber@dfci.harvard.edu

Locations
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Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Austrian Breast & Colorectal Cancer Study Group (ABCSG)
Investigators
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Study Chair: Judy E. Garber, MD, MPH Dana-Farber Cancer Institute
More Information
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Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT04711109    
Other Study ID Numbers: A211801
NCI-2020-11358 ( Registry Identifier: NCI Clinical Trial Reporting Program )
UG1CA189823 ( U.S. NIH Grant/Contract )
2017-002505-35 ( EudraCT Number )
ABCSG 50 ( Other Identifier: Austrian Breast & Colorectal Cancer Study Group )
First Posted: January 15, 2021    Key Record Dates
Last Update Posted: November 1, 2023
Last Verified: October 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alliance for Clinical Trials in Oncology:
RANKL
Breast Cancer Prevention
Denosumab
Bone Density Conservation Agents
Physiological Effects of Drugs
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms
Breast Diseases
Neoplasms by Site
 Skin Diseases
Denosumab
Bone Density Conservation Agents
Physiological Effects of Drugs