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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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BRCA1 Mutation, Breast Cancer, Breast Diseases, Breast Neoplasms, Breast Carcinoma, Neoplasms

Intervention / Treatment
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* Drug: Denosumab
* Drug: Placebo
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RANKL, Breast Cancer Prevention, Denosumab, Bone Density Conservation Agents, Physiological Effects of Drugs