Clinical trial NCT04711109: Studying the Effect of Denosumab on Preventing Breast Cancer in Women With a BRCA1 Germline Mutation
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: BRCA1 Mutation
Breast Cancer
Breast Diseases
Breast Neoplasms
Breast Carcinoma
Neoplasms
Keywords: RANKL
Breast Cancer Prevention
Denosumab
Bone Density Conservation Agents
Physiological Effects of Drugs
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: Austrian Breast & Colorectal Cancer Study Group (ABCSG)
First posted: 2021-01-15
Enrollment: 300
Sex: FEMALE
Minimum age (years): 25
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility 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)

Primary outcomes:
measure: Time to the occurrence of any breast cancer (invasive or ductal carcinoma in situ [DCIS])
timeFrame: From randomization to the occurrence of breast cancer (invasive or DCIS), assessed up to 5 years
Secondary outcomes:
measure: Time to invasive breast cancer
timeFrame: Up to 5 years post treatment
measure: Time to invasive triple negative breast cancer
timeFrame: Up to 5 years post treatment
measure: Time to ovarian, fallopian and peritoneal cancer (in women who have not undergone prophylactic bilateral salpingo-oophorectomy)
timeFrame: Up to 5 years post treatment
measure: Time to other (nonbreast or ovarian cancer) malignancies, including those known to be associated with BRCA1 mutations
timeFrame: Up to 5 years post treatment
measure: Time to clinical fractures in pre- and postmenopausal women
timeFrame: Up to 5 years post treatment
measure: Frequency of breast biopsies
timeFrame: Up to 5 years post treatment
measure: Frequency of benign breast lesions
timeFrame: Up to 5 years post treatment
measure: Assess incidence, nature and severity of adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
timeFrame: Up to 5 years post treatment
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mount Zion
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Centers-Aurora
state: Colorado
city: Aurora
country: United States
facility: UCHealth University of Colorado Hospital
state: Colorado
city: Boulder
country: United States
facility: Rocky Mountain Cancer Centers-Boulder
state: Colorado
city: Centennial
country: United States
facility: Rocky Mountain Cancer Centers - Centennial
state: Colorado
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers-Midtown
state: Colorado
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers-Rose
state: Colorado
city: Englewood
country: United States
facility: Mountain Blue Cancer Care Center - Swedish
state: Colorado
city: Englewood
country: United States
facility: Rocky Mountain Cancer Centers - Swedish
state: Colorado
city: Littleton
country: United States
facility: Rocky Mountain Cancer Centers-Littleton
state: Colorado
city: Lone Tree
country: United States
facility: Rocky Mountain Cancer Centers-Sky Ridge
state: Colorado
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Evanston
country: United States
facility: NorthShore University HealthSystem-Evanston Hospital
state: Illinois
city: Highland Park
country: United States
facility: NorthShore University HealthSystem-Highland Park Hospital
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Overland Park
country: United States
facility: University of Kansas Hospital-Indian Creek Campus
state: Kansas
city: Westwood
country: United States
facility: University of Kansas Hospital-Westwood Cancer Center
state: Kansas
city: Scarborough
country: United States
facility: Maine Medical Center- Scarborough Campus
state: Maine
city: South Portland
country: United States
facility: Maine Medical Partners - South Portland
state: Maine
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Grand Rapids
country: United States
facility: Corewell Health Grand Rapids Hospitals - Butterworth Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Las Vegas
country: United States
facility: OptumCare Cancer Care at Fort Apache
state: Nevada
city: New York
country: United States
facility: NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Greensboro
country: United States
facility: Novant Health Breast Surgery - Greensboro
state: North Carolina
city: Kernersville
country: United States
facility: Novant Health Cancer Institute - Kernersville
state: North Carolina
city: Mount Airy
country: United States
facility: Novant Health Cancer Institute - Mount Airy
state: North Carolina
city: Thomasville
country: United States
facility: Novant Health Cancer Institute - Thomasville
state: North Carolina
city: Winston-Salem
country: United States
facility: Novant Health Forsyth Medical Center
state: North Carolina
city: Fargo
country: United States
facility: Sanford Roger Maris Cancer Center
state: North Dakota
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania/Abramson Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Burlington
country: United States
facility: University of Vermont Medical Center
state: Vermont
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Judy E. Garber, MD, MPH
role: STUDY_CHAIR
References: