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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 : Not yet recruiting
First Posted : January 15, 2021
Last Update Posted : March 3, 2021
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Austrian Breast & Colorectal Cancer Study Group (ABCSG)
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Tracking Information
First Submitted Date  ICMJE January 13, 2021
First Posted Date  ICMJE January 15, 2021
Last Update Posted Date March 3, 2021
Estimated Study Start Date  ICMJE May 2021
Estimated Primary Completion Date July 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 13, 2021)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 13, 2021)
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Studying the Effect of Denosumab on Preventing Breast Cancer in Women With a BRCA1 Germline Mutation
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE BRCA1 Mutation
Intervention  ICMJE
  • Drug: Denosumab
    Given SC
  • Drug: Placebo
    Given SC
  • Other: Quality-of-Life Assessment
    Ancillary studies
Study Arms  ICMJE
  • Experimental: Arm A (denosumab)
    Patients receive denosumab SC q6m for up to 5 years in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Denosumab
    • Other: Quality-of-Life Assessment
  • Placebo Comparator: Arm B (placebo)
    Patients receive placebo SC q6m for up to 5 years in the absence of disease progression.
    Interventions:
    • Drug: Placebo
    • Other: Quality-of-Life Assessment
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: January 13, 2021)
300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2033
Estimated Primary Completion Date July 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 25 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Judy E. Garber, MD, MPH (617) 632-5961 judy_garber@dfci.harvard.edu
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04711109
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party Alliance for Clinical Trials in Oncology
Study Sponsor  ICMJE Alliance for Clinical Trials in Oncology
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Austrian Breast & Colorectal Cancer Study Group (ABCSG)
Investigators  ICMJE
Study Chair: Judy E. Garber, MD, MPH Dana-Farber Cancer Institute
PRS Account Alliance for Clinical Trials in Oncology
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP