RANKL Inhibition and Mammographic Breast Density

NCT04067726 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 201907039
• Study Type: interventional
• Target: 210
• Locations: 1 country
• Sites: 1

Brief Summary

Data supporting a role for RANKL signaling in mammographic density and breast cancer development has begun to emerge, but clinical trial data providing definitive evidence that would allow the adoption of RANKL inhibition in primary breast cancer prevention are not yet available. The hypothesis is that RANKL inhibition with denosumab will decrease mammographic density in high-risk premenopausal women with dense breasts. To address this, the investigators have developed this clinical trial to quantify the impact of RANKL inhibition on mammographic density in high-risk premenopausal women with dense breasts and to determine the effect of RANKL inhibition on markers of proliferation and biomarkers of breast cancer risk. Successful demonstration that RANKL inhibition reduces mammographic density could open up additional approaches to primary breast cancer prevention in high-risk premenopausal women, who do not have dominant genetic predisposition.

Conditions

Dense Breasts

Keywords

Mammographic density; Breast cancer; RANKL; Denosumab; Prevention; Premenopausal

Outcome Measures

Primary Outcomes (1)

• Change in mammographic breast density between the two arms as measured by volumetric percent density

  -The investigators will use volumetric percent density (VPD) as the primary mammographic breast density measure.

  From baseline to 12 months

Secondary Outcomes (9)

• Change in mammographic breast density between the two arms as measured by volumetric percent density

  From baseline to 24 months

• Change in mammographic breast density between the two arms as measured by volumetric percent density

  From 12 months to 24 months

• Change in expression gene related to RANK in breast tissue compared between the two arms

  Baseline and 12 months

• Change in expression gene related to progesterone in breast tissue compared between the two arms

  Baseline and 12 months

• Change in expression gene related to metabolics in breast tissue compared between the two arms

  Baseline and 12 months

Study Arms (2)

Denosumab

EXPERIMENTAL

* Subcutaneous injection of denosumab at a dose of 60 mg at two time points: baseline and 6 months * Participants will also be instructed to take calcium and vitamin D supplements daily for 12 months between baseline examination and 12-month mammographic breast density examination. * Mammographic breast density will be assessed at three time points in all participants: baseline, 12 months, and 24 months. A 36-month optional assessment may also occur. * Biopsies and blood draws will occur for research purposes at baseline and 12 months.

Drug: Denosumab; Drug: Calcium; Drug: Vitamin D3; Procedure: Core needle biopsy; Procedure: Blood draw

Placebo

PLACEBO COMPARATOR

* Subcutaneous injection of the placebo at a dose of 60 mg at two time points: baseline and 6 months * Participants will also be instructed to take calcium and vitamin D supplements daily for 12 months between baseline examination and 12 month mammographic breast density examination * Mammographic breast density will be assessed at three time points in all participants: baseline, 12 months, and 24 months. A 36 month optional assessment may also occur. * Biopsies and blood draws will occur for research purposes at baseline and 12 months.

Drug: Placebo; Drug: Calcium; Drug: Vitamin D3; Procedure: Core needle biopsy; Procedure: Blood draw

Interventions

Placebo DRUG

Placebo will be made available as 1 mL sterile, non-pyrogenic water solution in a single-use prefilled syringe.

Placebo

Calcium DRUG

-Participants will be instructed to take calcium (at least 500 mg) daily for 12 months between baseline examination and 12- month mammographic breast density examination.

Denosumab; Placebo

Denosumab DRUG

Denosumab is commercially available and will be provided at no cost to participants.

Also known as: Prolia

Denosumab

Vitamin D3 DRUG

Participants will be instructed to take vitamin D3 (at least 400 IU) supplements daily for 12 months between baseline examination and 12- month mammographic breast density examination.

Denosumab; Placebo

Core needle biopsy PROCEDURE

Baseline and 12 months

Denosumab; Placebo

Blood draw PROCEDURE

Baseline and 12 months

Denosumab; Placebo

Eligibility Criteria

• Age: 40 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female.
• Premenopausal (when menopausal status is uncertain, the investigators will measure follicle-stimulating hormone and estradiol to ascertain that a partcipant is premenopausal)
• At least 40 years of age.
• Dense breasts on routine mammogram (BI-RADS Category C and D)
• Able to understand and willing to sign an IRB-approved written informed consent document.

You may not qualify if:

• History of breast or any other invasive cancer except for DCIS (ductal carcinoma in situ) who received only lumpectomy, LCIS (lobular carcinoma in situ), atypical hyperplasia, non-melanoma skin cancer, carcinoma in situ of the cervix.
• Current use of tamoxifen, aromatase inhibitors, or bisphosphonates, or RANKL inhibitors
• Concurrent participation in another cancer chemoprevention trial (unless no longer receiving the intervention).
• Pregnant, lactating, or planning to get pregnant while the trial is ongoing.
• Recent history of invasive dental procedure (e.g. tooth extraction, dental implant, oral surgery).
• Unhealed and/or planned dental/oral surgery.
• History of osteonecrosis/osteomyelitis of the jaw.
• History of osteoporosis or severe osteopenia.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Denosumab; Calcium; Cholecalciferol; Biopsy, Large-Core Needle; Blood Specimen Collection

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Metals, Alkaline Earth; Elements; Inorganic Chemicals; Metals; Blood Coagulation Factors; Biological Factors; Cholestenes; Cholestanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Lipids; Biopsy, Needle; Biopsy; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Punctures; Investigative Techniques

Study Officials

• Adetunji T Toriola, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Stratified permuted block randomized design will be used to generate the randomization table where permuted block randomization will be used for each stratum by age, with a varying block size of 4 and 6.

Study Record Dates

• First Submitted: August 16, 2019
• First Posted: August 26, 2019
• Study Start: August 27, 2019
• Primary Completion: September 17, 2025
• Study Completion (Estimated): August 31, 2026
• Last Updated: March 31, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Time Frame: IPD will be shared beginning 12 months, and ending 24 months following article publication.
• Access Criteria: IPD will be shared with investigators who propose a methodologically sound proposal. These proposals should have been reviewed and approved by independent review committees, including institutional review boards. Proposals should be directed to the Principal Investigator, who will review the request with other co-Investigators. Proposals may also be subject to further review by the Protocol Review Monitoring Committee and Institutional Review Board at Principal Investigator's institution. Requestors will need to sign an institutional data access agreement to gain access to the data.

Locations

US (1)