RANKL Inhibition and Mammographic Breast Density (TRIDENT)

Randomized Clinical Trial of RANKL Inhibition With Denosumab on Mammographic Density in Premenopausal Women With Dense Breasts (TRIDENT)

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.

Study Overview

• Status: Recruiting
• Conditions: Dense Breasts
• Intervention / Treatment: Drug: Denosumab; Procedure: Core needle biopsy; Procedure: Blood draw; Drug: Placebo; Drug: Calcium; Drug: Vitamin D3

• Study Type: Interventional
• Enrollment (Estimated): 210
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Adetunji T Toriola, M.D., Ph.D. MPH; Phone Number: 314-286-2668; Email: a.toriola@wustl.edu
• Study Contact Backup: Name: Suleepon (Emmy) Uttamapinan, M.D., MSc.; Phone Number: 314-747-9992; Email: s.uttamapinan@wustl.edu

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Adetunji T Toriola, M.D., Ph.D., MPH; Phone Number: 314-286-2668; Email: a.toriola@wustl.edu
      • Principal Investigator: Adetunji T Toriola, M.D., Ph.D., MPH
      • Sub-Investigator: Graham Colditz, M.D., D. PH
      • Sub-Investigator: Ian Hagemann, M.D.
      • Sub-Investigator: Debbie Bennett, M.D.
      • Contact: Suleepon (Emmy) Uttamapinan, M.D., MSc.; Phone Number: 314-747-9992; Email: s.uttamapinan@wustl.edu
      • Sub-Investigator: Jingqin (Rosy) Luo, Ph.D.
      • Sub-Investigator: Katherine Weilbaecher, M.D.
      • Sub-Investigator: Julie Margenthaler, M.D.
      • Sub-Investigator: Christopher Maher, Ph.D.
      • Sub-Investigator: Lindsay Peterson, M.D.
      • Sub-Investigator: James Clanahan, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Denosumab; 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; Denosumab is commercially available and will be provided at no cost to participants.; Other Names: Prolia; Procedure: Core needle biopsy; Baseline and 12 months; Procedure: Blood draw; Baseline and 12 months; Drug: Calcium; -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.; Drug: Vitamin D3; 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.
Placebo Comparator: Placebo; 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.	Procedure: Core needle biopsy; Baseline and 12 months; Procedure: Blood draw; Baseline and 12 months; Drug: Placebo; Placebo will be made available as 1 mL sterile, non-pyrogenic water solution in a single-use prefilled syringe.; Drug: Calcium; -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.; Drug: Vitamin D3; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Time Frame
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

Other Outcome Measures

Outcome Measure	Time Frame
Change in expression of RANKL pathway genes compared between the two arms	Baseline and 12 months
Change in expression of progesterone receptor and progesterone-regulated pathway genes compared between the two arms	Baseline and 12 months
Change in expression of markers of epithelial proliferation compared between the two arms	Baseline and 12 months
Change in expression of markers of stromal proliferation and growth factors compared between the two arms	Baseline and 12 months
Change in expression of immune markers compared between the two arms	Baseline and 12 months
Change in expression of inflammatory markers compared between the two arms	Baseline and 12 months
Correlations between gene expression within the breast tissue and within the blood	Baseline

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Adetunji T Toriola, M.D., Ph.D., Washington University School of Medicine

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2019
• Primary Completion (Estimated): August 31, 2025
• Study Completion (Estimated): August 31, 2026

Study Registration Dates

• First Submitted: August 16, 2019
• First Submitted That Met QC Criteria: August 21, 2019
• First Posted (Actual): August 26, 2019

Study Record Updates

• Last Update Posted (Actual): April 24, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Breast cancer; Prevention; Premenopausal; RANKL; Denosumab; Mammographic density
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Calcium; Denosumab
• Other Study ID Numbers: 201907039

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified participant data used in generating tables and figures in published manuscripts.
• IPD Sharing Time Frame: IPD will be shared beginning 12 months, and ending 24 months following article publication.
• IPD Sharing 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No