TRIDENT: RANKL Inhibition and Mammographic Breast Density

Sponsor

Washington University School of Medicine (Other)

Overall Status

Recruiting

CT.gov ID

NCT04067726

Collaborator

National Institutes of Health (NIH) (NIH)

210

Enrollment

Location

Arms

84.1

Anticipated Duration (Months)

2.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Dense Breasts	Drug: Denosumab Drug: Placebo Drug: Calcium Drug: Vitamin D3 Procedure: Core needle biopsy Procedure: Blood draw	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

210 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

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.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.

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Aug 27, 2019

Anticipated Primary Completion Date :

Aug 31, 2025

Anticipated Study Completion Date :

Aug 31, 2026

Arms and Interventions

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 Drug: Calcium -Participants will be instructed to take calcium (600 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 (800 IU) supplements daily for 12 months between baseline examination and 12- month mammographic breast density examination. Procedure: Core needle biopsy Baseline and 12 months Procedure: Blood draw Baseline and 12 months
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.	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 (600 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 (800 IU) supplements daily for 12 months between baseline examination and 12- month mammographic breast density examination. Procedure: Core needle biopsy Baseline and 12 months Procedure: Blood draw Baseline and 12 months

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

Drug: Calcium

-Participants will be instructed to take calcium (600 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 (800 IU) supplements daily for 12 months between baseline examination and 12- month mammographic breast density examination.

Procedure: Core needle biopsy

Baseline and 12 months

Procedure: Blood draw

Baseline and 12 months

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.

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 (600 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 (800 IU) supplements daily for 12 months between baseline examination and 12- month mammographic breast density examination.

Procedure: Core needle biopsy

Baseline and 12 months

Procedure: Blood draw

Baseline and 12 months

Outcome Measures

Primary Outcome Measures

Change in mammographic breast density between the two arms as measured by volumetric percent density [From baseline to 12 months]
-The investigators will use volumetric percent density (VPD) as the primary mammographic breast density measure.

Secondary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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, i.e. volumetric percent density ≥ 7.5% on Volpara)
Able to understand and willing to sign an IRB-approved written informed consent document.

Exclusion Criteria:

History of ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), invasive breast cancer, or other cancer (except non-melanoma skin cancer).
Known BRCA mutation(s).
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.