RANKL Inhibition for Dense Breasts

(TRIDENT Trial)

Not currently recruiting at 1 trial location

Overseen By Suleepon (Emmy) Uttamapinan, M.D., MSc.

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: Tamoxifen, Aromatase inhibitors, Bisphosphonates, RANKL inhibitors

Disqualifiers: Invasive cancer history, Pregnancy, Osteoporosis, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether denosumab (also known as Prolia or Xgeva) can reduce mammographic density in women with dense breasts, potentially lowering their breast cancer risk. Researchers compare denosumab to a placebo to determine its effectiveness in decreasing breast density and affecting markers related to breast cancer risk. Premenopausal women with dense breasts on a routine mammogram may qualify to join. Participants will receive injections and undergo mammograms at various intervals to monitor changes. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant findings.

Will I have to stop taking my current medications?

If you are currently using tamoxifen, aromatase inhibitors, bisphosphonates, or RANKL inhibitors, you will need to stop taking them to participate in this trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that denosumab is generally safe for people. One study linked it to a 13% lower risk of breast cancer in postmenopausal women, suggesting its safety. Additionally, studies indicate that taking denosumab less frequently does not increase hospital visits, potentially leading to fewer side effects over time.

Denosumab already has approval for treating other bone-related conditions, supporting its safety profile. However, prospective trial participants should remain aware of possible side effects and discuss these with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for dense breasts?

Denosumab is unique because it targets the RANKL pathway, which is different from the usual hormonal treatments or lifestyle changes currently available for managing dense breasts. While most treatments address symptoms or risk factors, denosumab directly inhibits the activity of cells involved in bone metabolism and breast density. Researchers are excited about this treatment because it could offer a novel approach to reducing breast density, potentially lowering the risk of breast cancer while utilizing a well-tolerated delivery method through subcutaneous injections.

What evidence suggests that RANKL inhibition with denosumab might be an effective treatment for dense breasts?

Research has shown that denosumab, initially used for treating osteoporosis, might help lower breast density in women with dense breasts. Dense breasts can make cancer detection on a mammogram more difficult, and some researchers believe they might be linked to a higher risk of breast cancer. While denosumab is known to improve bone strength, its impact on breast tissue remains under investigation. In this trial, participants will receive either denosumab or a placebo to evaluate its effects. The researchers aim to determine if blocking a specific pathway called RANKL with denosumab can reduce breast density and possibly lower the risk of breast cancer. Early studies are underway to explore this possibility. ^{2 3 4 6 7}

Who Is on the Research Team?

Adetunji T Toriola, M.D., Ph.D., MPH

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

This trial is for premenopausal women at least 40 years old with dense breasts, as shown on a mammogram. Participants must be able to consent and not have a history of certain breast conditions or cancer, known BRCA mutations, or be using related medications. They should not be pregnant or planning pregnancy during the trial.

Inclusion Criteria

Dense breasts on routine mammogram (BI-RADS Category C and D, i.e. volumetric percent density ≥ 7.5% on Volpara)

I am 40 years old or older.

Able to understand and willing to sign an IRB-approved written informed consent document.

Exclusion Criteria

I have a history of breast cancer or another type of cancer, except for non-melanoma skin cancer.

Concurrent participation in another cancer chemoprevention trial (unless no longer receiving the intervention).

I have been diagnosed with osteoporosis or severe osteopenia.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive subcutaneous injections of denosumab or placebo at baseline and 6 months, with daily calcium and vitamin D supplements for 12 months

12 months

3 visits (in-person) at baseline, 6 months, and 12 months

Follow-up

Participants are monitored for changes in mammographic breast density and biomarkers at 24 months, with an optional assessment at 36 months

12-24 months

2 visits (in-person) at 24 months and optional at 36 months

What Are the Treatments Tested in This Trial?

Interventions

• Denosumab

Trial Overview The study tests if RANKL inhibition with denosumab can reduce mammographic density in high-risk women with dense breasts. It also examines its effect on proliferation markers and breast cancer risk biomarkers. The trial includes blood draws, biopsies, and supplements like calcium and vitamin D3.

How Is the Trial Designed?

Group I: Denosumab Experimental Treatment 5 Interventions

* 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.

Group II: Placebo Placebo Group 5 Interventions

* 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.

Denosumab is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Prolia for:

• Osteoporosis in postmenopausal women
• Bone loss associated with hormone ablation therapy for prostate cancer
• Bone loss associated with hormone ablation therapy for breast cancer

Approved in United States as Prolia for:

• Treatment of postmenopausal women with osteoporosis at high risk for fracture
• Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer
• Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer

Approved in Canada as Prolia for:

• Treatment of osteoporosis in postmenopausal women at high risk for fracture
• Treatment to increase bone mass in men with osteoporosis at high risk for fracture

Approved in Japan as Prolia for:

• Treatment of osteoporosis in postmenopausal women
• Treatment of bone loss associated with hormone ablation therapy for prostate cancer

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

Denosumab (XGEVA®) is a monoclonal antibody that effectively inhibits bone resorption by preventing the activation of osteoclasts, making it a targeted treatment for patients with bone metastases.

In Phase 3 clinical studies, denosumab was found to be superior to zoledronic acid in delaying skeletal-related events (SREs) by a median of 8.2 months, suggesting it may be a more effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors. Perez Ruixo, JJ., Doshi, S., Sohn, W., et al.[2015]

Denosumab, a monoclonal antibody that inhibits RANKL, shows consistent pharmacokinetics across a large population of 1,076 subjects, including both healthy individuals and cancer patients, indicating its effectiveness in preventing osteoclast activation and survival.

The study found that after administering denosumab, over 95% of patients achieved more than 97% RANKL occupancy, suggesting that dosage adjustments based on body weight, age, race, or tumor type are unnecessary for patients with bone metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours. Gibiansky, L., Sutjandra, L., Doshi, S., et al.[2021]

Denosumab, a monoclonal antibody used to treat skeletal-related events in advanced cancer patients, shows dose-dependent pharmacokinetics, meaning its absorption and effects vary with the dose given, particularly at doses below 60 mg.

In patients with solid tumors and bone metastases, denosumab effectively reduces bone turnover markers quickly, and its pharmacokinetics and pharmacodynamics remain consistent across different tumor types and cancer treatments, indicating its broad applicability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: a systematic review. Sohn, W., Simiens, MA., Jaeger, K., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36624318/

a systematic review and network meta-analysis In MPC on HAT, denosumab (relative to placebo) was effective at preventing vertebral fractures and improving BMD at the FN and LS.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04067726

RANKL Inhibition and Mammographic Breast Density The hypothesis is that RANKL inhibition with denosumab will decrease mammographic density in high-risk premenopausal women with dense breasts. To address this, ...

3. facingourrisk.org facingourrisk.org/research-clinical-trials/study/93/denosumab-and-mammographic-density-in-premenopausal-women-with-dense-breasts-trident

Denosumab and Mammographic Density in ... The purpose of this study is to evaluate if denosumab can reduce the breast density of premenopausal women who have dense breasts.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6708609/

Efficacy of denosumab for restoring normal bone mineral ... We evaluate the efficacy of denosumab for preventing loss of bone mineral density (BMD) induced by adjuvant therapy with AI s in breast cancer patients with ...

5. siteman.wustl.edu siteman.wustl.edu/breast-cancer-prevention-trial-underway/

Breast cancer prevention trial underway A phase 2 clinical trial to investigate an osteoporosis drug for its potential to lower breast density in women with dense breasts.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6265331/

Denosumab and breast cancer risk in postmenopausal ... Denosumab use was associated with a 13% decreased breast cancer risk (HR = 0.87; 95% CI 0.76–1.00). There was no relationship between increasing number of ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7768832/

Safety and efficacy of extended dosing intervals ... Extending denosumab dosing intervals does not appear to negatively impact time to first SRE and is associated with fewer hospitalizations in real-world ...