RANKL Inhibition for Dense Breasts

(TRIDENT Trial)

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

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

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

210 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug Denosumab for dense breasts?

Research shows that Denosumab, which blocks a protein called RANKL, has been effective in reducing tumor growth and improving chemotherapy response in certain types of breast cancer. It is also used to prevent bone problems in cancer patients, suggesting it may help in conditions related to breast cancer. ^{1 2 3 4 5}

Is denosumab safe for humans?

Denosumab, also known as Prolia or Xgeva, has been shown to be safe in humans for conditions like osteoporosis and bone metastases from solid tumors. It is approved for use in postmenopausal women with osteoporosis and has demonstrated safety even in patients with kidney issues. ^{6 7 8 9 10}

How is the drug Denosumab unique for treating dense breasts?

Denosumab is unique because it targets RANKL, a protein involved in bone resorption, and is administered as a subcutaneous injection, which is different from many other treatments that may not specifically target this pathway or use this method of administration. ^{6 7 8 9 10}

Research Team

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

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Denosumab for the treatment of bone metastases in advanced breast cancer. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Targeting the RANKL/RANK/OPG Axis for Cancer Therapy. [2020]

4. Netherlands pubmed.ncbi.nlm.nih.gov

The anti-tumor effect of RANKL inhibition in malignant solid tumors - A systematic review. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Α Humanized RANKL Transgenic Mouse Model of Progestin-Induced Mammary Carcinogenesis for Evaluation of Novel Therapeutics. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

The RANKL pathway and denosumab. [2015]

7. England pubmed.ncbi.nlm.nih.gov

Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors. [2015]

8. England pubmed.ncbi.nlm.nih.gov

The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: a systematic review. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. [2021]