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Denosumab

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Vitamin D3

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* 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.

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

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

Placebo

-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.

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.

Core needle biopsy

Blood draw

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

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

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

Graham Colditz, M.D., D. PH

Ian Hagemann, M.D.

Jingqin (Rosy) Luo, Ph.D.

Christopher Maher, Ph.D.

Julie Margenthaler, M.D.

Katherine Weilbaecher, M.D.

Lindsay Peterson, M.D.

Debbie Bennett, M.D.

James Clanahan, M.D.

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

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.

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.

RANKL Inhibition and Mammographic Breast Density

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

De-identified participant data used in generating tables and figures in published manuscripts.

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

National Institutes of Health (NIH)

Washington University School of Medicine

Carcinoma

Breast Diseases

Skin Diseases

Patients receive denosumab SC q6m for up to 5 years in the absence of disease progression or unacceptable toxicity.

Patients receive placebo SC q6m for up to 5 years in the absence of disease progression.

Quality-of-Life Assessment

Judy E. Garber, MD, MPH

Site Public Contact

Darcy V. Spicer

Marie E. Wood

Nicholas DiBella

Claudine Isaacs

Seema A. Khan

Katharine A. Yao

Kendrith M. Rowland

Lauren Nye

Nadine M. Tung

Judy E. Garber

Melissa L. Pilewskie

Kathleen J. Yost

Sandhya Pruthi

John A. Ellerton

Katherine D. Crew

Lori F. Gentile

Judith O. Hopkins

Sagar D. Sardesai

Susan M. Domchek

Phuong L. Mai

Rachel D. Wooldridge

Isabelle Bedrosian

Sarah V. Colonna

Kara K. Landry

Masey M. Ross

This phase III trial compares denosumab to placebo for the prevention of breast cancer in women with a BRCA1 germline mutation. A germline mutation is an inherited gene change which, in the BRCA1 gene, is associated with an increased risk of breast and other cancers. Denosumab is a monoclonal antibody that is used to treat bone loss in order to reduce the risk of bone fractures in healthy people, and to reduce new bone growths in cancer patients whose cancer has spread to their bones. Research has shown that denosumab may also reduce the risk of developing breast cancer in women carrying a BRCA1 germline mutation.

PRIMARY OBJECTIVE:

I. To evaluate the reduction in the risk of any breast cancer (invasive or ductal carcinoma in situ \[DCIS\]) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

SECONDARY OBJECTIVES:

I. To determine the reduction in the risk of invasive breast cancer in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

II. To determine the reduction in the risk of invasive triple negative breast cancer (TNBC) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

III. To determine the reduction in risk of ovarian, fallopian and peritoneal cancers (in women who have not undergone prophylactic bilateral salpingo-oophorectomy \[PBSO\]) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

IV. To determine the reduction in risk of other (i.e. non-breast and nonovarian) malignancies, including those known to be associated with BRCA1 germline mutations in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

V. To determine the reduction in the risk of clinical fractures in pre- and postmenopausal women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

VI. To compare rates of breast biopsies and rate of benign breast lesions in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive denosumab subcutaneously (SC) every 6 months (q6m) for up to 5 years in the absence of the development of breast cancer or unacceptable toxicity.

ARM B: Patients receive placebo SC q6m for up to 5 years in the absence of the development of breast cancer.

After completion of study treatment, patients are followed up every 12 months for 5 years.

Studying the Effect of Denosumab on Preventing Breast Cancer in Women With a BRCA1 Germline Mutation

BRCA-P: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center, International Phase 3 Study to Determine the Preventive Effect of Denosumab on Breast Cancer in Women Carrying a BRCA1 Germline Mutation

Time to breast cancer (invasive or DCIS) will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.

Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.

Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model. Time to ovarian cancer will be analyzed in the overall group and in different strata (oral contraceptive use, hormone replacement therapy use, and menopausal status).

May be recommended as part of care based on a finding on mammogram, MRI, ultrasound or physical exam performed as part of monitoring for breast cancer. Will be compared between the two treatment arms via chi-square analysis.

Overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment will be reported per treatment arm.

National Cancer Institute (NCI)

Austrian Breast & Colorectal Cancer Study Group (ABCSG)

Alliance for Clinical Trials in Oncology

Martine J Piccart, Prof.

Christos Sotiriou, MD

Hatem Azim, MD

Sherene Loi, MD,PhD

This is a prospective, single arm phase IIa trial in which patients with early breast cancer will receive pre-operatively two doses of denosumab 120mg subcutaneously one week apart (maximum 12 days) followed by surgery. Tumor, normal breast tissue and blood samples will be collected at baseline and at surgery. Post-operative treatment will be at the discretion of the investigator.

Primary objective: to determine if a short course of RANKL inhibition with denosumab can induce a decrease in tumor proliferation rates as determined by Ki67 immunohistochemistry (IHC) in newly diagnosed, early stage breast cancer in pre-menopausal women.

Secondary objectives:

* To determine the number of absolute Ki67 responders after a short course of denosumab (defined as \<2.7% IHC staining in the post treatment tumor biopsy).
* To determine the effects of a short course of denosumab on serum C-terminal telopeptide levels (CTX).
* To determine the effects of a short course of denosumab on RANK/RANKL gene expression and signaling as assessed by immunohistochemistry (IHC) and RNA sequencing in the tumor.
* To determine the effect of a short course of denosumab on tumor apoptosis rates using IHC
* To determine the effect of a short course of denosumab on modulating the immature mammary epithelial cell populations in the tumor.
* To determine the effect of a short course of denosumab on estrogen signaling pathways in the tumor.
* To determine the effect of a short course of denosumab on various immune
* To determine effect of safety profile of denosumab

A Study to Evaluate Denosumab in Young Patients With Primary Breast Cancer

A Pre-Operative Window Study Evaluating Denosumab, a RANKligand (RANKL) Inhibitor and Its Biological Effects in Young Premenopausal Women Diagnosed With Early Breast Cancer

Assessed by immunohistochemistry (IHC) from

KI 67 responders will be defined as below 2.7% Ki67 IHC staining in the post treatment tumor biopsy

Assessed by immunohistochemistry (IHC) and RNA sequencing profile in the tumor

Change in tumor proliferation rates using gene expression (single genes and gene modules, i.e. AURKA, Ki-67) and proliferation-related gene modules, i.e. GGI) in the tumor from baseline to prior to surgery

Change in tumor apoptosis rates as measured using TUNEL and caspase-3 IHC from baseline to prior to surgery

Change in expression levels from genes corresponding to immature mammary epithelial cell populations (MaSCs and luminal progenitors developed by Lim et al; Nature 2009), and in IHC expression of ALDH1, a stem cell marker in the tumor

Change in expression levels from single genes related to the estrogen pathways (i.e. ESR1, PgR, BCL2 using both gene expression and IHC) and estrogen-related gene expression modules (i.e. ESR module) in the tumor

Change in expression levels from single genes related to immune pathways using both gene expression and IHC, and in immune-related gene expression modules, to explore the hypothesis that RANKL can modulate T regulatory cells in the tumor

Change in the quantity of tumor infiltrating lymphocytes as measured by percentage infiltration of surrounding tumor stroma and intra-tumoral on the H\&E slide pre and post treatment

Melbourne Health

Jules Bordet Institute

denosumab: 120 mg subcutaneous injection

Surgery: 2-4 weeks after denosumab

denosumab

Surgery: approximately 2-4 weeks after dosing of denosumab

Surgery

Sylvia Adams, MD

The purpose of this study is to determine whether one dose of denosumab can lead to changes in the tumor, which may decrease the ability of tumor to spread.

Breast cancer is the most common cancer among women, affecting one in eight women, and is the second leading cause of mortality from cancer. Bone metastases are a frequent complication of breast cancer, and the mechanism of breast cancer metastases to bone is an ongoing area of research.. Receptor activator of NF-kB (RANK) and its ligand (RANKL) have been identified and characterized for its role in bone remodeling. RANKL is a member of the tumor necrosis factor (TNF) family of cytokines that binds to its receptor RANK to control osteoclast differentiation, activation, and survival. RANK protein expression is not only found on osteoclasts and dendritic cells but also on T cells and mammary epithelial cells. RANK and RANKL is important for lymph node and thymus formation as well as lactating mammary gland development during pregnancy. Furthermore, the RANK/RANKL axis has been linked to progestin driven breast carcinomas and bone metastases.

RANK is expressed in 6-57% of invasive human breast cancers (depending upon the parameters for defining positivity and antibodies utilized for immunohistochemistry (IHC)), and RANKL driven hormone (progesterone -dependent proliferation, survival, and nonproliferative expansion of mammary stem cells may contribute to breast cancer initiation, progression, and recurrence.

We hypothesize that denosumab can inhibit RANKL signaling in early breast tumors which express RANK, inhibiting pro-metastatic mechanisms and reducing immunosuppression in the tumor microenvironment. This will be tested in a pre-surgical clinical trial (Phase 0) to evaluate and select the pharmacodynamics markers of RANKL inhibition in breast cancer.

Presurgical Trial of Denosumab in Breast Cancer

Pre-surgical Evaluation of Denosumab in Patients With Operable Invasive Breast Cancer

Immunohistochemical analyses (IHC) of RANK and RANKL protein expression will be performed by Clarient Diagnostics Services Inc., Aliso Viejo, CA using prototype assays developed and optimized by Dako on their automated staining platform

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
RANKL Inhibition and Mammographic Breast Density	NCT04067726	Dense Breasts	Denosumab Placebo Calcium Vitamin D3 Core needle bio... Blood draw	40 Years -	Washington University School of Medicine
Studying the Effect of Denosumab on Preventing Breast Cancer in Women With a BRCA1 Germline Mutation	NCT04711109	BRCA1 Mutation Breast Cancer Breast Diseases Breast Neoplasm... Breast Carcinom... Neoplasms	Denosumab Placebo Quality-of-Life...	25 Years - 55 Years	Alliance for Clinical Trials in Oncology
A Study to Evaluate Denosumab in Young Patients With Primary Breast Cancer	NCT01864798	Breast Neoplasm...	Denosumab	18 Years -	Jules Bordet Institute
Presurgical Trial of Denosumab in Breast Cancer	NCT02900469	Breast Cancer	denosumab Surgery	18 Years -	NYU Langone Health

Spots Global Cancer Trial Database for rankl

Every month we try and update this database with for rankl cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for rankl

Every month we try and update this database with for rankl cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for rankl cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.