A Study to Evaluate Denosumab in Young Patients With Primary Breast Cancer (D-Beyond)

November 26, 2018 updated by: Jules Bordet Institute

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

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

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
27

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
      • Victoria, Australia, 3050
        • Royal Melbourne Hospital
  • Belgium
      • Brussels, Belgium, 1070
        • Hopital Erasme
      • Brussels, Belgium, 1000
        • Institute Jules Bordet
      • Leuven, Belgium, 3000
        • UZ Leuven
      • Mons, Belgium, 7000
        • CHU Ambroise Pare
      • Namur, Belgium, 5000
        • CMSE

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  1. Female gender
  2. Age ≥ 18 years
  3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  4. Premenopausal status defined as the presence of active menstrual cycle or normal menses during the 6 weeks preceding the start of study treatment. Biochemical evidence of phase of menstrual cycle is required (estradiol, FSH and LH). In women previously exposed to hysterectomy,or were using hormonal intrauterine device at the time of enrolment, premenopausal levels of estradiol, FSH and LH are required to be eligible

  5. Non-metastatic operable newly diagnosed primary invasive carcinoma of the breast that is:

    1. Histologically confirmed
    2. Primary tumor size greater than 1.5 cm, measured by any of clinical examination, mammography, ultrasound or magnetic resonance imaging
    3. Any clinical nodal status
    4. Fully operable and not fixed to chest wall.
  6. Known HER2 status
  7. Known estrogen receptor (ER) status and progesterone receptor status (PgR)

  8. Patient has adequate bone marrow and organ function as shown by:

    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    • Platelets ≥ 100 x 109/L
    • Hemoglobin (Hgb) ≥ 9.0 g/dL
    • Serum creatinine ≤ 1.5 x ULN
    • Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)
    • AST and ALT ≤ 1.5 x ULN
    • Random blood sugar (RBS) ≤ 200 mg/dL or ≤ 11.1 mmol/L
    • Glycosylated hemoglobin (HbA1c) ≤ 8 %
  9. Albumin-adjusted serum calcium ≥ 8.0 mg/dL (≥ 2.0 mmol/L)
  10. Women of childbearing potential must agree to use an active local contraception method for the duration of the study and for at least 7 months after the last dose of study treatment
  11. Patients must accept to take calcium and vitamin D supplementation until the completion of the study treatment
  12. Signed informed consent form (ICF) for all study procedures according to local regulatory requirements prior to beginning of the study
  13. Patients must accept to make available tumor and normal tissue samples for submission to central laboratory at the Jules Bordet Institute, Brussels, Belgium, to conduct translational studies as part of this protocol.

Exclusion Criteria:

  1. History of any prior (ipsi and/or contralateral) breast cancer
  2. Any "clinical" T4 tumor defined by TNM including inflammatory breast cancer
  3. History of non-breast malignancies within the 5 years prior to study entry (except carcinoma in situ of the cervix, of the colon, melanoma in situ and basal cell and squamous cell carcinomas of the skin)
  4. Prior or planned systemic anti-cancer therapy before definitive surgery
  5. Unhealed or planned dental/oral surgery, current or previous osteonecrosis or osteomyelitis of the jaw
  6. Pregnant or lactating women or women of childbearing potential without a negative serum or urinary pregnancy test within 7 days prior to starting study treatment; irrespective of the method of contraception used
  7. Active Hepatitis-B virus (HBV), Hepatitis-C virus (HCV) or human immunodeficiency virus (HIV) infection
  8. Known hypersensitivity to denosumab
  9. Bilateral invasive tumors

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Denosumab
Drug: Denosumab
Other Names:
  • XGEVA

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Geometric mean change in tumor Ki67 expression
Time Frame: Baseline and surgery at Day 10
Assessed by immunohistochemistry (IHC) from
Baseline and surgery at Day 10

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Absolute Ki67 responders
Time Frame: Baseline and surgery at Day 10
KI 67 responders will be defined as below 2.7% Ki67 IHC staining in the post treatment tumor biopsy
Baseline and surgery at Day 10
C-terminal telopeptide (CTX) serum levels
Time Frame: Baseline and surgery at Day 10
Baseline and surgery at Day 10
RANK/RANKL gene expression and signalling
Time Frame: Baseline and surgery at Day 10
Assessed by immunohistochemistry (IHC) and RNA sequencing profile in the tumor
Baseline and surgery at Day 10
gene expression (AURKA, Ki-67,GGI)
Time Frame: Baseline and surgery at Day 10
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
Baseline and surgery at Day 10
TUNEL and caspase-3 apoptosis markers
Time Frame: Baseline and surgery at Day 10
Change in tumor apoptosis rates as measured using TUNEL and caspase-3 IHC from baseline to prior to surgery
Baseline and surgery at Day 10
expression of immature mammary epithelial cell population: MaSCs, luminal progenitors , ALDH1
Time Frame: Baseline and surgery at Day 10
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
Baseline and surgery at Day 10
gene expression of the estrogen pathways (i.e. ESR1, PgR, BCL2) and estrogen-related gene expression modules (i.e. ESR module)
Time Frame: Baseline and surgery at Day 10
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
Baseline and surgery at Day 10
immune related genes
Time Frame: Baseline and surgery at Day 10
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
Baseline and surgery at Day 10
Quantity of tumor infiltrating lymphocytes
Time Frame: Baseline and surgery at Day 10
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
Baseline and surgery at Day 10
Safety and tolerability of a short course of denosumab
Time Frame: Day 1, day 8 and surgery Day 10
Day 1, day 8 and surgery Day 10

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Time Frame
PgR status (positive vs. negative)
Time Frame: Baseline and surgery at Day 10
Baseline and surgery at Day 10
RANKL status (IHC positive vs. negative) in normal breast tissue
Time Frame: Baseline and surgery at Day 10
Baseline and surgery at Day 10
RANKL status (IHC positive vs. negative) in infiltrating cells or stroma
Time Frame: Baseline and surgery at Day 10
Baseline and surgery at Day 10
RANKL status (IHC positive vs. negative) in tumor tissue
Time Frame: Baseline and surgery at Day 10
Baseline and surgery at Day 10
RANK status (IHC positive vs. negative) in normal tissue
Time Frame: Baseline and surgery at Day 10
Baseline and surgery at Day 10
RANK status (IHC positive vs. negative) in tumor tissue
Time Frame: Baseline and surgery at Day 10
Baseline and surgery at Day 10

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Jules Bordet Institute

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Melbourne Health

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Martine J Piccart, Prof., Jules Bordet Institute
  • Principal Investigator: Christos Sotiriou, MD, Jules Bordet Institute
  • Principal Investigator: Hatem Azim, MD, Jules Bordet Insitute
  • Principal Investigator: Sherene Loi, MD,PhD, Melbourne Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 1, 2013

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 1, 2017

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 1, 2017

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 21, 2013

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 24, 2013

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 30, 2013

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 27, 2018

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 26, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • IJB-BCTL- 20119167
  • 2011-006224-21 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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