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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2013 by Jules Bordet Institute
Sponsor:
Collaborator:
Melbourne Health
Information provided by (Responsible Party):
Jules Bordet Institute
ClinicalTrials.gov Identifier:
NCT01864798
First received: May 21, 2013
Last updated: May 13, 2014
Last verified: April 2013
  Purpose

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 gene expression profile 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

Condition Intervention Phase
Breast Neoplasms
Drug: Denosumab
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pre‐Operative Window Study Evaluating Denosumab, a RANKligand (RANKL) Inhibitor and Its Biological Effects in Young Premenopausal Women Diagnosed With Early Breast Cancer

Resource links provided by NLM:


Further study details as provided by Jules Bordet Institute:

Primary Outcome Measures:
  • Geometric mean change in tumor Ki67 expression [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
    Assessed by immunohistochemistry (IHC) from


Secondary Outcome Measures:
  • Absolute Ki67 responders [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
    KI 67 responders will be defined as below 2.7% Ki67 IHC staining in the post treatment tumor biopsy

  • C-terminal telopeptide (CTX) serum levels [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
  • RANK/RANKL gene expression and signalling [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
    Assessed by immunohistochemistry (IHC) and gene expression profile in the tumor

  • gene expression (AURKA, Ki-67,GGI) [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
    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

  • TUNEL and caspase-3 apoptosis markers [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
    Change in tumor apoptosis rates as measured using TUNEL and caspase-3 IHC from baseline to prior to surgery

  • expression of immature mammary epithelial cell population: MaSCs, luminal progenitors , ALDH1 [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
    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

  • 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 ] [ Designated as safety issue: No ]
    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

  • immune related genes [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
    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

  • Quantity of tumor infiltrating lymphocytes [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
    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

  • Safety and tolerability of a short course of denosumab [ Time Frame: Day 1, day 8 and surgery Day 10 ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • PgR status (positive vs. negative) [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
  • RANKL status (IHC positive vs. negative) in normal breast tissue [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
  • RANKL status (IHC positive vs. negative) in infiltrating cells or stroma [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
  • RANKL status (IHC positive vs. negative) in tumor tissue [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
  • RANK status (IHC positive vs. negative) in normal tissue [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]
  • RANK status (IHC positive vs. negative) in tumor tissue [ Time Frame: Baseline and surgery at Day 10 ] [ Designated as safety issue: No ]

Estimated Enrollment: 39
Study Start Date: July 2013
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Denosumab Drug: Denosumab
Other Name: XGEVA

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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, 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
  10. Multifocal/multicentric tumors
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01864798

Contacts
Contact: Hatem Azim, MD hatem.azim@bordet.be

Locations
Australia
Royal Melbourne Hospital Recruiting
Victoria, Australia, 3050
Principal Investigator: Geoff Geoff Lindeman, MD         
Belgium
Institute Jules Bordet Recruiting
Brussels, Belgium, 1000
Principal Investigator: Martine Piccart, MD         
Hopital Erasme Not yet recruiting
Brussels, Belgium, 1070
Principal Investigator: Philippe Simon, MD         
UZ Leuven Recruiting
Leuven, Belgium, 3000
Principal Investigator: Hans Wildiers, MD         
CMSE Recruiting
Namur, Belgium, 5000
Principal Investigator: Peter Vuylsteke, MD         
Sponsors and Collaborators
Jules Bordet Institute
Melbourne Health
Investigators
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
  More Information

No publications provided

Responsible Party: Jules Bordet Institute
ClinicalTrials.gov Identifier: NCT01864798     History of Changes
Other Study ID Numbers: IJB‐BCTL‐ 20119167, 2011‐006224‐21
Study First Received: May 21, 2013
Last Updated: May 13, 2014
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products

Keywords provided by Jules Bordet Institute:
Young
Breast Neoplasms
Denosumab
RANKL

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases

ClinicalTrials.gov processed this record on July 29, 2014