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

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: Terminated
• Conditions: Breast Neoplasms
• Intervention / Treatment: Drug: Denosumab

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Denosumab	Drug: Denosumab; Other Names: XGEVA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric mean change in tumor Ki67 expression	Assessed by immunohistochemistry (IHC) from	Baseline and surgery at Day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Ki67 responders	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		Baseline and surgery at Day 10
RANK/RANKL gene expression and signalling	Assessed by immunohistochemistry (IHC) and RNA sequencing profile in the tumor	Baseline and surgery at Day 10
gene expression (AURKA, Ki-67,GGI)	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	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	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)	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	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	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		Day 1, day 8 and surgery Day 10

Other Outcome Measures

Outcome Measure	Time Frame
PgR status (positive vs. negative)	Baseline and surgery at Day 10
RANKL status (IHC positive vs. negative) in normal breast tissue	Baseline and surgery at Day 10
RANKL status (IHC positive vs. negative) in infiltrating cells or stroma	Baseline and surgery at Day 10
RANKL status (IHC positive vs. negative) in tumor tissue	Baseline and surgery at Day 10
RANK status (IHC positive vs. negative) in normal tissue	Baseline and surgery at Day 10
RANK status (IHC positive vs. negative) in tumor tissue	Baseline and surgery at Day 10

Collaborators and Investigators

• Sponsor: Jules Bordet Institute
• Collaborators: 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

Publications and helpful links

General Publications

• Gomez-Aleza C, Nguyen B, Yoldi G, Ciscar M, Barranco A, Hernandez-Jimenez E, Maetens M, Salgado R, Zafeiroglou M, Pellegrini P, Venet D, Garaud S, Trinidad EM, Benitez S, Vuylsteke P, Polastro L, Wildiers H, Simon P, Lindeman G, Larsimont D, Van den Eynden G, Velghe C, Rothe F, Willard-Gallo K, Michiels S, Munoz P, Walzer T, Planelles L, Penninger J, Azim HA Jr, Loi S, Piccart M, Sotiriou C, Gonzalez-Suarez E. Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells. Nat Commun. 2020 Dec 10;11(1):6335. doi: 10.1038/s41467-020-20138-8.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): January 1, 2017
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: May 21, 2013
• First Submitted That Met QC Criteria: May 24, 2013
• First Posted (Estimate): May 30, 2013

Study Record Updates

• Last Update Posted (Actual): November 27, 2018
• Last Update Submitted That Met QC Criteria: November 26, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: Breast Neoplasms; RANKL; Young; Denosumab
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: IJB-BCTL- 20119167; 2011-006224-21 (EudraCT Number)