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

NCT01864798 | Terminated Phase 2

• 2 other identifiers: IJB-BCTL- 201191672011-006224-21
• Study Type: interventional
• Target: 27
• Locations: 2 countries
• Sites: 6

Brief Summary

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

Conditions

Breast Neoplasms

Keywords

Young; Breast Neoplasms; Denosumab; RANKL

Outcome Measures

Primary Outcomes (1)

• Geometric mean change in tumor Ki67 expression

  Assessed by immunohistochemistry (IHC) from

  Baseline and surgery at Day 10

Secondary Outcomes (10)

• Absolute Ki67 responders

  Baseline and surgery at Day 10

• C-terminal telopeptide (CTX) serum levels

  Baseline and surgery at Day 10

• RANK/RANKL gene expression and signalling

  Baseline and surgery at Day 10

• gene expression (AURKA, Ki-67,GGI)

  Baseline and surgery at Day 10

• TUNEL and caspase-3 apoptosis markers

  Baseline and surgery at Day 10

Other Outcomes (6)

• 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

Study Arms (1)

Denosumab

EXPERIMENTAL

Drug: Denosumab

Interventions

Denosumab DRUG

Also known as: XGEVA

Denosumab

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female gender
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• 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
• Non-metastatic operable newly diagnosed primary invasive carcinoma of the breast that is:
• Histologically confirmed
• Primary tumor size greater than 1.5 cm, measured by any of clinical examination, mammography, ultrasound or magnetic resonance imaging
• Any clinical nodal status
• Fully operable and not fixed to chest wall.
• Known HER2 status
• Known estrogen receptor (ER) status and progesterone receptor status (PgR)
• 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

You may not qualify if:

• History of any prior (ipsi and/or contralateral) breast cancer
• Any "clinical" T4 tumor defined by TNM including inflammatory breast cancer
• 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)
• Prior or planned systemic anti-cancer therapy before definitive surgery
• Unhealed or planned dental/oral surgery, current or previous osteonecrosis or osteomyelitis of the jaw
• 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
• Active Hepatitis-B virus (HBV), Hepatitis-C virus (HCV) or human immunodeficiency virus (HIV) infection
• Known hypersensitivity to denosumab
• Bilateral invasive tumors

Sponsors & Collaborators

• Jules Bordet Institute: lead
• Melbourne Health: collaborator

Study Sites (6)

Royal Melbourne Hospital

Victoria, 3050, Australia

Location

Institute Jules Bordet

Brussels, 1000, Belgium

Location

Hopital Erasme

Brussels, 1070, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

CHU Ambroise Paré

Mons, 7000, Belgium

Location

CMSE

Namur, 5000, Belgium

Location

Related Publications (1)

• 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.

  PMID: 33303745 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Denosumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Martine J Piccart, Prof.

  Jules Bordet Institute

  STUDY CHAIR

• Christos Sotiriou, MD

  Jules Bordet Institute

  PRINCIPAL INVESTIGATOR

• Hatem Azim, MD

  Jules Bordet Insitute

  PRINCIPAL INVESTIGATOR

• Sherene Loi, MD,PhD

  Melbourne Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2013
• First Posted: May 30, 2013
• Study Start: July 1, 2013
• Primary Completion: January 1, 2017
• Study Completion: January 1, 2017
• Last Updated: November 27, 2018

Record last verified: 2018-11

Locations

BE (5); AU (1)