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

Primary Purpose

Breast Neoplasms

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Denosumab

About this trial

This is an interventional treatment trial for Breast Neoplasms focused on measuring Young, Breast Neoplasms, Denosumab, RANKL

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

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:
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.
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
- 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 %
Albumin-adjusted serum calcium ≥ 8.0 mg/dL (≥ 2.0 mmol/L)
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
Patients must accept to take calcium and vitamin D supplementation until the completion of the study treatment
Signed informed consent form (ICF) for all study procedures according to local regulatory requirements prior to beginning of the study
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:

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

Sites / Locations

Royal Melbourne Hospital
Institute Jules Bordet
Hopital Erasme
UZ Leuven
CHU Ambroise Paré
CMSE

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Denosumab

Arm Description

Outcomes

Primary Outcome Measures

Geometric mean change in tumor Ki67 expression

Assessed by immunohistochemistry (IHC) from

Secondary Outcome Measures

Absolute Ki67 responders

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

RANK/RANKL gene expression and signalling

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

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

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

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

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

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

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

Safety and tolerability of a short course of denosumab

Full Information

NCT ID

NCT01864798

First Posted

May 21, 2013

Last Updated

November 26, 2018

Sponsor

Jules Bordet Institute

Collaborators

Melbourne Health

1. Study Identification

Unique Protocol Identification Number

NCT01864798

Brief Title

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

Acronym

D-Beyond

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2018

Overall Recruitment Status

Terminated

Why Stopped

Poor recruitment

Study Start Date

July 2013 (undefined)

Primary Completion Date

January 2017 (Actual)

Study Completion Date

January 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Jules Bordet Institute

Collaborators

Melbourne Health

4. Oversight

Data Monitoring Committee

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Breast Neoplasms

Keywords

Young, Breast Neoplasms, Denosumab, RANKL

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

27 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Denosumab

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Denosumab

Other Intervention Name(s)

XGEVA

Primary Outcome Measure Information:

Title

Geometric mean change in tumor Ki67 expression

Description

Assessed by immunohistochemistry (IHC) from

Time Frame

Baseline and surgery at Day 10

Secondary Outcome Measure Information:

Title

Absolute Ki67 responders

Description

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

Time Frame

Baseline and surgery at Day 10

Title

C-terminal telopeptide (CTX) serum levels

Time Frame

Baseline and surgery at Day 10

Title

RANK/RANKL gene expression and signalling

Description

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

Time Frame

Baseline and surgery at Day 10

Title

gene expression (AURKA, Ki-67,GGI)

Description

Time Frame

Baseline and surgery at Day 10

Title

TUNEL and caspase-3 apoptosis markers

Description

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

Time Frame

Baseline and surgery at Day 10

Title

expression of immature mammary epithelial cell population: MaSCs, luminal progenitors , ALDH1

Description

Time Frame

Baseline and surgery at Day 10

Title

gene expression of the estrogen pathways (i.e. ESR1, PgR, BCL2) and estrogen-related gene expression modules (i.e. ESR module)

Description

Time Frame

Baseline and surgery at Day 10

Title

immune related genes

Description

Time Frame

Baseline and surgery at Day 10

Title

Quantity of tumor infiltrating lymphocytes

Description

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

Time Frame

Baseline and surgery at Day 10

Title

Safety and tolerability of a short course of denosumab

Time Frame

Day 1, day 8 and surgery Day 10

Other Pre-specified Outcome Measures:

Title

PgR status (positive vs. negative)

Time Frame

Baseline and surgery at Day 10

Title

RANKL status (IHC positive vs. negative) in normal breast tissue

Time Frame

Baseline and surgery at Day 10

Title

RANKL status (IHC positive vs. negative) in infiltrating cells or stroma

Time Frame

Baseline and surgery at Day 10

Title

RANKL status (IHC positive vs. negative) in tumor tissue

Time Frame

Baseline and surgery at Day 10

Title

RANK status (IHC positive vs. negative) in normal tissue

Time Frame

Baseline and surgery at Day 10

Title

RANK status (IHC positive vs. negative) in tumor tissue

Time Frame

Baseline and surgery at Day 10

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 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 % Albumin-adjusted serum calcium ≥ 8.0 mg/dL (≥ 2.0 mmol/L) 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 Patients must accept to take calcium and vitamin D supplementation until the completion of the study treatment Signed informed consent form (ICF) for all study procedures according to local regulatory requirements prior to beginning of the study 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: 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Martine J Piccart, Prof.

Organizational Affiliation

Jules Bordet Institute

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Christos Sotiriou, MD

Organizational Affiliation

Jules Bordet Institute

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Hatem Azim, MD

Organizational Affiliation

Jules Bordet Insitute

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Sherene Loi, MD,PhD

Organizational Affiliation

Melbourne Health

Official's Role

Principal Investigator

Facility Information:

Facility Name

Royal Melbourne Hospital

City

Victoria

ZIP/Postal Code

3050

Country

Australia

Facility Name

Institute Jules Bordet

City

Brussels

ZIP/Postal Code

1000

Country

Belgium

Facility Name

Hopital Erasme

City

Brussels

ZIP/Postal Code

1070

Country

Belgium

Facility Name

UZ Leuven

City

Leuven

ZIP/Postal Code

3000

Country

Belgium

Facility Name

CHU Ambroise Paré

City

Mons

ZIP/Postal Code

7000

Country

Belgium

Facility Name

CMSE

City

Namur

ZIP/Postal Code

5000

Country

Belgium

12. IPD Sharing Statement

Citations:

PubMed Identifier

33303745

Citation

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.

Results Reference

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

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