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| ID | Type | Description | Link |
|---|---|---|---|
| 2011-006224-21 | EudraCT Number |
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Poor recruitment
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| Name | Class |
|---|---|
| Melbourne Health | OTHER |
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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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Denosumab | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Denosumab | Drug |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Geometric mean change in tumor Ki67 expression | Assessed by immunohistochemistry (IHC) from | Baseline and surgery at Day 10 |
| 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 |
| Measure | Description | 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 | |
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:
Known HER2 status
Known estrogen receptor (ER) status and progesterone receptor status (PgR)
Patient has adequate bone marrow and organ function as shown by:
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:
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| Name | Affiliation | Role |
|---|---|---|
| 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 |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Royal Melbourne Hospital | Victoria | 3050 | Australia | |||
| Institute Jules Bordet |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33303745 | Derived | 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. |
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| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| D000069448 | Denosumab |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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| 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 |
| 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 |
| Brussels |
| 1000 |
| Belgium |
| Hopital Erasme | Brussels | 1070 | Belgium |
| UZ Leuven | Leuven | 3000 | Belgium |
| CHU Ambroise Paré | Mons | 7000 | Belgium |
| CMSE | Namur | 5000 | Belgium |
| D017437 |
| Skin and Connective Tissue Diseases |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |