We have designed this study to investigate if denosumab can modulate a number of biological processes including prolferation, RANK signaling and the mammary stem cell subpopulation. MedDRA version: 19.0 Level: LLT Classification code 10006190 Term: Breast cancer invasive NOS System Organ Class: 100000004864
Conditions
Interventions
Trade Name: XGEVA
Pharmaceutical Form: Solution for injection
INN or Proposed INN: DENOSUMAB
CAS Number: 615258-40-7
Other descriptive name: XGEVA
Concentration unit: mg milligram(s)
Concentration typ
Sponsors
Jules Bordet Institute
Eligibility
Sex/Gender
All
Inclusion 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. Plasma levels of estradiol, FSH and LH are required to document phase of menstrual cycle. In women previously exposed to hysterectomy, or were using hormonal intrauterine device at the time of enrollment, 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: a. Histologically confirmed b. Primary tumor size greater than 1.5 cm, measured by any of clinical examination, mammography, ultrasound or magnetic resonance imaging c. Any clinical nodal status d. Fully operable and not fixed to chest wall. 6) Known HER2 status 7) Known estrogen receptor status (ER) and progesterone 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 - HbA1c = 8 % 9) Albumin-adjusted serum calcium = 8.0 mg/dL (= 2.0 mmol/L) 10) Women of childbearing potential must agree to use 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 are required to take calcium and vitamin D supplementation until the completion of the study treatment 12) Written informed consent form (ICF) for all study procedures according to local regulatory requirements prior to beginning of the study 13) Patients 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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 39 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine if a short course of RANKL inhibition with denosumab can induce a decrease in proliferation rates as determined by KI67 immunohistochemistry (IHC) in newly diagnosed, early stage breast cancer in pre-menopausal women;Secondary Objective: -To determine the number of absolute Ki67 responders -To determine the effects of denosumab on serum C-terminal telepeptide levels -To determine the effects of denosumab on RANK/RANKL gene expression and signaling -To determine the effect of denosumab on tumor apoptosis rates using IHC. -To determine the effect of denosumab on modulating the immature mammary epithelial cell populations -To determine the effect of on estrogen signaling pathways -To determine the effect of denosumab on various immune functions, particularly modulation of T regulatory cells -To determine effect of safety profile of denosumab -To determine these relative changes described above in surrounding serial normal tissue biopsies -To compare the relative changes in surrounding normal tissue to that occuring in the serial tumor biopsies -To determine relative changes according to subgroups defined on PgR status and on RANKL status -To determine the above changes taking phase of menstrual cycle ;Primary end point(s): Geometric mean change in Ki67 response assessed by immunohistochemistry from baseline to prior to surgery;Timepoint(s) of evaluation of this end point: Surgery | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Absolute Ki67 responders after a short course of denosumab treatment, defined as below 2.7% Ki67 IHC staining in the post treatment tumor biopsy - Decrease in serum C-terminal telepeptide (CTX) levels - Change in RANK/RANKL gene expression and signaling as assessed by immunohistochemistry (IHC) and gene expression profile in the tumor. - Change in tumor proliferation rates using gene expression (single genes and gene modules, i.e. AURKA, Ki-67, and proliferation-related gene modules, ie. GGI) in the tumor - Change in tumor apoptosis rates as measured using TUNEL and caspase-3 IHC from baseline to prior to surgery - 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. - 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 - Change in expression levels from single genes related to immune pathways using both gene expression and IHC, and in immune-related gene expression modules. This will be done to explore the hypothesis that RANKL can modulate T regulatory cells in the tumor. - 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. - The above endpoints will also be characterized in the paired samples of surrounding normal tissue - The above endpoints in surrounding normal tissue will be compared to that occurring in the serial tumor tissue biopsies Subgroup analyses will also be performed according to: - PgR status (positive vs negative) - RANKL status (IHC high vs low) in normal breast tissue, in infiltrat | — |
Countries
Belgium
Contacts
Public ContactHatem Azim
Jules Bordet Institute
Outcome results
None listed