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    Summary
    EudraCT Number:2011-006224-21
    Sponsor's Protocol Code Number:IJB-BCTL-20119167
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-04-18
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2011-006224-21
    A.3Full title of the trial
    A pre-operative window study evaluating Denosumab, a RANK-Ligand (RANKL) inhibitor and its biological effects in young pre-menopausal women diagnosed with early breast cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effects of the inhibition of RANKL in pre-menopausal early breast cancer patients
    A.3.2Name or abbreviated title of the trial where available
    D-BEYOND
    A.4.1Sponsor's protocol code numberIJB-BCTL-20119167
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorJules Bordet Institute
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAmgen N.V.
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJules Bordet Institute
    B.5.2Functional name of contact pointHatem Azim
    B.5.3 Address:
    B.5.3.1Street AddressRue Héger-Bordet, 1
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1000
    B.5.3.4CountryBelgium
    B.5.4Telephone number003225413854
    B.5.5Fax number003225413477
    B.5.6E-mailhatem.azim@bordet.be
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name XGEVA
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDENOSUMAB
    D.3.9.1CAS number 615258-40-7
    D.3.9.3Other descriptive nameXGEVA
    D.3.9.4EV Substance CodeSUB29173
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibody
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    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.
    E.1.1.1Medical condition in easily understood language
    Pre-menopausal women diagnosed with primary invasive breast cancer who have not undergone previous treatment or surgery for breast cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10006190
    E.1.2Term Breast cancer invasive NOS
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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
    E.2.2Secondary objectives of the trial
    -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
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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
    E.5 End points
    E.5.1Primary end point(s)
    Geometric mean change in Ki67 response assessed by immunohistochemistry from baseline to prior to surgery
    E.5.1.1Timepoint(s) of evaluation of this end point
    Surgery
    E.5.2Secondary 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 infiltrating cells or stroma and in tumor tissue
    - RANK status ( IHC high vs low ) in tumor and normal tissue
    - According to stage of menstrual cycle (luteal or follicular)
    E.5.2.1Timepoint(s) of evaluation of this end point
    end of the study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Genomic changes in the breast tumor
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Yes
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The study is considered as completed 3 months after the last enrolled patient has received their last dose of denosumab.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days12
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days12
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 39
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state34
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 39
    F.4.2.2In the whole clinical trial 39
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Following surgical excision, additional adjuvant therapy will be at the discretion of the investigator.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-05-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-06-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-01-06
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