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    Summary
    EudraCT Number:2015-005063-16
    Sponsor's Protocol Code Number:IEO370
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-12-15
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-005063-16
    A.3Full title of the trial
    A randomized presurgical study with different schedules of exemestane in postmenopausal women with stage 0-II ER-positive breast cancer
    Studio prechirurgico randomizzato con exemestane a posologie diverse in donne in postmenopausa con tumore mammario (stadio 0-II) ormonoresponsivo.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Different schedules of Exemestane in breast cancer women waiting for surgery
    Posologie variabili di exemestane in donne in postmenopausa con tumore alla mammella in attesa di intervento chirurgico
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberIEO370
    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 SponsorISTITUTO EUROPEO DI ONCOLOGIA
    B.1.3.4CountryItaly
    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 supportMD ANDERSON
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIstituto Europeo di Oncologia
    B.5.2Functional name of contact pointUfficio Studi Clinici e a Attività
    B.5.3 Address:
    B.5.3.1Street AddressVia Adamello 16
    B.5.3.2Town/ cityMilano
    B.5.3.3Post code20139
    B.5.3.4CountryItaly
    B.5.4Telephone number0257489848
    B.5.5Fax number0257489781
    B.5.6E-mailufficio.studiclinici@ieo.it
    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 No
    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.3.1Product nameEXEMESTANE
    D.3.2Product code [EXEMESTANE]
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEXEMESTANE
    D.3.9.2Current sponsor codeEXEMESTANE
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 No
    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 No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Postmenopausal ER positive breast cancer, waiting for surgery.
    Tumore della mammella ormono responsivo (stadio 0-II) in donne in postmenopausa in attesa di intervento chirurgico.
    E.1.1.1Medical condition in easily understood language
    Postmenopausal breast cancer patients waiting for surgery
    Tumore al seno in donne In postmenopausa in attesa di intervento chirurgico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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
    Postmenopausal ER positive breast cancer, waiting for surgery.
    Valutare se schemi di dosaggio di exemestane inferiori allo standard siano in grado di produrre la stessa riduzione di livelli sierici di estradiolo ottenuta con la dose standard
    E.2.2Secondary objectives of the trial
    To assess safety and toxicity.
    - To support the preventive activity of exemestane we will investigate the change in Ki-67 and PgR levels in tumor cells and the adjacent intraepithelial neoplasia or benign histologic structures.
    - To assess possible association of estradiol level with tissue and circulating biomarkers.
    - To investigate possible pharmacogenetic markers.
    - To assess drug levels on tissue samples.
    - To investigate tissue and circulating proteomics profiling.
    la tossicità e sicurezza d’impiego del farmaco
    le variazione di Ki 67 e dei livelli di PgR nel tessuto tumorale e peritumorale
    possibile associazione dei livelli di estradiolo con i biomarkers circolanti
    markers farmacogenetici
    livelli tissutali del farmaco
    profiling proteomico tissutale e circolante
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Postmenopausal women (postmenopausal: age >60 years, or amenorrhea = 12 months, or bilateral oophorectomy, or, in women with hysterectomy only, FSH in the menopausal levels as per local institutional guidelines if < 60 years old) with histologically-confirmed ER positive (= 10%) primary breast cancer stage T0-2, N0-1, Mx. Women with larger tumors who refuse chemo and/or endocrine neoadjuvant therapy can be eligible.
    • ECOG performance status =1 (Karnofsky =70%)
    • Pazienti in postmenopausa (età superiore o uguale a 60 anni o amenorrea da 12 mesi o ovariectomia bilaterale o, in pazienti isterectomizzate, valori postmenopausali di FSH centro specifici, se con età< 60 anni), con tumore mammario istologicamente confermato ER positivo (=10%) stadio 0-II. Sono anche eleggibili donne con tumori maggiori che abbiano rifiutato la terapia neoadiuvante.
    • ECOG performance status =1 (Karnofsky =70%)
    E.4Principal exclusion criteria
    • BMI < 18.5 Kg/m2
    • Previous treatment for breast cancer including chemotherapy, endocrine therapy as well as radiotherapy. Women with prior DCIS who were treated with surgery only and whose treatment ended >2 years prior to enrollment are eligible for the trial.
    • Women who are planned to receive neoadjuvant therapy.
    • Participants may not be receiving investigational agents.
    • History of allergic reactions attributed to compounds of similar chemical or biologic composition to exemestane.
    • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
    • Other co-existing malignancies (with the exclusion of basal cell carcinoma or skin squamous cell carcinoma) diagnosed during the last 2 years before randomization.
    • History of severe osteoporosis (T score < -4 either spine or hip), or presence of vertebral fracture
    • Use of HRT systemic in the last 30 days prior to the randomization.
    • Use of any chemopreventive agents (SERM) in the last 3 months.
    • Concomitant use of CYP3A4 inducer medication (rifampicin, phenytonin, carbamazepine, phenobarbital, and St. John’s wort)
    • BMI < 18.5 Kg/m2
    • Precedente trattamento per tumore al seno, sia chemioterapia, ormonoterapia che radioterapia. Soggetti che abbiano avuto una pregressa neoplasia in situ trattati con la sola chirurgia da almeno due anni possono essere eleggibili
    • Donne candidate a terapia neoadiuvante.
    • Donne in trattamento con terapie sperimentali.
    • Anamnesi di allergia a sostanze simili all’exemestane
    • Malattie intercorrenti non controllate
    • Diagnosi di tumori diversi dal tumore al seno negli ultimi due anni (con l’esclusione di basaliomi o carcinoma squamoso della cute)
    • Grave osteoporosi (T score = -4 o al rachide o all’anca)
    • Uso di HRT sistemica nei 30 giorni precedenti la randomizzazione
    • Uso di SERM negli ultimi 3 mesi
    • Uso concomitante di farmaci induttori di CYP3A4 (rifampicina, fentoina, carbamazepina, phenobarbital, e iperico)
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the percentage change of serum estradiol concentration from baseline and we will compare the median change and percentage changes among arms.
    Variazione percentuale rispetto al basale della concentrazione di estradiolo circolante (variazione mediana e variazione percentuale) nei tre bracci di trattamento
    E.5.1.1Timepoint(s) of evaluation of this end point
    Enrollment period 24 months, treatment period 4-6 week. The analysis on the primary endpoint will be performed at the end of treatment completion of all participants.
    L’analisi dell’ endpoint principale sarà effettuata alla fine del trattamento di tutti i soggetti.
    E.5.2Secondary end point(s)
    • Exemestane safety and toxicity will be evaluated at the clinic visit according to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) and by a self-administered Quality of Life questionnaire (MENQOL).
    • Change in Ki-67 expression comparing pre-treatment versus post-treatment specimen to compare the antiproliferative effect among the different dosages.
    • Serum drug measurements of exemestane and 17-dihydroxyexemestane at the end of treatment.
    • Additional validated method of estradiol measurement. This method has a lower detection limit (1 pg/ml) than the CLIA certified estradiol test (Quest) and will serve as a quality control since it has proven to more effectively detect estradiol concentrations at the very low level, which is characteristic of older postmenopausal women.
    • Serum concentrations of estrone, estrone-sulfate, will be measured by LC-MS/MS while androstenedione and testosterone will be measured by RIA. Sex hormone binding globulin serum levels will be measured by a chemiluminescent microparticle immunoassay (CMIA) on the ARCHITECT i System (Abbott Laboratories, Weisbaden, Germany).
    • Insulin and glucose concentrations will be measured with the Architect Immunoassay analyzer (Abbott Laboratories, Abbott Park, IL, US).
    • Adipokines: change in leptin and adiponectin serum concentrations will be analyzed and compared among the different treatments arms. These measurements will be performed by the use of commercially available enzyme linked immunoassays purchased from R&D systems (SPACE Import-Export Srl, Milan, Italy).
    • Measurement of breast tissue estradiol concentration in tumor and breast fat at time of surgery.
    • Centralized evaluation of ER, PgR, Her2 expression in tumor comparing pre-treatment levels (tru-cut biopsy) to post-treatment level expression (surgical specimen). Centralized evaluation of Ki-67 in adjacent intraepithelial neoplasia and or grossly benign tissue.
    • Drug measurements of exemestane and 17-dihydroxyexemestane on frozen tissue samples, when available.
    • Proteomic analysis will be performed with the new Fusion Tribrid mass spectrometer in Dr. Chen’s Proteomics Shared Resource for the Herbert Irving Comprehensive Cancer Center (HICCC) at CUMC.
    • To analyze the UGT2B17 gene we will use Taqman copy number variation assay (Life Technologies, Monza, Italy).
    • Crown like structures in mammary fat tissue by IHC (CD68), comparing pre-treatment (tru-cut biopsy) versus post-treatment (surgical specimens).; Lipid profile variations
    • Sicurezza e tossicità del farmaco tramite registrazione eventi avversi e valutazione questionario MENQOL prima e dopo il trattamento
    • Variazione di espressione di Ki-67 (biopsia/intervento chirurgico) per confrontare l’effetto antiproliferativo tra i tre dosaggi
    • Misurazione di farmaco e metaboliti circolanti alla fine del trattamento
    • Misurazione di estradiolo circolante con metodo ultrasensibile
    • Variazione di livelli circolanti di estrone, estrone solfato, androstenedione, testostserone, SHBG
    • Variazione di concentrazione di insulina e glicemia
    • Variazione di livelli circolanti di adipochine (leptina ed adiponectina)
    • Misurazione di livelli di estradiolo tissutale in tessuto tumorale e tessuto adiposo adiacente
    • Misurazione centralizzata di parametri istopatologici (biopsia e istologia definitiva); misurazione del Ki-67 in eventuale neoplasia intraepiteliale adiacente e tessuto non tumorale adiacente
    • Misurazione di livelli di farmaco in tessuto congelato
    • Proteomica
    • Analisi del polimorfismo del gene UGT2B17 coinvolto nel metabolismo del farmaco
    • Analisi delle Crown-like structures nel tessuto mammario adiposo; Variazione di valori del profilo lipidico
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoint analysis will be available at the end of the fourth year; At baseline and before surgery
    L’analisi sugli endpoint secondari sarà disponibile alla fine del quarto anno; In condizioni basali e prima dell'intervento chirurgico
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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 No
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned2
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months36
    E.8.9.2In all countries concerned by the trial days0
    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: 65
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 35
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 180
    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)
    Participants will continue their follow-up according to their oncological status
    I partecipanti proseguiranno con i follow-up di routine previsti dalla loro condizione oncologica
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation University of Texas MD Anderson Early Phase Clinical Research Consortium
    G.4.3.4Network Country United States
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-04-12
    P. End of Trial
    P.End of Trial StatusOngoing
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