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    Summary
    EudraCT Number:2019-001447-40
    Sponsor's Protocol Code Number:28UCS2019
    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:2021-04-16
    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 number2019-001447-40
    A.3Full title of the trial
    Pilot Study of Daily Exemestane in Women with Complex Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial Neoplasia or Low Grade Endometrial Cancer
    Studio pilota con exemestane giornaliero in donne con iperplasia atipica complessa dell’endometrio / neoplasia intraepiteliale dell’endometrio o tumore dell’endometrio di basso grado
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Short Course of a Daily Exemestane Tablet Before Surgery for Hyperplasia or Low Grade Cancer of the Endometrium
    Studio pilota con exemestane giornaliero in donne con iperplasia o tumore di basso grado dell'endometrio
    A.3.2Name or abbreviated title of the trial where available
    UWI2016-08-01
    Exe Endometrio
    A.4.1Sponsor's protocol code number28UCS2019
    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 SponsorENTE OSPEDALIERO OSPEDALI GALLIERA
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationE.O. Ospedali Galliera
    B.5.2Functional name of contact pointS.C. Oncologia Medica
    B.5.3 Address:
    B.5.3.1Street AddressMura delle Cappuccine 14
    B.5.3.2Town/ cityGenova
    B.5.3.3Post code16128
    B.5.3.4CountryItaly
    B.5.4Telephone number0105634501
    B.5.6E-mailandrea.decensi@galliera.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 Yes
    D.2.1.1.1Trade name Aromasin
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 [nd]
    D.3.4Pharmaceutical form 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.3.9.1CAS number 107868-30-4
    D.3.9.2Current sponsor code28UCS2019
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Complex Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial Neoplasia or Low Grade Endometrial Cancer in post-menopausal women
    iperplasia atipica complessa dell’endometrio / neoplasia intraepiteliale dell’endometrio o tumore dell’endometrio di basso grado (grado 1 o grado 2) in donne in post menopausa
    E.1.1.1Medical condition in easily understood language
    Pre cancerous lesion of endometrium/endometrial cancer
    Lesione precancerosa dell’endometrio/Tumore dell’endometrio
    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 PT
    E.1.2Classification code 10014755
    E.1.2Term Endometrial hyperplasia
    E.1.2System Organ Class 10038604 - Reproductive system and breast disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10014733
    E.1.2Term Endometrial cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary: Change in tumor proliferation (measured by change in Ki-67 expression) pre and post exemestane treatment.
    L’obiettivo primario dello studio è determinare se c’è una riduzione nell’indice di proliferazione, misurato come espressione di Ki-67, nell’iperplasia complessa atipica (CAH)/neoplasia endometriale intraepiteliale (EIN) o carcinoma endometriale di basso grado (grado 1 o 2) dal basale rispetto a dopo trattamento con exemestane.
    E.2.2Secondary objectives of the trial
    1. Circulating serum estradiol and progesterone
    2. Pathological response (regression of CAH/EIN or low grade (grade 1 and grade 2)
    endometrial carcinoma
    4. DNA mutational analysis through Next Generation Sequencing and methylation status of endometrial tumor
    5. Protein markers via tampon recovery before and after treatment
    6. DNA markers via tampon recovery
    7. Safety and adverse effects of treatment
    6. Comparison of Ki-67 expression between participants samples and historically matched samples
    7. Evaluation of plasma levels of exemestane pre and post treatment
    - Livelli sierici di estradiolo e progesterone pre e post trattamento
    - Risposte patologiche al trattamento (regressione del CAH/EIN o del tumore dell’endometrio di basso grado)
    - Biomarker tissutali
    - Analisi mutazionale mediante Next Generation Sequencing e stato di metilazione del tumore endometriale
    - Analisi delle proteine su tampone vaginale pre e post trattamento
    - Markers del DNA su tampone vaginale
    - Valutazione della safety e degli eventi avversi
    - Confronto dell’espressione di Ki-67 tra popolazione in studio e una coorte storica
    - Misurazione dei livelli plasmatici di exemestane pre e post-trattamento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Females with a histologically proven CAH/ EIN or low grade (grade 1 or grade 2) endometrial carcinoma (EC) for which surgery is planned. The pathologic report from the referring facility will be used to determine pathologic eligibility. This report must be within 45 days of their baseline (pre-surgical) clinic visit.
    - No prior treatment for CAH/EIN/EC
    - Age =45 years
    - Post-menopausal (= 60 years of age or with FSH >30 IU/L if age 45-59). The Ki-67 expression changes based on menopausal status and specifically varies based on what phase of the menstrual cycle the sample is collected. Therefore, in order to eliminate this source of variability, only postmenopausal women will be included in this trial. In addition, exemestane is currently FDA approved for use in post-menopausal women only.
    - ECOG performance status =1 (appendix A)
    - Participants must have normal organ and marrow function as defined below:
    • Hemoglobin = 9 g/dL
    • Serum creatinine = 1.5× upper limit of normal or calculated creatinine clearance = 60 mL/min using Cockcroft-Gault equation for patients with creatinine levels > 1.5× Institutional ULN
    • Total bilirubin = 1.5× ULN OR direct bilirubin = 1× ULN,
    • AST and ALT = 2.5× ULN
    • Hematologic function: WBC ¿ 3000/mcl; platelets ¿ 100,000/mcl.
    - Able and willing to take oral medications.
    - Ability to understand and the willingness to sign a written informed consent document.
    - BMI > 20
    - Donne con diagnosi istologica di CAH/EIN o carcinoma endometriale di basso grado (EC grado 1 o 2) candidate a chirurgia. Il report istologico sarà utilizzato per determinare l’eleggibilità. Questo report deve essere entro i 45 giorni prima della visita di baseline.
    - Nessun trattamento precedente per CAH/EIN/EC
    - Età =45 anni
    - Stato post-menopausale (= 60 anni o FSH >30 IU/L se età 45-59).
    - ECOG performance status =1
    - Funzione degli organi e midollare conservate come qui definito:
    o Emoglobina = 9 g/dL
    o Creatinina = 1.5 x limite superiore della norma (ULN) o clearance della creatinina = 60 mL/min calcolata con la formula di Cockroft-Gault per le pazienti con valori di creatinina > 1.5 volte ULN
    o Bilirubina totale = 1.5× ULN o bilirubina diretta = 1× ULN,
    o AST e ALT = 2.5× ULN
    o Funzione ematologica: Globuli bianchi = 3000/mcl; piastrine = 100.000/mcl.
    - Pazienti in grado di assumere farmaci orali
    - Capacità di comprendere ed esprimere la volontà di firmare un consenso informato
    - BMI > 20
    E.4Principal exclusion criteria
    - Participants who had curatively treated invasive malignancies for which all treatments ended within 1 year prior to the study (with the exception of basal cell or squamous cell carcinoma of the skin),
    - Not a surgical candidate or surgery is not scheduled within 43 days from starting the study drug.
    - Receiving any other investigational agents.
    - Any gastrointestinal condition causing malabsorption or obstruction (e.g. celiac sprue, gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome).
    - Has been on any hormonal treatment (including progestin-containing IUD) for CAH/EIN or low grade (grade 1 or grade 2) endometrial carcinoma in last 3 months.
    - Use hormone replacement therapy (including systemic or topical estrogen, progesterone, or testosterone based medication) or/and phytoestrogen supplements (i.e. black cohosh) or has been on progestin (including progestin containing IUD), tamoxifen or aromatase inhibitor within the prior 3 months.
    - Concomitant use of strong CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s wort as these may significantly reduce the availability of exemestane.
    - Known hypersensitivity to exemestane or its excipients.
    - Known intercurrent illness or psychiatric illness/social situations that will limit compliance with study requirements.
    - Evidence or high suspicion of metastatic disease at enrollment.
    - Women with severe bone density issues/osteoporosis (defined as any medical treatment for osteoporosis, and/or a T-score of -2.5 or lower, and/or history of fracture of the hip or spine).
    - Unwilling or unable to undergo research biopsy during the baseline (pre-surgical) clinic visit, or inadequate research biopsy obtained during the baseline (pre-surgical) clinic visit (determined by the gynecologic oncologist at the time of the subject’s pelvic exam).
    - Pazienti che siano stati sottoposti ad trattamenti per tumori maligni (eccetto il carcinoma basocellulare o squamocellulare della cute) entro un anno prima dello studio.
    - Pazienti non candidate a chirurgia o per cui la chirurgia non sia programmata entro 43 giorno dall’inizio dell’assunzione del farmaco dello studio.
    - Pazienti che ricevono altri farmaci sperimentali
    - Patologie gastro-intestinali concomitanti che determinano malassorbimento o occlusione (ad esempio celiachia, chirurgia di bypass gastrico, aderenze, stenosi, storia di resezione del piccolo intestino, sindrome dell’ansa cieca)
    - Pazienti che abbiano assunto qualsiasi terapia ormonale (compresi gli IUD contenenti progestinico) per CAH/EIN o neoplasia endometrioide di basso grado (grado 1 o 2) negli ultimi 3 mesi
    - Uso di terapia ormonale sostitutiva (compresi estrogeni sistemici o topici, progestinici, o farmaci a base di testosterone) e/o integratori a base di fitoestrogeni (cimicifuga racemosa) o che abbiano utilizzato progesterone (compresi gli IUD contenenti progestinici), tamoxifene o inibitori dell’aromatasi negli ultimi 3 mesi.
    - Uso concomitante di induttori del CYP3A4 come rifampicina, fenitoina, carbamazepina, fenobarbital, erba di San Giovanni
    - Intolleranza accertata a exemestane o ai suoi eccipienti.
    - Gravi patologie concomitanti o disturbi psichiatrici o situazioni sociali che limitino l’aderenza al trattamento
    - Evidenza o sospetto di malattia metastatica al momento dell’arruolamento nello studio
    - Donne con osteopenia severa/osteoporosi (definita come: terapia medica per osteoporosi, e/o T Score di 2.5 o minore e/o storia di fratture del femore o della colonna)
    - Rifiuto o incapacità di sottoporsi alla biopsia di ricerca durante la visita clinica basale (pre-chirurgica) o campione bioptico di ricerca inadeguato ottenuto durante la visita
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the absolute change in Ki-67 expression in endometrial cancer cells from baseline to post-exposure
    L’endpoint primario dello studio è determinare una variazione dell’indice di proliferazione, misurato con l’espressione di Ki-67, nell’iperplasia complessa atipica (CAH)/neoplasia endometriale intraepiteliale (EIN) o carcinoma endometriale di basso grado (grado 1 o 2) dal basale rispetto a dopo trattamento con exemestane.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months
    12 mesi
    E.5.2Secondary end point(s)
    1. Changes in circulating serum estradiol and progesterone pre and post exemestane treatment
    2. Pathological response to exemestane – (regression of CAH/EIN or low grade endometrial carcinoma
    3. Tissue biomarkers
    a. Apoptosis (cleaved caspase 3)
    b. Proliferation (cyclin D1)
    c. Insulin pathway (pAKT, IGF-1R)
    d. Endocrine regulation (ER/PR/AR)
    4. DNA mutational analysis through Next Generations Sequencing and methylation status of
    endometrial tumor
    5. Protein and DNA markers via tampon recovery pre and post exemestane treatment
    6. Comparison of Ki-67 expression between participants samples and historically matched samples
    7. Evaluation of plasma levels of exemestane pre and post treatment
    Gli endpoint secondari dello studio sono:
    1 Modifica dei livelli sierici di estradiolo e progesterone pre e post trattamento
    2 Valutare le risposte patologiche al trattamento (regressione del CAH/EIN o del tumore dell’endometrio di basso grado)
    3 Valutare i seguenti biomarker:
    a Apoptosi (caspasi 3 clivata)
    b Proliferazione (ciclina D1)
    c Pathway dell’insulina (pAKT, IGF-1R)
    d Regolazione endocrina (ER/PR/AR)
    4 Analisi mutazionale mediante Next Generation Sequencing e stato di metilazione del tumore endometriale
    5 Analisi delle proteine e di markers del DNA su tampone vaginale pre e post trattamento
    6 Confronto dell’espressione di Ki-67 tra popolazione in studio e una coorte storica
    7 Misurazione dei livelli plasmatici di exemestane pre e post-trattamento
    E.5.2.1Timepoint(s) of evaluation of this end point
    12 months
    12 mesi
    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 No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    per la valutazione dell'obiettivo secondario sull'espressione di KI67, le pazienti in studio verrann
    For KI67 expression (secondary objective), study participants will be matched with a historical nonr
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    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 Yes
    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 years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 8
    F.4.2.2In the whole clinical trial 40
    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)
    The patient will continue to be followed by the medical staff as before participating in the study.
    il paziente continuerà ad essere seguito dallo staff medico presso cui è in cura come prima della partecipazione allo studio.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-05-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-29
    P. End of Trial
    P.End of Trial StatusOngoing
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