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    The EU Clinical Trials Register currently displays   41228   clinical trials with a EudraCT protocol, of which   6756   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2018-001856-36
    Sponsor's Protocol Code Number:RF-2016-02362383
    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:2021-06-08
    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 number2018-001856-36
    A.3Full title of the trial
    A RANDOMIZED PHASE 2 CLINICAL TRIAL TO EVALUATE THE ACTIVITY OF ATRA IN COMBINATION WITH ANASTROZOLE IN PRE-OPERATIVE PHASE OF OPERABLE HR-POSITIVE/HER2-NEGATIVE EARLY BREAST CANCER
    EBC ATRA TRIAL
    L¿acido retinoico tutto-trans nel trattamento neo-adiuvante di pazienti affette da carcinoma mammario positivo al recettore per gli estrogeni: un studio clinico controllato di tipo ¿window-of-opportunity¿ mirato a verificare l¿attivit¿ del retinoide e a valutare il potenziale diagnostico di un modello di espressione genica predittivo della sensibilit¿ al farmaco
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A RANDOMIZED PHASE 2 CLINICAL TRIAL TO EVALUATE THE ACTIVITY OF ATRA IN COMBINATION WITH ANASTROZOLE IN PRE-OPERATIVE PHASE OF OPERABLE HR-POSITIVE/HER2-NEGATIVE EARLY BREAST CANCER
    EBC ATRA TRIAL
    L¿acido retinoico tutto-trans nel trattamento neo-adiuvante di pazienti affette da carcinoma mammario positivo al recettore per gli estrogeni: un studio clinico controllato di tipo ¿window-of-opportunity¿ mirato a verificare l¿attivit¿ del retinoide e a valutare il potenziale diagnostico di un modello di espressione genica predittivo della sensibilit¿ al farmaco
    A.3.2Name or abbreviated title of the trial where available
    eBC ATRA TRIAL
    eBC ATRA TRIAL
    A.4.1Sponsor's protocol code numberRF-2016-02362383
    A.5.4Other Identifiers
    Name:Codice protocolloNumber:RF-2016-02362383
    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 SponsorIRCCS- ISTITUTO DI RICERCHE FARMACOLOGICHE MARIO NEGRI
    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 supportMinistero della Salute
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportCHEPLAPHARM Arzneimittel GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIRCCS Istituto di Ricerche Farmacologiche Mario Negri
    B.5.2Functional name of contact pointLaboratorio Metodologia per la Rice
    B.5.3 Address:
    B.5.3.1Street AddressVia Giuseppe La Masa, 19
    B.5.3.2Town/ cityMilano
    B.5.3.3Post code20156
    B.5.3.4CountryItaly
    B.5.4Telephone number+390239014695
    B.5.5Fax number+390233200231
    B.5.6E-mailveronica.giuliano@marionegri.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 VESANOID - 100 CAPSULE MOLLI 10 MG IN FLACONE IN VETRO
    D.2.1.1.2Name of the Marketing Authorisation holderCHEPLAPHARM
    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 nameVESANOID
    D.3.2Product code ATRA
    D.3.4Pharmaceutical form Capsule, soft
    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 INNTRETINOINA
    D.3.9.2Current sponsor codeATRA
    D.3.9.3Other descriptive nameAll trans retinoic acid
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Patients with newly, untreated, resectable HR+/HER2- eBCs, suitable for pre-operative therapy with anastrozole
    carcinoma mammario resecabile HR + / HER2- non precedentemente trattati, candidabili alla terapia preoperatoria con anastrozolo
    E.1.1.1Medical condition in easily understood language
    Patients with newly, untreated, resectable HR+/HER2- eBCs, suitable for pre-operative therapy with anastrozole
    carcinoma mammario resecabile HR + / HER2- non precedentemente trattati, candidabili alla terapia preoperatoria con anastrozolo
    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 10006187
    E.1.2Term Breast 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
    To determine the pre-operative activity of ATRA in combination with anastrozole vs. anastrozole alone in operable HR+/HER2- eBCs, via assessment of the proliferative arrest of BC cells (Ki67 level <2.7%).
    - Determinare l¿attivit¿ antitumorale di ATRA, in combinazione con anastrozolo vs anastrozolo da solo in pazienti con carcinoma mammario operabile HR + / HER2- attraverso la misura dell'arresto proliferativo secondo il livello di Ki67 <2,7%.
    E.2.2Secondary objectives of the trial
    1. To assess the activity of ATRA according to the % of Ki67 reduction, measured before and after treatment.
    2. To assess the activity of ATRA in terms of tumor size reduction and response rate, according to the RECIST criteria, after 4 weeks of therapy.
    3. To validate the predictive power of ATRA-21, a gene-expression model associated with ATRA activity.
    4. To assess the safety and tolerability of ATRA administrated daily p.o. for 4 weeks in combination with anastrozole.
    1. Valutare l'attivit¿ di ATRA in base alla riduzione % di Ki67, misurata prima e dopo il trattamento
    2. Valutare l'efficacia di ATRA in termini di riduzione della dimensione del tumore dopo 4 settimane di terapia, secondo i criteri RECIST
    3. Valutare i potenziali biomarcatori predittivi di sensibilit¿ ad ATRA (i.e.ATRA21)
    4. Valutare la sicurezza e la tollerabilit¿ di ATRA somministrato quotidianamente per via orale per 4 settimane in combinazione con anastrozolo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed, informed consent
    2. Histologically confirmed non-metastatic operable primary invasive HR-positive breast cancer subjected to diagnostic core biopsy
    3. Menopausal status
    4. HR-positive/HER2-negative eBC defined as
    - ER>1% on immunohistochemistry (IHC) staining
    - HER2 score equal to 0, 1+, 2+ (if FISH neg) on IHC staining
    5. Available paraffin-embedded tumor block (FFPE) taken at diagnostic biopsy for Ki67 determination (IHC)
    6. Adequate bone marrow, hepatic and renal function including the following
    a. Hb = 9.0 g/dL, absolute neutrophil count = 1.5 x 109/L, platelets =100 x 109/L
    b. Total bilirubin = 1.5 x upper normal limit, excluding cases where elevated bilirubin can be attributed to Gilberts Syndrome
    c. AST (SGOT), ALT (SGPT) = 2.5 x upper normal limit (or 5x UNL in the presence of liver metastases)
    d. Creatinine = 1.5 x upper normal limit
    7. Age = 18 years
    8. Performance status (PS) = 1 (ECOG scale).
    1. Consenso informato scritto
    2. Diagnosi di Carcinoma mammario infiltrante HR positivo, non metastatico, confermato istologicamente
    3. Stato menopausale
    4. Positività immunoistochimica per HR / HER2 definita come: ER> 1%, HER2 uguale a 0, 1+, 2+ (se FISH neg)
    5. Disponibilità di tessuto tumorale della biopsia incluso in paraffina (FFPE) per la determinazione immunoistochimica di Ki67
    6. Funzionalità adeguata funzionalità epatica, renale ed emopoietica:
    a. Hb = 9,0 g / dL, conta assoluta dei neutrofili = 1,5 x 109 / L, piastrine =100 x 109 / L
    b. Bilirubina totale = 1,5 x UNL, esclusi i casi in cui la bilirubina elevata può essere attribuita alla sindrome di Gilberts
    c. AST (SGOT), ALT (SGPT) = 2,5 x UNL (o 5x UNL in presenza di metastasi epatiche)
    d. Creatinina = 1,5 x UNL
    7. Età = 18 anni
    8. Pazienti con performance status (Eastern Cooperative Oncology Group) = 1 .
    E.4Principal exclusion criteria
    1. Presence of metastatic disease
    2. Pre-menopausal status
    3. Previous investigational treatment for any condition within 4 weeks of randomization date
    4. Treatment including radiation therapy, chemotherapy, biotherapy and/or hormonal therapy for the currently diagnosed breast cancer prior to study entry
    5. Co-existing active infection or serious concurrent illness
    6. Any medical or other condition that in the Investigator’s opinion renders the patient unsuitable for this study due to unacceptable risk
    7. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies
    8. Gastrointestinal disorders that may interfere with absorption of the study drug.
    1. Presenza di malattia metastatica
    2. Stato pre-menopausale
    3. Precedente trattamento con farmaci sperimentali entro 4 settimane dalla data di randomizzazione
    4. Trattamento comprendente radioterapia, chemioterapia, bioterapia e / o terapia ormonale per il carcinoma mammario attuale prima dell'ingresso nello studio
    5. Infezione attiva coesistente o malattia concomitante grave
    6. Qualsiasi condizione medica o di altra natura che secondo l'opinione dell'investigatore rende il paziente inadatto alla partecipazione allo studio a causa di un rischio inaccettabile
    7. Disturbi psichiatrici o alterazione dello stato mentale che impediscono la comprensione del consenso informato e / o il completamento delle valutazioni richieste da protocollo
    8. Disturbi gastrointestinali che possono interferire con l'assorbimento del farmaco in studio.
    E.5 End points
    E.5.1Primary end point(s)
    to investigate the primary objective, we will compare the proportion of responder patients in the 2 arm (Aa vs. a) according to the Ki67 assessment, measured at baseline and after treatment.
    per studiare l'obiettivo primario, confronteremo la proporzione di pazienti responder nel braccio Aa vs. a, secondo la valutazione del Ki67, misurata al basale e dopo il trattamento.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary study end-point will be evaluated at the time of surgery after 28 days of treatment.
    L'endpoint primario dello studio sarà valutato al momento dell'intervento chirurgico dopo 28 giorni di trattamento.
    E.5.2Secondary end point(s)
    we will compare the % change in the Ki67 level from baseline in the two treatment groups.; we will determine clinical efficacy (overall response rate, ORR) in terms of tumor size reduction (RECIST criteria) and in terms of pathologic complete responses at the time of surgical resection.; Further exploratory analysis for the identification of correlative biomarkers: we will calculate associations between the Ki67 results and the PAM50 proliferative signature. Moreover we will evaluate the association between Ki67 level and ATRA-21 to test the predictive power of the gene-expression model. Moreover we will determine the ATRA-21 signature, which predicts sensitivity of BC cell lines with great accuracy, and will be validated in the current clinical trial. ATRA-21 consists of 21 genes and the gene-expression signature can be determined from the RNA-sequencing data obtained in basal conditions. Correlations between ATRA-21 predictions and the response of patients to ATRA+anastrozole will be evaluated.; Patients will be monitored for adverse events (AEs) bi-weekly using the definitions and criteria for grading provided in the Common Terminology Criteria for adverse Events (CTCAE) 4.03.
    confronteremo la variazione% nel livello di Ki67 rispetto al basale nei due gruppi di trattamento.; b) determineremo l'efficacia clinica (tasso di risposta globale, ORR) in termini di riduzione della dimensione del tumore (criteri RECIST) e in termini di risposte patologiche complete al momento della resezione chirurgica.; c) Ulteriori analisi esplorative per l'identificazione di biomarcatori correlati: calcoleremo le associazioni tra i risultati del Ki67 e la firma proliferativa del PAM50. Inoltre valuteremo l'associazione tra il livello di Ki67 e l'ATRA-21 per testare il potere predittivo del modello di espressione genica, previamente definito. Inoltre determineremo la capacit¿ della firma genica definita ATRA-21 nel predire la sensibilit¿ al trattamento. ATRA-21 consiste di 21 geni e la firma di espressione genica potr¿ essere determinata per sequenziamento dell'RNA tumorale ottenuto in condizioni basali. Verranno valutate le correlazioni tra l¿espressione di ATRA-21 e la risposta dei pazienti al trattamento; I pazienti saranno monitorati per eventi avversi (AE) bisettimanale utilizzando le definizioni e i criteri per la classificazione forniti nei Common Terminology Criteria for adverse Events (CTCAE) 4.03.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary study end-point will be evaluated at the time of surgery after 28 days of treatment.; The secondary study end-point will be evaluated at the time of surgery after 28 days of treatment.; The secondary study end-point will be evaluated at the time of surgery after 28 days of treatment.; 30 days after the last dose of study treatment.
    L'endpoint secondario dello studio sar¿ valutato al momento dell'intervento chirurgico dopo 28 giorni di trattamento.; L'endpoint secondario dello studio sar¿ valutato al momento dell'intervento chirurgico dopo 28 giorni di trattamento.; L'endpoint secondario dello studio sar¿ valutato al momento dell'intervento chirurgico dopo 28 giorni di trattamento.; 30 giorni dopo l'utlima dose del farmaco in studio.
    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 Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.5.1Number of sites anticipated in the EEA1
    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 Information not present in EudraCT
    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 years2
    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 years2
    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: 51
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 61
    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 state112
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 112
    F.4.2.2In the whole clinical trial 112
    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)
    standard of care.
    Secondo pratica clinica.
    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 Decision2018-08-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-05
    P. End of Trial
    P.End of Trial StatusOngoing
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