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    Summary
    EudraCT Number:2018-002998-21
    Sponsor's Protocol Code Number:CLEE011O12301C
    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:2021-01-22
    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 number2018-002998-21
    A.3Full title of the trial
    A phase III, multicenter, randomized, open-label trial to evaluate efficacy and safety of ribociclib with endocrine therapy as an adjuvant treatment in patients with hormone receptor-positive, HER2-negative, early breast cancer (New Adjuvant TriAl with Ribociclib [LEE011]: NATALEE)
    Sperimentazione multicentrica di fase III, randomizzata, in aperto per valutare efficacia e sicurezza di ribociclib e terapia endocrina come trattamento adiuvante nelle pazienti con carcinoma della mammella allo stadio iniziale positivo per i recettori ormonali, HER2-negativo (New Adjuvant TriAl with Ribociclib, Sperimentazione su ribociclib con nuovoadiuvante [LEE011]: NATALEE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase III, multicenter, randomized, open-label trial toevaluate efficacy and safety of ribociclib with endocrine therapy as an adjuvant treatment in patients with hormone receptor-positive, HER2-negative, early breast cancer (New Adjuvant TriAl with Ribociclib [LEE011]: NATALEE)
    Sperimentazione multicentrica di fase III, randomizzata, in aperto per valutare efficacia e sicurezza di ribociclib e terapia endocrina come trattamento adiuvante nelle pazienti con carcinoma della mammella allo stadio iniziale positivo per i recettori ormonali, HER2-negativo (New Adjuvant TriAl with Ribociclib, Sperimentazione su ribociclib con nuovoadiuvante [LEE011]: NATALEE)
    A.3.2Name or abbreviated title of the trial where available
    NATALEE
    NATALEE
    A.4.1Sponsor's protocol code numberCLEE011O12301C
    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 SponsorNOVARTIS PHARMA AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedical Trials Analysis Italy srl
    B.5.2Functional name of contact pointMedical Trials Analysis Italy srl
    B.5.3 Address:
    B.5.3.1Street AddressVia Ariosto, 28
    B.5.3.2Town/ cityFerrara
    B.5.3.3Post code44121
    B.5.3.4CountryItaly
    B.5.4Telephone number00390532241595
    B.5.5Fax number00390532203237
    B.5.6E-mailrvergura@mtagroup.net
    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 FEMARA - 30 COMPRESSE 2.5 MG
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS EUROPHARM LTD
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameLetrozolo
    D.3.2Product code [Letrozolo]
    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.3.8INN - Proposed INNLETROZOLO
    D.3.9.1CAS number 112809-51-5
    D.3.9.2Current sponsor codeLetrozolo
    D.3.9.4EV Substance CodeSUB08444MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2500
    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.IMP: 2
    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 Reseligo
    D.2.1.1.2Name of the Marketing Authorisation holderAlvogen IPCo S-àr.1
    D.2.1.2Country which granted the Marketing AuthorisationPoland
    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 nameGoserelin
    D.3.2Product code [Goserelin]
    D.3.4Pharmaceutical form Implant
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPImplantation
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGoserelin
    D.3.9.1CAS number 65807-02-5
    D.3.9.2Current sponsor codeGoserelin
    D.3.9.4EV Substance CodeSUB07962MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3600
    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.IMP: 3
    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 Anastrozole STADA
    D.2.1.1.2Name of the Marketing Authorisation holderSTADApharm GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameAnastrozolo
    D.3.2Product code [Anastrozolo]
    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.3.8INN - Proposed INNAnastrozolo
    D.3.9.1CAS number 120511-73-1
    D.3.9.2Current sponsor codeanastrozolo
    D.3.9.4EV Substance CodeSUB05502MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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.IMP: 4
    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 Kisqali
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    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.3.1Product nameRibociclib
    D.3.2Product code [LEE011]
    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 INNRibociclib
    D.3.9.1CAS number 1374639-75-4
    D.3.9.2Current sponsor codeLEE011
    D.3.9.4EV Substance CodeSUB180246
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    Hormone receptor-positive, HER2-negative, early breast cancer
    Carcinoma della mammella allo stadio iniziale positivo per i recettori ormonali, HER2-negativo
    E.1.1.1Medical condition in easily understood language
    Hormone receptor-positive, HER2-negative, early breast cancer
    Carcinoma della mammella allo stadio iniziale positivo per i recettori ormonali, HER2-negativo
    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 10006203
    E.1.2Term Breast cancer stage unspecified
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level LLT
    E.1.2Classification code 10070575
    E.1.2Term Estrogen receptor positive breast cancer
    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 compare iDFS for ribociclib + ET versus ET in patients with HRpositive, HER2-negative, EBC
    Confrontare l’iDFS per ribociclib + ET contro ET in pazienti con EBC HRpositivo, HER2-negativo
    E.2.2Secondary objectives of the trial
    1. To evaluate the two treatment arms with respect to recurrence-free survival (RFS)
    2. To evaluate the two treatment arms with respect to distant diseasefree survival (DDFS)
    3. To evaluate the two treatment arms with respect to OS
    4. To evaluate patient reported outcomes (PRO) for health-related quality of life (QoL) in the two treatment arms
    5. To evaluate the safety and tolerability of the treatment regimen
    1. Valutare i due bracci di trattamento in relazione alla sopravvivenza libera da recidive (RFS)
    2. Valutare i due bracci di trattamento in relazione alla sopravvivenza libera da recidive a distanza (DDFS)
    3. Valutare i due bracci di trattamento in relazione alla sopravvivenza complessiva (OS)
    4. Valutare gli esiti riferiti dal paziente (PRO) per la qualità della vita (QoL) in relazione alla salute nei due bracci di trattamento
    5. Valutare sicurezza e tollerabilità del regime di trattamento
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for inclusion in this trial must meet all of the following criteria:
    1. Signed and dated Patient Informed Consent Form (PICF) obtained prior to any trial-specific screening procedure.
    2. Patient is = or >18 years-old at the time of PICF signature.
    3. Patient is female with known menopausal status at the time of randomization or initiation of adjuvant ET (whichever occurs earlier), or male.
    4. Patient with histologically confirmed unilateral primary invasive adenocarcinoma of the breast with a date of initial cytologic or histologic diagnosis (i.e. date of the pathology report that
    confirmed the BC diagnosis)within 18 months prior to randomization.
    5. Patient has breast cancer that is positive for ER and/or PgR.
    6. Patient has HER2-negative breast cancer.
    7. Patient has available archival tumor tissue from the surgical specimen.
    8. Patient after surgical resection where tumor was removed completely, with the final surgical specimen microscopic margins free from tumor, and who belongs to one of the following: categories anatomic Stage Group II or Group III
    9. If indicated, patient has completed adjuvant and/or neoadjuvant chemotherapy according to the institutional guidelines, prior to screening.
    10. If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines, prior to screening.
    11. Patient has no contraindication for the adjuvant ET in the trial and is planned to be treated with ET for 5 years
    1. Modulo di consenso informato (MCI) firmato e datato ottenuto prima di qualsiasi procedura di screening specifica per la sperimentazione.
    2. Paziente di età uguale o superiore a 18 anni al momento della firma del MCI.
    3. Paziente di sesso femminile con stato menopausale noto al momento della randomizzazione o dell’avvio di una terapia ET adiuvante (qualunque di essi si presenti per primo) o di sesso maschile.
    4. Paziente con adenocarcinoma della mammella unilaterale primario invasivo istologicamente confermato con una data di diagnosi citologica o istologica iniziale (ovvero data del rapporto patologico che ha confermato la diagnosi di BC) entro 18 mesi prima della randomizzazione.
    5. Paziente con tumore della mammella positivo per ER e/o PgR.
    6. Paziente con carcinoma della mammella HER2-negativo.
    7. Paziente con tessuto tumorale d'archivio disponibile da campioni chirurgici.
    8. Paziente post-resezione chirurgica con rimozione totale del tumore, con campione chirurgico finale con margini microscopici liberi da tumore, appartenente a una delle categorie che seguono: stadiazione anatomica di Gruppo II o Gruppo III.
    9. Ove indicato, la paziente ha completato una chemioterapia adiuvante e/o neoadiuvante secondo le linee guida dell’istituto prima dello screening.
    10. Ove indicato, la paziente ha completato una radioterapia adiuvante secondo le linee guida dell’istituto prima dello screening.
    11. Paziente senza controindicazioni per l’ET adiuvante nella sperimentazione e con previsione di essere trattata con ET per 5 anni (dalla data di randomizzazione) o più.
    E.4Principal exclusion criteria
    1. Patient has received any CDK4/6 inhibitor.
    2. Patient has received prior treatment with tamoxifen, raloxifene or AIs for reduction in risk (“chemoprevention”) of breast cancer and/or treatment
    for osteoporosis within the last 2 years prior to randomization.Patient is concurrently using hormone replacement therapy.
    3. Patient has received prior treatment with anthracyclines at cumulative doses of 450 mg/m² or more for doxorubicin, or 900 mg/m² or more for
    epirubicin.
    4. Patient with a known hypersensitivity to any of the excipients of ribociclib and/or ET (e.g. rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, and soy allergy).
    5. Patient with distant metastases of breast cancer beyond regional lymph nodes (stage IV according to AJCC 8th edition) and/or evidence of recurrence after curative surgery.
    6. Patient is concurrently using other anti-neoplastic therapy with the exception of adjuvant ET (see Inclusion Criterion #12).
    7. Patient has had major surgery, chemotherapy or radiotherapy within 14 days prior to randomization.
    8. Patient has not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies to a NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03 Grade > or =1 at day of randomization. Exception to this criterion: patients with any grade of alopecia and amenorrhea are allowed to enter the trial.
    9. Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before randomization. Note: Patients with prior or concurrent in situ malignancies are eligible provided that adequate curative treatment is completed prior to randomization.
    10. Patient has known history of human immunodeficiency virus (HIV) infection.
    11. Patient has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
    12. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.
    13. Patient that is currently receiving any of the following substances within 7 days before randomization – Concomitant medications, herbal supplements, and/or fruits that are known as strong inhibitors or inducers of CYP3A4/5 or Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
    14. Patient that is currently receiving or has received systemic corticosteroids = 2 weeks prior to starting trial treatment
    15. Patient has impairment of GI function or GI disease that may significantly alter the absorption of the oral trial treatments
    16. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol
    17. Participation in other studies involving interventional drug(s) within 30 days prior to randomization or within 5 half-lives of the investigational drug(s), whichever is longer or participation in any other type of medical research judged not to be scientifically or medically compatible with this trial. If the patient is enrolled or planned to be enrolled in another study that does not involve an investigational drug, the agreement of the Medical Monitor is required to establish eligibility.
    18. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial.

    Additional exclusion criteria as per full protocol may apply.
    1. Paziente che ha ricevuto qualsiasi inibitore del CDK4/6.
    2. Paziente che ha ricevuto un trattamento precedente con tamoxifene, raloxifene o AI per la riduzione del rischio (“chemioprevenzione”) del carcinoma mammario e/o un trattamento per l’osteoporosi entro i 2 anni precedenti la randomizzazione. Il paziente utilizza contemporaneamente una terapia ormonale sostitutiva.
    3. Paziente che ha ricevuto un trattamento precedente con antracicline a dosi cumulative di 450 mg/m² o più per doxorubicina, o 900 mg/m² o più per epirubicina.
    4. Paziente con ipersensibilità nota a uno qualsiasi degli eccipienti di ribociclib e/o dell'ET (ad es. rari problemi ereditari di intolleranza al galattosio, deficit di Lapp lattasi, malassorbimento glucosio-galattosio e allergia alla soia).
    5. Paziente con metastasi a distanza del carcinoma mammario oltre i linfonodi regionali (stadio IV secondo lo AJCC 8° edizione) e/o prova di recidiva dopo la chirurgia curativa.
    6. Paziente attualmente in trattamento con altra terapia antineoplastica con l’eccezione dell’ET adiuvante (si veda il criterio di inclusione N° 12).
    7. Paziente sottoposta a intervento chirurgico maggiore, chemioterapia o radioterapia entro 14 giorni prima della randomizzazione.
    8. Paziente non guarita da tossicità acute cliniche e di laboratorio correlate a precedenti terapie antitumorali a un grado di tossicità > o =1 secondo NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) versione 4.03 al giorno della randomizzazione. Eccezioni a questo criterio: i pazienti con qualsiasi grado di alopecia e amenorrea possono partecipare alla sperimentazione.
    9. Pazienti con malignità invasiva concomitante o precedente malignità invasiva con trattamento completato entro 2 anni prima della randomizzazione. Nota: I pazienti con malignità precedenti o concomitanti in situ sono eleggibili, a patto che il trattamento adeguato e curativo sia stato completato prima della randomizzazione.
    10. Paziente con anamnesi nota di infezione da virus dell’immunodeficienza umana (HIV).
    11. Paziente con infezione attiva nota da virus dell’epatite B (HBV) o epatite C (HCV).
    12. Cardiopatia e/o anomalia della ripolarizzazione cardiaca clinicamente significativa e non controllata.
    13. Pazienti che stanno attualmente ricevendo una qualsiasi delle seguenti sostanze entro 7 giorni prima della randomizzazione - Farmaci concomitanti, integratori a base di erbe e / o frutti che sono noti come forti inibitori o induttori di CYP3A4/5 o farmaci che hanno una stretta finestra terapeutica e sono prevalentemente metabolizzati attraverso CYP3A4/5.
    14. Pazienti che stanno attualmente ricevendo o hanno ricevuto corticosteroidi sistemici = o < a 2 settimane prima di avviare il trattamento di studio.
    15. Paziente con compromissione della funzionalità gastrointestinale o patologia gastrointestinale in grado di alterare in modo significativo l'assorbimento dei trattamenti di studio orali.
    16. Paziente con qualsiasi altra condizione medica concomitante grave e / o non controllata che, a giudizio dello Sperimentatore, causerebbe rischi inaccettabili per la sicurezza, controindicherebbe la partecipazione del paziente alla sperimentazione clinica o comprometterebbe il rispetto del protocollo.
    17. Paziente che partecipa ad un altro studio interventistico con farmaco entro 30 giorni prima della randomizzazione o entro 5 emivite del farmaco sperimentale, qualunque di essi sia più lungo o la partecipazione a qualsiasi altro tipo di ricerca medica giudicata non scientificamente o scientificamente compatibile con questo studio. Se il paziente viene arruolato o pianificato di essere arruolato in un altro studio che non coinvolge un farmaco sperimentale, è necessario l'accordo del Medical Monitor per stabilire l'idoneità.
    18. Donne in gravidanza o allattamento o che prevedono di avere una gravidanza o allattare durante lo studio.
    Possono essere applicati ulteriori criteri di esclusione come da protocollo completo.
    E.5 End points
    E.5.1Primary end point(s)
    iDFS using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials), as assessed by Investigator
    iDFS secondo i criteri STEEP (definizioni standard per gli endpoint di efficacia nelle sperimentazioni sugli adiuvanti nel carcinoma mammario [Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials]), valutata da uno sperimentatore
    E.5.1.1Timepoint(s) of evaluation of this end point
    3.5 years
    3,5 anni
    E.5.2Secondary end point(s)
    - recurrence free survival (RFS) using STEEP criteria
    - Distant disease free survival (DDFS) using STEEP criteria
    - overall survival (OS)
    - Change from baseline in the physical functioning subscale score and global health status/Quality of life scale score as assessed by EORTC QLQ-C30
    - sopravvivenza libera da recidiva (RFS) utilizzando i criteri STEEP
    - Sopravvivenza libera da malattia (DDFS) usando i criteri STEEP
    - sopravvivenza globale (OS)
    - Cambiamento dal basale del punteggio della sub-scala di funzione fisica e del punteggio della scala di stato generale di salute/QoL valutati secondo il questionario EORTC QLQ-C30
    E.5.2.1Timepoint(s) of evaluation of this end point
    - 3.5 years
    - 3.5 years
    - 7.5 years
    - 3.5 years
    - 3,5 anni
    - 3,5 anni
    - 7,5 anni
    - 3,5 anni
    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 Yes
    E.6.13.1Other scope of the trial description
    - Quality of life (QoL) and patient reported outcomes (PRO)
    Qualità della vita (QoL) ed esiti riferiti dal paziente (PRO)
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 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 concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA201
    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
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Canada
    China
    France
    Germany
    Hungary
    Ireland
    Italy
    Korea, Republic of
    Peru
    Poland
    Romania
    Russian Federation
    Spain
    Taiwan
    United Kingdom
    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
    End of trial will be declared when 60 months + 30 days have elapsed from the date the last patient has been randomized
    La fine dello studio verrà dichiarata quando saranno trascorsi 60 mesi + 30 giorni dalla data in cui l'ultimo paziente è stato randomizzato
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days28
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days4
    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: 2000
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2000
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    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 state104
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1764
    F.4.2.2In the whole clinical trial 4000
    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)
    Endocrine therapy or any other anti-cancer treatment according to investigator's clinical judgement
    Terapia endocrina o qualsiasi altro trattamento anticancro secondo il giudizio clinico dell'investigatore
    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 Decision2019-05-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-20
    P. End of Trial
    P.End of Trial StatusOngoing
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