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    Summary
    EudraCT Number:2015-000617-43
    Sponsor's Protocol Code Number:CLEE011F2301
    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:2021-06-17
    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 number2015-000617-43
    A.3Full title of the trial
    MONALEESA-3: A randomized double-blind, placebo-controlled study of ribociclib in combination with fulvestrant for the treatment of men and postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment
    MONALEESA-3: Studio randomizzato, in doppio cieco, controllato versus placebo, con ribociclib in associazione a fulvestrant per il trattamento degli uomini e delle donne in post-menopausa con carcinoma mammario positivo per il recettore ormonale, HER2-negativo, in stadio avanzato che non hanno ricevuto alcuna linea di terapia o hanno ricevuto solo una linea di terapia endocrina precedente
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Efficacy and Safety of LEE011 with endocrine treatment in men and Postmenopausal Women with Advanced Breast Cancer
    Studio di valutazione dell’efficacia e della sicurezza d’impiego di ribociclib + fulvestrant in uomini e in donne in post-menopausa con carcinoma mammario in stadio avanzato che non hanno ricevuto alcuna linea di terapia o hanno ricevuto solo una linea di terapia endocrina precedente
    A.3.2Name or abbreviated title of the trial where available
    MONALEESA-3
    MONALEESA-3
    A.4.1Sponsor's protocol code numberCLEE011F2301
    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 FARMA S.P.A.
    B.1.3.4CountryItaly
    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 Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farma S.p.A.
    B.5.2Functional name of contact pointDrug Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressLargo Umberto Boccioni, 1
    B.5.3.2Town/ cityOriggio (VA)
    B.5.3.3Post code21040
    B.5.3.4CountryItaly
    B.5.4Telephone number0296541
    B.5.5Fax number029659066
    B.5.6E-mailinfo.studiclinici@novartis.com
    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 nameLEE011
    D.3.2Product code LEE011
    D.3.4Pharmaceutical form Capsule, hard
    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.3.9.3Other descriptive nameLEE011
    D.3.9.4EV Substance CodeSUB31644
    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.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 Faslodex
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca UK limited
    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 nameFulvestrant
    D.3.2Product code [-]
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFULVESTRANT
    D.3.9.1CAS number 129453-61-8
    D.3.9.2Current sponsor code-
    D.3.9.4EV Substance CodeSUB13933MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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 placeboCapsule, hard
    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
    Men and postmenopausal women with HR+, HER2-negative advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer.
    Uomini e donne in post-menopausa con carcinoma mammario HR+, HER2-negativo avanzato (ricorrenza loco regionale non suscettibile alla terapia curativa o metastatico).
    E.1.1.1Medical condition in easily understood language
    Advanced metastatic breast cancer.
    Carcinoma mammario metastatico avanzato.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10072737
    E.1.2Term Advanced 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 determine whether treatment with ribociclib + fulvestrant prolongs progression free survival (PFS) compared to treatment with placebo + fulvestrant in men and postmenopausal women with HR+, HER2- negative breast cancer.
    L’obiettivo primario è confrontare la sopravvivenza libera da progressione (PFS) tra ribociclib in associazione a fulvestrant e placebo in associazione a fulvestrant in uomini e in donne in post-menopausa con carcinoma mammario HR+, HER2-negativo.
    E.2.2Secondary objectives of the trial
    1. To determine whether treatment with ribociclib + fulvestrant prolongs overall survival (OS) compared to treatment with placebo + fulvestrant.
    2. To evaluate the two treatment arms with respect to overall response rate (ORR), clinical benefit rate (CBR), time to response (TTR) and duration of response (DOR).
    3. To evaluate the two treatment arms with respect to time to deterioration of ECOG performance status.
    4. To evaluate the safety and tolerability of ribociclib in combination with fulvestrant.
    5. To evaluate patient reported outcomes for health-related quality of life in the two treatment arms.
    6. To characterize the pharmacokinetics (PK) of ribociclib (and relevant metabolites) when given in combination with fulvestrant.
    1. Confrontare i due bracci di trattamento rispetto alla sopravvivenza globale;
    2. Valutare i due bracci di trattamento riguardo all'ORR, al CBR, al TTR e alla DOR.
    3. Valutare i due bracci di trattamento riguardo al tempo al deterioramento dell’ECOG performance status;
    4. Valutare la sicurezza d’impiego e la tollerabilità di ribociclib in associazione a fulvestrant,
    5. Valutare il “patient reported outcome” per la determinazione della qualità della vita correlata alla salute nei due bracci di trattamento.
    6. Valutare la farmacocinetica di ribociclib (e dei metaboliti rilevanti) quando somministrato in associazione a fulvestrant.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient is an adult male/female = 18 years
    2. Female patient is postmenopausal.
    3. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory (based on most recent analyzed biopsy) and has HER2-negative breast cancer (based on most recent analyzed biopsy).
    4. Patient has HER2-negative breast cancer (based on most recent analyzed biopsy) defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing.
    5. Patient must have either:
    • Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1. (a lesion at a previously irradiated site may only be counted as a target lesion if there is a clear sign of progression since the irradiation).
    OR
    • If no measurable disease is present, then at least one predominantly lytic bone lesion must be present (patients with no measurable disease and only one predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation).
    6. Patient has advanced (loco regionally recurrent not amenable to curative therapy (e.g. surgery and/or radiotherapy) or metastatic) breast cancer.
    Patients may be:
    • newly diagnosed advanced/ metastatic breast cancer, treatment naïve
    • relapsed with documented evidence of relapse more than 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for advanced/metastatic disease
    • relapsed with documented evidence of relapse on or within 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for advanced/metastatic disease
    • relapsed with documented evidence of relapse more than 12 months from completion of (neo)adjuvant endocrine therapy and then subsequently progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor) for advanced/metastatic disease
    • advanced/metastatic breast cancer at diagnosis that progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor)
    7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
    8. Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by central laboratory for eligibility):
    • Absolute neutrophil count = 1.5 × 109/L
    • Platelets = 100 × 109/L
    • Hemoglobin = 9.0 g/dL
    • INR =1.5
    • Serum creatinine < 1.5 mg/dL
    • Total bilirubin < ULN except for patients with Gilbert’s syndrome who may only be
    included if the total bilirubin is = 3.0 × ULN or direct bilirubin = 1.5 × ULN.
    • Aspartate transaminase (AST) < 2.5 × ULN, except for patients with liver metastasis, who are only included if the AST is < 5 × ULN
    • Alanine transaminase (ALT) < 2.5 × ULN, except for patients with liver metastasis,
    who are only included if the ALT is < 5 × ULN
    • Patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements before the first dose of study medication:
    - Sodium
    - Potassium
    - Magnesium
    - Total Calcium (corrected for serum albumin)
    1. Pazienti adulti, maschi/femmine, di età > 18 anni al momento del consenso informato.
    2. Le pazienti devono essere in post-menopausa.
    3. Pazienti con una diagnosi istologica e/o citologica confermata di carcinoma mammario positivo per il recettore dell’estrogeno e/o positivo per il recettore del progesterone, stabilita dal laboratorio locale (sulla base della biopsia analizzata più recentemente).
    4. Pazienti con carcinoma mammario HER2-negativo (sulla base della biopsia analizzata più recentemente) definito dalla negatività del test di ibridizzazione in situ o da uno status IHC di 0, 1+ o 2+. Se IHC fosse 2+ è necessario un test di ibridizzazione in situ negativo (FISH, CISH o SISH) mediante valutazione del laboratorio locale.
    5. I pazienti devono presentare:
    • Malattia misurabile, ossia almeno una lesione misurabile in base ai criteri RECIST 1.1 (una lesione tumorale in un sito precedentemente irradiato sarà considerata una lesione target solo in presenza di un chiaro segno di progressione dal momento dell’irradiazione),
    oppure
    • Se non è presente malattia misurabile, dovrà essere presente almeno una lesione ossea prevalentemente litica (i pazienti con malattia non misurabile e solo una lesione ossea prevalentemente litica che sia stata precedentemente irradiata sono eleggibili se vi è evidenza documentata di progressione della lesione ossea dopo irradiazione).
    6. Pazienti con carcinoma mammario in stadio avanzato (in recidiva locoregionale non candidabile alla terapia curativa, ossia chirurgia e/o radioterapia, o metastatico).
    I pazienti possono presentare:
    • Carcinoma mammario in stadio avanzato/metastatico di nuova diagnosi e naïve al trattamento
    • Recidiva con evidenza documentata di recidiva oltre 12 mesi dal completamento della terapia endocrina (neo)adiuvante senza alcun trattamento per la malattia in stadio avanzato/metastatica
    • Recidiva con evidenza documentata di recidiva durante o entro 12 mesi dal completamento della terapia endocrina (neo)adiuvante senza alcun trattamento per la malattia in stadio avanzato/metastatica
    • Recidiva con evidenza documentata di recidiva oltre 12 mesi dal completamento della terapia endocrina (neo)adiuvante e successiva progressione con evidenza documentata di progressione dopo una linea di terapia endocrina (con un antiestrogeno o un inibitore dell’aromatasi) per la malattia in stadio avanzato/metastatica
    • Carcinoma mammario in stadio avanzato/metastatico alla diagnosi che ha manifestato progressione con evidenza documentata di progressione dopo una linea di terapia endocrina (con un antiestrogeno o un inibitore dell’aromatasi).
    7. Eastern Cooperative Oncology Group (ECOG) performance status di 0 o 1.
    8. Pazienti con funzionalità midollare e d’organo adeguatadefinita dai seguenti valori di laboratorio (valutata dal laboratorio centralizzato per l’eleggibilità):
    • Conta neutrofilica assoluta > 1,5 x 109/L
    • Piastrine > 100 x 109/L
    • Emoglobina > 9,0 g/dL
    • INR < 1,5
    • Creatinina sierica < 1,5 mg/dL
    • Bilirubina sierica totale < ULN a eccezione delle pazienti con sindrome di Gilbert che potranno essere incluse solo se la bilirubina totale è < 3,0 x ULN o la bilirubina diretta è < 1,5 x ULN.
    • Aspartato aminotrasferasi (AST) < 2,5 x ULN a eccezione delle pazienti con metastasi epatiche, che saranno incluse solo se AST è < 5 x ULN.
    • Alanina-aminotrasferasi (ALT) < 2,5 x ULN a eccezione delle pazienti con metastasi epatiche, che saranno incluse solo se ALT è < 5 x ULN.
    • I pazienti devono presentare i seguenti valori di laboratorio entro i limiti della norma o corretti con integratori entro i limiti della norma prima della somministrazione della prima dose del trattamento in studio:
    - Sodio
    - Potassio
    - Magnesio
    - Calcio totale (corretto per l’albumina sierica)
    E.4Principal exclusion criteria
    1. Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator’s best judgment.
    2. Patient has received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant or any CDK4/6 inhibitor.
    3. Patients has received prior neoadjuvant/adjuvant treatment with anthracyclines at cumulative doses of 450mg/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 or fulvestrant.
    5. Patient with inflammatory breast cancer at screening.
    6. Patient is concurrently using other anti-cancer therapy.
    7. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
    8. Patients with Child pugh score B or C.
    9. Patient is currently receiving warfarin or other Coumadin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.
    10. Patient has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade =1. Exception to this criterion: patients with any grade of alopecia are allowed to enter the study.
    11. Patient has received radiotherapy = 4 weeks or limited field radiation for palliation = 2 weeks prior to randomization, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia) and/or from whom = 25% (Ellis 1961) of the bone marrow was irradiated.
    12. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated, basal or squamous cell skin carcinoma or curatively resected cervical cancer.
    13. Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
    • At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment.
    • Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases.
    14. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
    15. Patient has a known history of HIV infection (testing not mandatory)
    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 study or compromise compliance with the protocol: (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.).

    For further exclusion criteria please refer to the protocol.
    1. Pazienti con malattia viscerale sintomatica o qualsiasi carico di malattia che renda il paziente non eleggibile alla terapia endocrina, secondo il giudizio dello sperimentatore.
    2. Pazienti sottoposti a trattamento precedente con chemioterapia (a eccezione di chemioterapia neoadiuvante/adiuvante), fulvestrant o qualsiasi inibitore di CDK4/6.
    3. Pazienti sottoposti a trattamento neoadiuvante/adiuvante precedente con antracicline a dosi cumulative di 450 mg/m2 o superiori per doxorubicina oppure di 900 mg/m2 o superiori per epirubicina.
    4. Pazienti con un’ipersensibilità nota a qualunque degli eccipienti di ribociclib o fulvestrant.
    5. Pazienti che manifestano carcinoma mammario infiammatorio al momento dello screening.
    6. Pazienti che stanno ricevendo attualmente altra terapia antitumorale.
    7. Pazienti sottoposti a intervento chirurgico maggiore entro 14 giorni prima dell’inizio del trattamento in studio o che non hanno presentato guarigione degli effetti collaterali principali.
    8. Pazienti con punteggio Child-Pugh B o C.
    9. Pazienti che stanno attualmente assumendo warfarin sodico o altro anticoagulante derivato del Coumadin, come trattamento o profilassi o altro. La terapia con eparina, eparina a basso peso molecolare (LMWH) o fondaparinux è consentita.
    10. Pazienti che non hanno presentato risoluzione di tutte le tossicità della terapia antitumorale precedente a Grado < 1 NCI CTCAE versione 4.03. Eccezione a questo criterio: ai pazienti con qualsiasi grado di alopecia è consentita la partecipazione allo studio.
    11. Pazienti che hanno ricevuto radioterapia < 4 settimane o radioterapia a campo limitato a scopo palliativo < 2 settimane prima della randomizzazione e che non hanno presentato risoluzione a Grado 1 o inferiore degli effetti collaterali correlati a questa terapia (a eccezione di alopecia) e/o nei quali > 25% (Ellis 1961) del midollo osseo sia stato irradiato.
    12. Pazienti con una neoplasia concomitante o una neoplasia entro 3 anni dalla randomizzazione, a eccezione di: carcinoma cutaneo a cellule basali o a cellule squamose adeguatamente trattati o carcinoma della cervice sottoposto a trattamento chirurgico curativo.
    13. Pazienti con coinvolgimento metastatico del SNC, a meno che non soddisfino TUTTI i criteri seguenti:
    • Almeno 4 settimane dal termine della terapia precedente (comprese radioterapia e/o intervento chirurgico) per iniziare il trattamento in studio.
    • Tumore del SNC clinicamente stabile al momento dello screening e nessuna terapia con corticosteroidi e/o farmaci antiepilettici induttori enzimatici per le metastasi cerebrali.
    14. Pazienti con compromissione della funzionalità gastrointestinale (GI) o con patologie gastrointestinali che possono alterare significativamente l’assorbimento dei trattamenti in studio (ad es. colite ulcerosa, nausea non controllata, vomito, diarrea, sindrome da malassorbimento o resezione dell’intestino tenue).
    15. Diagnosi nota d’infezione da HIV (i test non sono obbligatori).
    16. Pazienti con patologie concomitanti gravi e/o non controllate che, a giudizio dello sperimentatore, potrebbero determinare rischi per la sicurezza d’impiego inaccettabili, potrebbero controindicare la partecipazione del paziente allo studio o potrebbero compromettere la compliance con il protocollo (ad es. pancreatite cronica, epatite cronica in fase attiva, infezioni micotiche, batteriche o virali in fase attiva, non trattate o non controllate, ecc.).

    Per ulteriori criteri di esclusione si prega di far riferimento al protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is PFS, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed according to RECIST 1.1.
    L'endpoint primario dello studio è la sopravvivenza libera da malattia (PFS), definita come il tempo dalla data di randomizzazione alla data della prima progressione di malattia documentata o morte dovuta a qualsiasi causa. PFS sarà misurata in accordo ai criteri RECIST 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Final analysis around 26 months from the date of first patient randomized.
    Analisi finale a circa 26 mesi dalla data del primo paziente randomizzato.
    E.5.2Secondary end point(s)
    1. Overall survival: Time from date of randomization to the date of death
    from any cause.
    2. ORR: Proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR) according to RECIST 1.1.
    3. CBR: Percentage of patients with complete response (CR) or partial
    response (PR) or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1.
    4. TTR: Time from randomization to the first documented and confirmed
    response (complete response or partial response) as defined in RECIST
    1.1.
    5. DOR: Time from the first documented response (CR or PR) to the first
    documented progression or death due to underlying cancer as defined in
    RECIST 1.1.
    6. ECOG: Time to definitive deterioration of ECOG performance status
    from baseline: Time to deterioration of ECOG performance Status.
    7. Safety and tolerability of LEE001: Determined by type, frequency and
    severity of Adverse Events per CTCAE version 4.03 and type, frequency
    and severity of laboratory toxicities per CTCAE version 4.03.
    8. Time to 10% deterioration in the global health status/QOL scale score
    of the EORTC QLQ-C30: Patient reported outcomes for health related
    quality of life.
    9. A change from baseline in the global health status/QOL scale score of
    the EORTC QLQ-C30: Patient reported outcomes for health related quality of life.
    10. Concentration by time point for ribociclib (and relevant metabolites).
    1. Sopravvivenza globale: tempo dalla data di randomizzazione alla data di morte per qualsiasi causa.
    2. ORR: proporzione di pazienti con la migliore risposta globale (BOR) o la risposta completa (CR) o la risposta parziale (PR) in accordo al RECIST 1.1.
    3. CBR: percentuale di pazienti con risposta completa (CR) o risposta parziale (PR) o malattia stabile (SD) della durata di 24 settimane o più come definito dai criteri RECIST 1.1.
    4. TTR: tempo dalla randomizzazione alla prima risposta documentata e confermata (risposta completa o parziale) come definito dai criteri RECIST 1.1.
    5. DOR: tempo dalla prima risposta documentata (CR o PR) alla prima progressione di malattia documentata o morte dovuta al carcinoma così come definito dai criteri RECIST 1.1.
    6. ECOG: tempo dal peggioramento definitivo dello status di performance di ECOG dal baseline: tempo di peggioramento dello status di performance ECOG.
    7. Sicurezza e tollerabilità di LEE011: determinati dal tipo, frequenza e gravità degli eventi avversi per CTCAE versione 4.03 e tipo, frequenza e gravità delle tossicità di laboratorio per CTCAE versione 4.03.
    8. Tempo al 10% di peggioramento nello status di salute globale/punteggio della scala EORTC QLQ-C30: pazienti hanno riportato risultati per QoL relativo alla salute.
    9. Un cambiamento dal baseline nello status di salute globale/punteggio della scala EORTC QLQ-C30: pazienti che hanno riportato risultati per QoL relativo alla salute.
    10. Concentrazione di ribociclib (e metaboliti rilevanti) a tempi prestabiliti.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. 58 months from date of first patient randomized
    2. ORR: up to approximately 26 months
    3. CBR: up to approximately 26 months
    4. TTR: up to approximately 26 months
    5. DOR: up to approximately 26 months
    6. ECOG performance status deterioration: up to approximately 26 months
    7. Safety and tolerability: up to approximately 26 months
    8. 10% deterioration in QOL: up to approximately 26 months
    9. Change from baseline in QOL: up to approximately 26 months
    10. Concentration by time point: up to approximately 26 months
    1. 58 mesi dalla data del primo paziente randomizzato.
    2. ORR: fino a circa 26 mesi
    3. CBR: fino a circa 26 mesi
    4. TTR: fino a circa 26 mesi
    5. DOR: fino a circa 26 mesi
    6. Status di deterioramento della performance ECOG: fino a circa 26 mesi
    7. Sicurezza e tollerabilità: fino a circa 26 mesi
    8. Peggioramento del 10% nella QoL: fino a circa 26 mesi
    9. Cambiamento dal basale nel QOL, fino a circa 26 mesi
    10. Concentrazione a tempi prestabiliti, fino a circa 26 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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of Life (QoL)
    Qualità di vita
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    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) No
    E.8.2.2Placebo Yes
    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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA146
    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
    Bulgaria
    Canada
    Colombia
    Czechia
    Denmark
    France
    Germany
    Hungary
    Israel
    Italy
    Jordan
    Korea, Republic of
    Lebanon
    Malaysia
    Mexico
    Netherlands
    Norway
    Poland
    Portugal
    Russian Federation
    Singapore
    Spain
    Sweden
    Switzerland
    Thailand
    Turkey
    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
    The end of the study for a given patient is defined as when the patient permanently discontinues study treatment with ribociclib + fulvestrant or placebo + fulvestrant and all the end of trial procedures are completed.
    La fine dello studio è definita quando un paziente interrompe in modo permanente il trattamento in studio con ribociclib + fulvestrant o placebo + fulvestrant e tutte le procedure dello studio sono completate.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days20
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days20
    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: 396
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 264
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 289
    F.4.2.2In the whole clinical trial 660
    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)
    Patients continuing to derive benefit from study treatment at the end of the study in the opinion of the investigator will be able to continue receiving trial therapy on a separate protocol. Alternatively Novartis will provide study treatment to the investigator as per local regulations.
    I pazienti che continueranno a beneficiare del trattamento alla fine dello studio, secondo l'opinione del medico, potranno continuare a ricevere la terapia sperimentale in un protocollo separato. Alternativamente Novartis provvederà a fornire al medico il trattamento di studio secondo le regole locali.
    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 Decision2015-07-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-07
    P. End of Trial
    P.End of Trial StatusOngoing
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