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    Summary
    EudraCT Number:2014-001931-36
    Sponsor's Protocol Code Number:CLEE011E2301
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-02-09
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2014-001931-36
    A.3Full title of the trial
    A Phase III randomized, double-blind, placebo-controlled study of LEE011 or placebo in combination with tamoxifen and goserelin or a non-steroidal aromatase inhibitor (NSAI) and goserelin for the treatment of premenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer
    Estudio fase III, aleatorizado, doble ciego, controlado con placebo, de LEE011 o placebo en combinación con tamoxifeno y goserelina o de un inhibidor de la aromatasa no esteroideo (IANE) y goserelina para el tratamiento de mujeres premenopáusicas con cáncer de mama avanzado con receptor hormonal positivo, HER2 negativo.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Efficacy and Safety of LEE011 in Premenopausal Women With Advanced Breast Cancer
    Estudio que evalúa la eficacia y seguridad de LEE011 en mujeres premenopáusicas con cáncer de mama avanzado
    A.3.2Name or abbreviated title of the trial where available
    Monaleesa-7
    Monaleesa-7
    A.4.1Sponsor's protocol code numberCLEE011E2301
    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 Farmacéutica, S.A.
    B.1.3.4CountrySpain
    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 Farmacéutica, S.A.
    B.5.2Functional name of contact pointDepartamento Médico Oncología (GMO)
    B.5.3 Address:
    B.5.3.1Street AddressGran Vía de les Corts Catalanes, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number34900353036
    B.5.5Fax number34932479903
    B.5.6E-maileecc.novartis@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.3.2Product 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 INNLEE011
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 Femara
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Farmacéutica, S.A.
    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 nameFemara
    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 INNLETROZOL
    D.3.9.1CAS number 112809-51-5
    D.3.9.2Current sponsor codeLETROZOL
    D.3.9.3Other descriptive nameLETROZOL
    D.3.9.4EV Substance CodeSUB08444MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 Zoladex
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca Farmacéutica Spain, S.A.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameZoladex
    D.3.4Pharmaceutical form Implant in pre-filled syringe
    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.3.9.3Other descriptive nameACETATO DE GOSERELIN
    D.3.9.4EV Substance CodeSUB02400MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.6
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.2.5The 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.3.4Pharmaceutical 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 INNtamoxifeno
    D.3.9.1CAS number 10540-29-1
    D.3.9.2Current sponsor codeTAMOXIFENO
    D.3.9.3Other descriptive nameCITRATO DE TAMOXIFENO
    D.3.9.4EV Substance CodeSUB04672MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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: 5
    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.2.5The 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.3.4Pharmaceutical 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 INNanastrozol
    D.3.9.1CAS number 120511-73-1
    D.3.9.2Current sponsor codeANASTROZOL
    D.3.9.3Other descriptive nameANASTROZOL
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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
    premenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer
    mujeres premenopáusicas con cáncer de mama avanzado con receptor hormonal positivo, HER2 negativo
    E.1.1.1Medical condition in easily understood language
    Advanced, Metastatic Breast Cancer
    Cáncer de Mama Avanzado, Metastásico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    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 tamoxifen/NSAI + goserelin + LEE011 prolongs PFS compared to treatment with tamoxifen/NSAI + goserelin + placebo in premenopausal women with HR+, HER2-negative breast cancer
    Determinar si el tratamiento con tamoxifeno o un IANE + goserelina + LEE011 prolonga la SLP comparado con el tratamiento con tamoxifeno o un IANE + goserelina + placebo en mujeres premenopáusicas con cáncer de mama avanzado HR+, HER2-negativo.
    E.2.2Secondary objectives of the trial
    Key secondary:
    To determine whether treatment with tamoxifen/NSAI + goserelin + LEE011 prolongs OS compared to treatment with tamoxifen/NSAI + goserelin + placebo
    Secundario principal
    Determinar si el tratamiento con tamoxifeno o un IANE + goserelina + LEE011 prolonga la supervivencia global (SG) comparado con el tratamiento con tamoxifeno o un IANE + goserelina + placebo en mujeres premenopáusicas con cáncer de mama avanzado HR+, HER2-negativo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient is an adult, female ? 18 years old and < 60 years old at the time of informed consent and has signed informed consent before any trial related activities are conducted and according to local guidelines.
    2. Confirmed negative serum pregnancy test (?-hCG) within 72 hrs before starting study treatment.
    3. Patient is premenopausal or perimenopausal at the time of study entry.
    4. Patient has advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy (e.g. surgery and/or radiotherapy).
    5. Patients who received (neo) adjuvant therapy for breast cancer are eligible:
    ? If the patient has never received any prior endocrine therapy OR if ? 12 months have elapsed since the patient?s last dose of adjuvant therapy, then the patient is eligible to receive tamoxifen + goserelin OR a NSAI + goserelin for advanced breast cancer based on the investigator?s choice.
    ? 12 months prior to randomization, then the patient is eligible to receive a NSAI (letrozole or anastrazole) + goserelin for advanced breast cancer.
    ? If letrozole, anastrozole, fulvestrant, or exemestane was the last prior (neo) adjuvant therapy and the last dose was given < 12 months prior to randomization, then the patient is eligible to receive tamoxifen + goserelin for advanced breast cancer.
    Note: Prior (neo) adjuvant anti-cancer therapy must be stopped at least 5 half-lives or 7 days before randomization, whichever is longer.
    6. Patients who received ? 14 days of tamoxifen or a NSAI (letrozole or anastrozole) with or without goserelin for advanced breast cancer prior to randomization are eligible. Patients must continue treatment with the same hormonal agent + goserelin during the study. No treatment interruption is required for these patients prior to randomization.
    7. Patients who have received up to 1 line of chemotherapy for advanced breast cancer and have been discontinued 28 days before randomization are eligible.
    8. 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 recently analyzed biopsy).
    9. Patient has HER2-negative breast cancer (based on most recently 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.
    10. Patient must have either:
    ? Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria.
    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).
    11. Patient has ECOG PS 0 or 1.
    12. Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by central laboratory).

    Other inclusion criteria as per full protocol may apply.
    1.Pacientes adultas, mujeres ? 18 años y < 60 años en el momento del consentimiento informado y que hayan firmado el consentimiento informado antes de que se realice cualquier actividad relacionada con el ensayo según las pautas locales.
    2.Prueba de embarazo en suero negativa confirmada (?-hCG) dentro de las 72 horas antes de iniciar el tratamiento del estudio.
    3.La paciente sea premenopáusica o perimenopáusica en el momento del inicio del estudio.
    4.Pacientes con cáncer de mama avanzado (metastásico o recurrente locorregionalmente) no aptas para terapia curativa (por ejemplo, cirugía y/o radioterapia).
    5.Las pacientes que hayan recibido terapia (neo) adyuvante para el cáncer de mama son elegibles.
    o Si la paciente nunca ha recibido ninguna terapia previa endocrina O si han transcurrido ? 12 meses desde la última dosis de la paciente de terapia adyuvante, entonces, la paciente es elegible para recibir tamoxifeno + goserelina O un IANE + goserelina para el cáncer de mama avanzado basado en la elección del investigador.
    o Si tamoxifeno fue la última terapia (neo) adyuvante previa y la última dosis se administró < 12 meses antes de la aleatorización, entonces la paciente es elegible para recibir un IANE (letrozol o anastrozol) + goserelina para el cáncer de mama avanzado.
    o Si letrozol, anastrozol, fulvestrant o exemestano fue la última terapia (neo) adyuvante previa y la última dosis se administró < 12 meses antes de la aleatorización, entonces la paciente es elegible para recibir tamoxifeno + goserelina para el cáncer de mama avanzado
    Nota: Cualquier terapia antineoplásica (neo) adyuvante previa deberá suspenderse por lo menos 5 semividas o 7 días, lo que sea más largo, antes de la aleatorización
    6. Son elegibles pacientes que recibieron ? 14 días de tamoxifeno o un IANE (letrozol o anastrozol) con o sin goserelina para el cáncer de mama avanzado antes de la aleatorización. Las pacientes deberán continuar el tratamiento con el mismo agente hormonal + goserelina durante el estudio. No se precisa interrupción del tratamiento para estas pacientes antes de la aleatorización.
    7. Son elegibles pacientes que hayan recibido hasta 1 línea de quimioterapia para el cáncer de mama avanzado y se les haya suspendido por lo menos 28 días antes de la aleatorización.
    8. Pacientes con diagnóstico histológicamente y/o citológicamente confirmado de cáncer de mama con receptor progesterónico positivo y/o receptor estrogénico positivo por el laboratorio local (basado en la biopsia analizada más recientemente).
    9. Paciente con cáncer de mama HER2-negativo (basado en la biopsia analizada más recientemente) definido como un test de hibridización in situ negativo o un estado de IHC de 0, 1+ o 2+. Si el IHC es 2+, se requiere un test de hibridización in situ negativo (FISH, CISH o SISH) en el análisis de laboratorio local.
    10. La paciente deberá presentar:
    o Enfermedad medible, es decir, por lo menos una lesión medible según los criterios RECIST 1.1
    O
    o En caso de ausencia de enfermedad medible, entonces deberá estar presente por lo menos una lesión ósea predominantemente lítica (las pacientes sin enfermedad medible y sólo una lesión ósea predominantemente lítica que haya sido irradiada previamente son elegibles, si existe evidencia documentada de progresión de la enfermedad de la lesión ósea después de la irradiación).
    11. Pacientes con una puntuación de 0 ó 1 en el PS del ECOG.
    12. Pacientes con una función orgánica y de médula ósea adecuada definida por los siguientes valores de laboratorio (evaluado por el laboratorio central):
    o Recuento absoluto de neutrófilos ? 1.5 × 109/L
    o Plaquetas ? 100 × 109/L
    o Hemoglobina ? 9.0 g/dL
    o Potasio, sodio, calcio (corregido para albúmina sérica), magnesio y fósforo dentro de los límites de normalidad del laboratorio central
    o INR ?1.5
    o Creatinina sérica dentro de los límites de normalidad del laboratorio central
    o En caso de ausencia de metástasis hepáticas, la alanina aminotransferasa (ALT) y la aspartato aminotransferasa (AST) debería encontrarse por debajo de 2.5 x LSN. Si la paciente presenta metástasis hepáticas, la ALT y la AST deberían ser < 5 x LSN
    o Bilirrubina sérica total < LSN; o bilirrubina total ? 3.0 × LSN con bilirrubina directa dentro del rango de normalidad del laboratorio central en pacientes con síndrome de Gilbert bien documentado
    E.4Principal exclusion criteria
    1. Patient who has received a prior CDK4/6 inhibitor.
    2. Patient has a known hypersensitivity to any of the excipients of LEE011 or goserelin or hormonal treatment assigned (tamoxifen, NSAI (letrozole or anastrozole)).
    3. Patient is postmenopausal.
    4. Patients who currently have inflammatory breast cancer on screening.
    5. Patient who received any prior hormonal anti-cancer therapy for advanced breast cancer, except for ? 14 days of tamoxifen or NSAI ± goserelin for advanced breast cancer prior to randomization.
    6. Patient who has not had resolution of all acute toxic effects of prior anti-cancer therapy to NCI CTCAE version 4.03 Grade ?1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
    7. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated basal cell skin carcinoma, squamous cell skin carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.
    8. Patient with CNS metastases.
    9. 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)
    10. Patient has a known history of HIV infection (testing not mandatory)
    11. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator?s judgment, contraindicate patient participation in the clinical study (e.g., chronic pancreatitis, chronic active hepatitis, etc.)
    12. Patient has active cardiac disease or a history of cardiac dysfunction
    13. Patient is currently receiving any of the substances described in the protocol and cannot be discontinued 7 days prior to the start of the treatment.
    14. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
    15. 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.
    16. Patient is currently receiving or has received systemic corticosteroids ? 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment.
    17. Patient is concurrently using other antineoplastic agents (except for patients who are receiving ? 14 days of tamoxifen or NSAI ± goserelin for advanced breast cancer prior to randomization).
    18. Patient who 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 if ? 25% of the bone marrow was irradiated.
    19. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
    20. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment. Highly effective contraception methods include:
    a. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    b. Tubal ligation at least six weeks before taking study treatment.
    c. Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject.
    ? Combination of the following:
    a. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository

    Other exclusion criteria as per full protocol may apply.
    1. Pacientes que hayan recibido un inhibidor de CDK4/6 previo
    2. Pacientes con hipersensibilidad conocida a cualquier excipiente de LEE011, tamoxifeno, IANE (letrozol o anastrozol) o goserelina
    3. La paciente sea postmenopáusica.
    4. Pacientes con cáncer de mama inflamatorio actualmente en la selección
    5. Pacientes que hayan recibido cualquier terapia antineoplásica hormonal previa para el cáncer de mama avanzado excepto ? 14 días de tamoxifeno o un IANE ± goserelina para el cáncer de mama avanzado antes de la aleatorización.
    6. Pacientes que no presenten resolución de todos los efectos tóxicos agudos de la terapia antineoplásica a grado ?1 de la versión 4.03 de los CTCAE del INC (excepto alopecia u otras toxicidades que no se consideren un riesgo de seguridad para la paciente, a discreción del investigador).
    7. Pacientes con una enfermedad maligna concurrente o enfermedad maligna dentro de los 3 años de la aleatorización, con la excepción de carcinoma cutáneo de células basales, carcinoma cutáneo escamoso, carcinoma cutáneo no melanomatoso adecuadamente tratados o cáncer del cuello del útero extirpado curativamente.
    8. Pacientes con metástasis del SNC.
    9. Pacientes con deterioro de la función gastrointestinal (GI) o enfermedad GI que pueda alterar significativamente la absorción de las medicaciones del estudio (por ejemplo, enfermedades ulcerosas, náuseas incontroladas, vómitos, diarrea, síndrome de mala absorción o resección del intestino delgado).
    10. Pacientes con antecedentes conocidos de infección por VIH (la prueba no es obligatoria)
    11. Pacientes con otras condiciones médicas concomitantes graves y/o incontroladas concurrentes que pudiesen, a juicio del investigador, contraindicar la participación de la paciente en el estudio clínico (por ejemplo, pancreatitis crónica, hepatitis crónica activa, etc.).
    12. Pacientes con enfermedad cardiaca activa o antecedentes de disfunción cardíaca
    13. Pacientes que actualmente estén recibiendo alguna de las sustancias descritas en el protocolo y que no puedan ser suspendidas 7 días antes de iniciar el tratamiento
    14. Pacientes que hayan sido sometidas a cirugía mayor dentro de los 14 días antes de iniciar la medicación del estudio o que no se hayan recuperado de los efectos secundarios principales de la cirugía.
    15. Pacientes que estén recibiendo actualmente warfarina u otro anticoagulante derivado cumarínico, para tratamiento, profilaxis o por otro motivo. Se permite la terapia con heparina, heparina de bajo peso molecular (LMWH) o fondaparinux.
    16. Pacientes que actualmente estén recibiendo o hayan recibido corticosteroides sistémicos ? 2 semanas antes del inicio de la medicación del estudio o que no se hayan recuperado completamente de los efectos secundarios de dicho tratamiento.
    17. Pacientes que estén utilizando concomitantemente otros agentes antineoplásicos (excepto para pacientes que están recibiendo ? 14 días de tamoxifeno o un IANE ± goserelina para el cáncer de mama avanzado antes de la aleatorización).
    18. Pacientes que hayan recibido radioterapia ? 4 semanas o radiación de campo limitado para paliación ? 2 semanas antes de la aleatorización o que no se hayan recuperado a grado 1 o mejor de los efectos secundarios relacionados de dicha terapia (con la excepción de alopecia) y/o cuya médula ósea haya sido irradiada ? 25%.
    19. Mujeres embarazadas o periodo de lactancia, donde el embarazo se define como el estado de una mujer después de la concepción y hasta el final de la gestación, confirmado con una prueba de laboratorio hCG positiva.
    20. Mujeres físicamente fértiles, definidas como todas las mujeres fisiológicamente capaces de quedarse embarazadas, a no ser que estén utilizando métodos anticonceptivos altamente eficaces durante la dosis del tratamiento del estudio. Los métodos anticonceptivos altamente eficaces incluyen:
    a. Abstinencia total (cuando esté en consonancia con el estilo de vida habitual y preferida del sujeto). La abstinencia periódica (por ejemplo, calendario, ovulación, métodos sintotérmicos, de postovulación) y el coitus interruptus no son métodos anticonceptivos aceptables.
    b. Ligadura de trompas por lo menos seis semanas antes de tomar el tratamiento del estudio.
    c. Esterilización masculina (por lo menos 6 meses antes de la selección). Para las pacientes mujeres del estudio, la pareja varón vasectomizado debería ser la única pareja de dicha paciente.

    ? Combinación de lo siguiente:
    a. Colocación de un dispositivo intrauterino (DIU) o sistema intrauterino (SIU).
    b. Métodos anticonceptivos de barrera: preservativo o capuchón oclusivo (diafragma o capuchón en bóveda/cervical) con gel/espuma/película/crema /supositorio vaginal espermicida.
    E.5 End points
    E.5.1Primary end point(s)
    PFS per local assessment and RECIST 1.1
    SLP según la evaluación local y los RECIST 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    median PFS of 13.4 months
    mediana de SLP a los 13.4 meses
    E.5.2Secondary end point(s)
    Key secondary:
    Overall Survival (OS)
    Secundario principal:
    SG: Supervivencia global
    E.5.2.1Timepoint(s) of evaluation of this end point
    median OS of 47 months
    mediana de SG a los 47 meses
    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
    - patient reported outcome
    - hospital resource utilization
    Resultados notificados por la paciente
    Utilización de recursos sanitarios
    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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA119
    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 No
    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
    Brazil
    Bulgaria
    Canada
    China
    Colombia
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Greece
    Hong Kong
    Hungary
    India
    Israel
    Italy
    Japan
    Jordan
    Korea, Republic of
    Lebanon
    Mexico
    Norway
    Poland
    Portugal
    Russian Federation
    Saudi Arabia
    Singapore
    Slovakia
    South Africa
    Spain
    Sweden
    Switzerland
    Taiwan
    Thailand
    Turkey
    United Arab Emirates
    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 is defined as when the patient permanently discontinues treatment with tamoxifen or a NSAI + goserelin + LEE011 or tamoxifen or a NSAI + goserelin + placebo and all the end of trial procedures are completed.
    El final del estudio para una paciente determinada se define cuando la paciente suspenda el tratamiento del estudio permanentemente con tamoxifeno o un IANE + goserelina + LEE011 o tamoxifeno o un IANE + goserelina + placebo y se hayan completado todos los procedimientos de final del estudio
    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 months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days12
    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: 660
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 225
    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.
    Los pacientes que continuen obteniendo beneficio del tratamiento del ensayo al final de éste, según la opinión del investigador, podrán seguir recibiendo la terapia del ensayo en un protocolo separado. Alternativamente, Novartis proporcionará tratamiento del estudio al investigador según normativa local.
    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 Decision2015-03-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-05
    P. End of Trial
    P.End of Trial StatusOngoing
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