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    EudraCT Number:2016-003467-19
    Sponsor's Protocol Code Number:CLEE011A2404
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-02-10
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2016-003467-19
    A.3Full title of the trial
    COMPLEEMENT-1: An open-label, multicenter, Phase IIIb study to assess the safety and efficacy of ribociclib (LEE011) in combination with letrozole for the treatment of men and pre/postmenopausal women with hormone receptorpositive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease
    COMPLEEMENT-1: Estudio de fase IIIb, abierto, multicéntrico, para evaluar la seguridad y la eficacia de ribociclib (LEE011) en combinación con letrozol en el tratamiento de hombres y mujeres pre/postmenopáusicas con cáncer de mama avanzado (CMA) con receptor hormonal positivo (HR+) y HER2 negativo (HER2-) que no hayan recibido tratamiento hormonal para la enfermedad avanzada
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and efficacy of ribociclib (LEE011) in combination with letrozole for the treatment of men and pre/postmenopausal women with hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease
    Estudio para evaluar la seguridad y la eficacia de ribociclib (LEE011) en
    combinación con letrozol para el tratamiento de hombres y mujeres
    pre/postmenopáusicas con con cáncer de mama avanzado (CMA) con receptor hormonal positivo (HR+) HER2 negativo (HER2-) que no hayan recibido tratamiento hormonal para la enfermedad avanzada
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberCLEE011A2404
    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.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.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.5.4Telephone number+34900353036
    B.5.5Fax number+34932479903
    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 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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease
    cancer de mama avanzado (CMA) con receptor hormonal positivo (HR+) y HER2 negativo (HER2-) que no hayan recibido tratamiento hormonal para la enfermedad avanzada
    E.1.1.1Medical condition in easily understood language
    Hormone positive HER2 negative advanced Breast Cancer
    Cancer de mama avanzado con receptor hormonal positivo y 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 19.1
    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 evaluate the safety and tolerability of ribociclib with letrozole in men and pre/postmenopausal women with HR+, HER2- aBC who received no prior hormonal therapy for advanced disease
    Evaluar la seguridad y la tolerabilidad de ribociclib con letrozol en hombres y mujeres premenopáusicas/postmenopáusicas con CMA HR+, HER2- que no hayan recibido tratamiento hormonal para la enfermedad avanzada.
    E.2.2Secondary objectives of the trial
    • To assess the clinical efficacy of ribociclib + letrozole measured by Time-to-Progression (TTP) and tumor response by overall response rate (ORR) and clinical benefit rate (CBR).
    • To evaluate long-term safety of ribociclib + letrozole during Extension Phase
    • To evaluate clinical benefit of ribociclib + letrozole as assessed by
    investigator during Extension Phase
    - Evaluar la eficacia clínica de ribociclib + letrozol medida según el
    tiempo hasta la progresión (TTP) y la respuesta del tumor según la
    tasa de respuesta global (ORR) y la tasa de beneficio clínico (CBR).
    - Evaluar la seguridad a largo plazo de ribociclib + letrozol durante la
    Fase de Extensión.
    - Evaluar el beneficio clínico de ribociclib + letrozol según la evaluación del investigador durante la Fase de Extensión.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient is an adult, male or female ≥ 18 years old at the time of informed consent
    NOTE: Sexually active males should use a condom during intercourse while taking drug and for 21 days after stopping medication and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid
    2. Male or female with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy.
    3. In the case of women, both pre/perimenopausal and postmenopausal patients are allowed to be included in this study; menopausal status is relevant for the requirement of goserelin to be used concomitantly with ribociclib and letrozole:
    a) Postmenopausal status is defined either by:
    ● Prior bilateral oophorectomy OR
    ● Age ≥ 60 OR
    ● Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range
    If patient is taking tamoxifen or toremifene and age < 60, then FSH and plasma estradiol levels should be in post-menopausal range per local normal range.
    b) Premenopausal status is defined as either:
    i) Patient had last menstrual period within the last 12 months, OR
    ii) If on tamoxifen or toremifene within the past 14 days, plasma
    estradiol and FSH must be in the premenopausal range per local normal range, OR
    iii) In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range.
    c) Perimenopausal status is defined as neither premenopausal nor
    4. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory.
    5. Patient has HER2-negative breast cancer 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.
    6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
    7. Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by local laboratory):
    ● Absolute neutrophil count ≥ 1.5 × 109/L
    ● Platelets ≥ 100 × 109/L
    ● Hemoglobin ≥ 9.0 g/dL
    ● Potassium, sodium, calcium corrected for serum albumin and magnesium within normal limits or corrected to within normal limits with supplements before first dose of the study medication
    ● INR ≤ 1.5
    ● Serum creatinine < 1.5 mg/dl or creatinine clearance ≥ 50 mL/min
    ● In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be below 2.5 × ULN. If the patient has liver metastases, ALT and AST should be < 5 × ULN.
    ● Total serum bilirubin < ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with well-documented Gilbert’s Syndrome
    8. Patient must have a 12-lead ECG with all of the following parameters at screening:
    ● QTcF interval at screening < 450 msec (using Fridericia’s correction)
    ● Resting heart rate ≥ 50 bpm
    9. Patient must be able to swallow ribociclib and letrozole tablets
    10. Patient has signed informed consent obtained before any trial-related activities and according to local guidelines
    11. Patients must be able to communicate with the investigator and comply with the requirements of the study procedures
    1. Pacientes adultos de ambos sexos ≥ 18 años de edad en el momento en que otorguen el consentimiento informado.
    Nota: Los varones sexualmente activos deberán utilizar un preservative durante el coito mientras estén tomando el fármaco y durante los 21 días posteriores a la suspensión de la medicación y no deberán engendrar un bebé durante este periodo. Los varones a quienes se les haya practicado una vasectomía también deberán utilizar un preservativo para evitar la emission del fármaco a través del semen.
    2. Hombres o mujeres con cáncer de mama avanzado (locorregionalmente recurrente o metastásico) NO susceptibles de recibir tratamiento curativo.
    3. En el caso de mujeres, se permite la inclusión en el estudio tanto de
    pacientes pre/perimenopáusicas como pacientes postmenopáusicas; el estado menopáusico es relevante para el uso concomitante de goserelina con ribociclib y letrozol.
    a) El estado postmenopáusico se define por alguno de los siguientes:
    ● Ooforectomía bilateral previa.
    ● Edad ≥ 60 años.
    ● Pacientes < 60 años de edad, que hayan presentado amenorrea durante ≥ 12 meses (sin haber recibido quimioterapia, tamoxifeno ni toremifeno, ni haberse sometido a supresión de la función ovárica) y tengan niveles de FSH y estradiol dentro del rango postmenopáusico local normal. Si la paciente está tomando tamoxifeno o toremifeno y es menor de 60 años, los niveles de FSH y estradiol en plasma deberán estar dentro del rango postmenopáusico local normal.
    b) El estado premenopáusico se define como:
    i) Una paciente con el último periodo menstrual dentro de los 12
    meses anteriores, O
    ii) Si la paciente ha recibido tamoxifeno o toremifeno durante los 14
    días anteriores, los niveles de estradiol en plasma y FSH deberán
    estar dentro del rango premenopáusico local normal. O
    iii) En caso de amenorrea inducida por tratamiento, los niveles de
    estradiol en plasma o FSH deberán estar dentro del rango
    premenopáusico local normal.
    c) El estado perimenopáusico se define como un estado que no es ni
    premenopáusico ni postmenopáusico.
    4 Pacientes con diagnóstico histológica o citológicamente confirmado de cáncer de mama con receptor de estrógenos positivo y/o receptor de progesterona positivo según el laboratorio local.
    5. Pacientes con cáncer de mama HER2 negativo definido como un
    resultado negativo en la prueba de hibridización in situ o un estado 0, 1+ o 2+ de IHQ. En caso de un estado 2+ de IHQ, se necesitará una prueba local de hibridación in situ (FISH, CISH o SISH) con un resultado negativo.
    6. Pacientes con un estado funcional del Eastern Cooperative Oncology Group (ECOG) ≤ 2.
    7. Pacientes con una función adecuada de los órganos y la médula ósea, según se define en TODOS los siguientes parámetros (evaluados en un laboratorio local):
    ● Recuento absoluto de neutrófilos ≥ 1,5 × 109/l
    ● Plaquetas ≥ 100 × 109/l
    ● Hemoglobina ≥ 9,0 g/dl
    ● Niveles de potasio, sodio, calcio corregido para albúmina sérica y
    magnesio dentro de los límites normales o corregidos con suplementos a un valor dentro de los límites normales antes de la primera dosis de la medicación del estudio.
    ● INR ≤ 1,5
    ● Creatinina sérica < 1,5 mg/dl o aclaramiento de la creatinina ≥ 50
    ● En caso de que no existen metástasis hepáticas, los valores de
    alanino aminotransferasa (ALT) y aspartato aminotransferasa (AST)
    deberán ser < 2,5 × LSN. Si el paciente presenta metástasis hepáticas,
    los valores de ALT y AST deberán ser < 5 × LSN.
    ● Bilirrubina sérica total < LSN o bilirrubina total ≤ 3,0 × LSN con
    bilirrubina directa dentro del rango normal en pacientes con síndrome de Gilbert documentado.
    8. Los pacientes deberán tener un ECG de 12 derivaciones con TODOS los siguientes parámetros en la selección:
    ● Intervalo QTcF en la selección < 450 mseg (utilizando la corrección
    de Fridericia).
    ● Frecuencia cardíaca en reposo ≥ 50 lpm.
    9. Los pacientes tienen que ser capaces de tragar comprimidos de ribociclib y letrozol.
    10. Pacientes que hayan firmado el consentimiento informado antes de realizar cualquier actividad relacionada con el ensayo y de acuerdo con las normas locales.
    11. Los pacientes tienen que ser capaces de comunicarse con el investigador y cumplir los requisitos de los procedimientos del studio.
    E.4Principal exclusion criteria
    1. Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole
    2. Patient who received any CDK4/6 inhibitor
    3.Patient who received any prior systemic hormonal therapy for advanced breast cancer; no more than one prior regimen of chemotherapy for the treatment of metastatic disease is permitted
    ●Patients who received (neo) adjuvant therapy for breast cancer are eligible. If the prior neo (adjuvant) included letrozole or anastrozole the disease free interval must be greater than 12 months from the completion of treatment until study entry.
    ●Patients who received ≤ 28 days of letrozole or anastrozole for advanced disease prior to inclusion in this trial are eligible.
    ●Any prior (neo) adjuvant anti-cancer therapy or prior chemotherapy for metastatic disease must be stopped at least 5 half-lives or 7 days, whichever is longer, before study inclusion.
    4. Patient is concurrently using other anti-cancer therapy.
    5. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
    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 who has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to start of treatment, 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 R E 1961) of the bone marrow was irradiated.
    8. Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer
    9. Patient with central nervous system (CNS) metastases unless they meet ALL of the following criteria:
    ● At least 4 weeks from prior therapy for CNS disease completion (including radiation and/or surgery) to starting the study treatment.
    ● Clinically stable CNS lesions at the time of study treatment initiation and not receiving steroids and/or enzyme-inducing anti-epileptic medications for the management of brain metastases for at least 2 weeks.
    10. 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)
    11. Patient has a known history of HIV infection (testing not mandatory)
    12. 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.)
    13. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following:
    ● History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening
    ● History of documented congestive heart failure (New York Heart Association functional classification III-IV)
    ● Documented cardiomyopathy
    ● Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV block)
    ● Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, ● Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening
    14. Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug:
    ● Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
    ● That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
    ● Herbal preparations/medications, dietary supplements
    15. 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. Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)
    16. Participation in a prior investigational study within 30 days prior to enrollment or within 5-half-lives of the investigational product, whichever is longer
    17. Pregnant or nursing (lactating) woman
    1 Pat con hipersensibilidad conocida a cualquiera de los excipientes de ribociclib o letrozol.
    2 Pat que hayan recibido tto con cualquier inhibidor CDK4/6.
    3 Pat que hayan recibido algún tto hormonal sistémico para CAM; no se permite más de un régimen previo de QT para el tto de la enfermedad metastásica.
    Los pat que hayan recibido tto (neo)adyuvante para el CAM son elegibles. Si el tto neo(adyuvante) previo incluye letrozol o anastrozol, el intervalo sin enfermedad debe ser superior a 12 meses desde el fin del tto hasta la entrada en el estudio.
    ● Los pat que antes de la inclusión en este ensayo hayan recibido letrozol o anastrozol para enfermedad avanzada durante ≤ 28
    días son elegibles.
    ● Cualquier tto (neo)adyuvante previo contra el cáncer o QT previa para la enf. metastásica debe haberse suspendido al menos 5 semividas o 7 días antes de entrar en el estudio, el periodo que sea más largo.
    4. Pte que estén recibiendo otro tto concomitante contra el cáncer.
    5. Pte que se hayan sometido a una cirugía mayor dentro de los 14 días antes del inicio del fármaco o que no se hayan recuperado de efectos secundarios importantes.
    6. Pte en los que todos los efectos tóxicos agudos del tto contra el cáncer no se hayan resuelto a un grado ≤ 1 de los CTCAE v4.03 del NCI (salvo alopecia u otras toxicidades que no se consideren un riesgo de seguridad para el pte según el criterio del investigador).
    7. Pte que hayan recibido RT dentro de ≤ 4 semanas o RT paliativa de campo limitado dentro de ≤ 2 semanas del inicio del tto y que no se hayan recuperado a grado 1 o mejor de los efectos secundarios relacionados con dicho tto (salvo alopecia) o en los que se haya irradiado ≥ 25 % (Ellis R E 1961) de la médula ósea
    8. Los ptes que tengan un tumor maligno concurrente o tumor maligno durante los 3 años anteriores al inicio del fármaco, salvo carcinoma de células basales o escamosas adecuadamente tratado, cancer de piel no melanoma o cáncer de cuello uterino resecado de forma curativa.
    9. Pte con metástasis en el sistema nervioso central (SNC), salvo que cumplan TODOS los criterios siguientes:
    ● Al menos 4 semanas desde la finalización del tto anterior
    para la enfermedad del SNC (incluida radiación o cirugía) hasta el inicio del tto.
    ● Lesiones clínicamente estables en el SNC cuando se
    inicie el tto del estudio y que no hayan recibido esteroides ni
    medicamentos inductores enzimáticos antiepilépticos para el tto de las metástasis cerebrales durante al menos 2 semanas.
    10. Pte con deterioro de la función gastrointestinal (GI) o enfermedad GI que pueda alterar significativamente la absorción de los fármacos del estudio
    11. Pte con antecedentes conocidos de infección por VIH
    12. Pte con cualquier otra enfermedad grave o no controlada
    concurrente que pudiese, en opinión del investigador, causar riesgos de seguridad inaceptables, desaconsejar la participación del pte en el estudio clínico o afectar al cumplimiento del protocolo
    13. Enfermedad cardíaca clínicamente significativa no controlada o
    anomalías en la repolarización cardíaca, incluidas las siguientes:
    Antecedentes de síndromes coronarios agudos o pericarditis sintomática, dentro de los 6 meses anteriores a la selección.
    Antecedentes de insuficiencia cardíaca congestiva documentada.
    Cardiomiopatía documentada.
    Arritmias cardíacas clínicamente significativas, bloqueo completo de rama izquierda del haz de His, bloqueo AV de grado alto (p. ej., bloqueo bifascicular, bloqueo AV de tipo II de Mobitz y de tercer grado).
    Síndrome del QT prolongado o antecedentes familiares de muerte
    súbita idiopática o síndrome del QT prolongado congénito
    PAS >160 mmHg o < 90 mmHg en la selección.
    14. El pte está recibiendo actualmente alguno de los medicamentos siguientes y no pueden suspenderse de forma definitiva 7 días antes del inicio del fármaco del estudio:
    ● Inductores o inhibidores potentes conocidos de CYP3A4/5, incluido
    el pomelo, los híbridos de pomelo, la pamplemusa, la carambola y las
    naranja sevillana.
    ● Medicamentos que presenten una ventana terapéutica estrecha y que se metabolicen principalmente a través de CYP3A4/5.
    ● Preparaciones/medicamentos a base de plantas medicinales y
    suplementos dietéticos.
    15. Pte que estén recibiendo actualmente o hayan recibido
    corticosteroides sistémicos ≤ 2 semanas antes de empezar a recibir el
    fármaco del estudio o que no se hayan recuperado completamente de los efectos secundarios de dicho tratamiento. Nota: Se permite el siguiente uso de corticosteroides: dosis únicas, aplicaciones tópicas (p. ej., para erupción), aerosoles inhalados (p. ej., para enfermedades obstructivas de las vías respiratorias), colirios o inyecciones locales (p. ej., intraarticular).
    16. Participación en un estudio de investigación previo dentro de los 30 días anteriores a la inclusión o dentro de las 5 semividas del producto en investigación, aquel periodo que sea más largo.
    17. Mujeres embarazadas o en periodo de lactancia
    E.5 End points
    E.5.1Primary end point(s)
    Incidence of AEs, Grade 3/4 AEs & SAEs during treatment with ribociclib + letrozole
    Incidencia de AAs, Grado 3/4 AAs y AAG durante el tratamiento con ribociclib + letrozole
    E.5.1.1Timepoint(s) of evaluation of this end point
    refer to section 10.4. of the protocol
    Referirse a la sección 10.4 del protocolo
    E.5.2Secondary end point(s)
    • Time-to-Progression (TTP) (RECIST 1.1), based on investigators’ assessment
    • Overall response rate (ORR) as defined by RECIST 1.1 for patients with measurable disease
    • Clinical Benefit Rate (CBR) as defined by RECIST 1.1 (including patients with CR, PR, SD, NCRNPD >24 weeks)
    • Patient Reported Outcome (PRO) using FACT-B questionnaire
    • Frequency and severity of AEs & SAEs during Extension Phase
    • Proportion of patients with clinical benefit as assessed by investigator during Extension Phase
    Tiempo hasta la progression (TTP) (RECIST 1.1), basado en la evulación del investigador
    Tasa de respuesta global (ORR) según definición de RECIST 1.1 para pacientes con enfermedad medible
    Tasa de Beneficio Clínico (CBR) según definición de RECIST 1.1 (incluyendo pacientes con CR, PR, SD, NCRNPD >24 semanas)
    Efecto del tratamiento en el resultado notificado por el
    paciente (PRO) medido según las variaciones en las puntuaciones
    del cuestionario FACT-B
    Frecuencia y Severidad de los AA y AAG durante la fase de extension
    Proporción de pacientes con beneficio clinic o según la
    evaluación del investigador durante la Fase de Extensión.
    E.5.2.1Timepoint(s) of evaluation of this end point
    refer to section 10.5.1 of the protocol
    Referirse a la sección 10.5.1 del protocolo
    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
    Patient Reported Outcome (PRO)
    Efecto del tratamiento en el resultado notificado por el paciente (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. 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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned 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 concerned56
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA300
    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
    Costa Rica
    Czech Republic
    Hong Kong
    Russian Federation
    Saudi Arabia
    United Arab Emirates
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Planned overall study duration of the Core Phase will be up to 36 months, from FPFV to 18 months counted after LPFV. At the time of Core Phase end (18 months after LPFV), if patients are still deriving benefit and ribociclib is not approved or available and reimbursed, patients may be transitioned to the extension trial period
    La duración prevista global de la fase principal será de un máximo de 36 meses desde la primera visita del primer paciente (FPFV) hasta18 meses después de la primera vista del ultimo paciente (LPFV). Cuando finalice la fase principal (18 meses después de la LPFV), si los pacientes todavía están obteniendo beneficio y ribociclib no está aprobado o no está disponible ni con precio de reembolso, los pacientes podrán pasar a la fase de extensión del ensayo.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    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: 1800
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1200
    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 state550
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 2000
    F.4.2.2In the whole clinical trial 3000
    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)
    At the time of Core Phase end (18 months after LPFV), if patients are still deriving benefit and ribociclib is not approved or available and reimbursed, patients may be transitioned to the extension trial period and continue to receive the drugs until progression, intolerance, death or physician/patient decision, but only safety and clinical benefit as assessed by investigator will be collected during the Extension Phase.
    Cuando finalice la fase principal (18 meses después de la LPFV), si los pacientes todavía estén obteniendo beneficio y ribociclib no está aprobado o no está disponible ni con precio de reembolso, los pacientes podrán pasar a esta Fase de Extensión y continuar recibiendo los fármacos hasta progresión, intolerancia, muerte o por decisión del médico/paciente; pero durante la fase de extensión solo se recogerán la seguridad y el beneficio clínico evaluados por el investigador
    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 Decision2017-03-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-12-03
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