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    Summary
    EudraCT Number:2016-003098-17
    Sponsor's Protocol Code Number:SOLTI-1402
    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
    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 number2016-003098-17
    A.3Full title of the trial
    CORALLEEN: A Phase 2 Clinical Trial of multi-agent Chemotherapy or letrozole plus Ribociclib (LEE001) as neoadjuvant treatment for postmenopausal patients with Luminal B/HER2-negative breast cancer.
    CORALLEEN: Ensayo clínico de fase 2 de poliquimioterapia o letrozol más ribociclib (LEE001) como tratamiento neoadyuvante en pacientes posmenopáusicas con cáncer de mama de tipo luminal B y HER2 negativo.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    CORALLEEN: A Phase 2 Clinical Trial of multi-agent Chemotherapy or letrozole plus Ribociclib (LEE001) as neoadjuvant treatment for postmenopausal patients with Luminal B/HER2-negative breast cancer.
    CORALLEEN: Ensayo clínico de fase 2 de poliquimioterapia o letrozol más ribociclib (LEE001) como tratamiento neoadyuvante en pacientes posmenopáusicas con cáncer de mama de tipo luminal B y HER2 negativo.
    A.3.2Name or abbreviated title of the trial where available
    CORALLEEN
    CORALLEEN
    A.4.1Sponsor's protocol code numberSOLTI-1402
    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 SponsorSOLTI
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharmaceutical
    B.4.2CountrySpain
    B.4.1Name of organisation providing supportNanoString Technologies, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSOLTI
    B.5.2Functional name of contact pointGestion de Proyectos
    B.5.3 Address:
    B.5.3.1Street AddressBalmes 89, 3-7
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08008
    B.5.3.4CountrySpain
    B.5.4Telephone number34933436302
    B.5.5Fax number34932702383
    B.5.6E-mailoriol.vidal@gruposolti.org
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name FEMARA
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Farmacéutica, 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 nameLetrozole
    D.3.4Pharmaceutical form 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 INNLETROZOLE
    D.3.9.1CAS number 112809-51-5
    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: 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 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 Capsule
    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 INN7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin- 2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide
    D.3.9.1CAS number 1374639-75-4
    D.3.9.3Other descriptive nameRIBOCICLIB SUCCINATE
    D.3.9.4EV Substance CodeSUB184164
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number600
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Luminal B/HER2-negative breast cancer.
    Cáncer de mama de tipo luminal B y HER2 negativo.
    E.1.1.1Medical condition in easily understood language
    Breast cancer.
    Cáncer de mama.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the clinical benefit of ribociclib plus letrozole versus chemotherapy.
    Comparar el beneficio clínico de ribociclib más letrozol frente a quimioterapia.
    E.2.2Secondary objectives of the trial
    1. To compare additional measures of clinical benefit of ribociclib plus letrozole versus chemotherapy.
    2. To compare the rate of breast conserving surgery (BCS) and transition to BCS of investigational treatment arms versus their corresponding standard treatment arm.
    3. To compare the anti-proliferative effect of treatment arms as per molecular indicators.
    4. To assess the effect of investigational treatment versus standard treatment on patient reported outcomes (PROs).
    5. To evaluate the safety and tolerability of investigational treatment versus their corresponding standard treatment.
    6. To identify biomarkers of response or resistance to the study treatments.
    1. Comparar otras medidas del beneficio clínico de ribociclib más letrozol frente a quimioterapia.
    2. Comparar la tasa de cirugía con conservación de la mama (CCM) y la transición a CCM entre los grupos del tratamiento en investigación y el grupo de tratamiento de referencia correspondiente.
    3. Comparar el efecto antiproliferativo de los grupos de tratamiento utilizando indicadores moleculares.
    4. Evaluar el efecto del tratamiento en investigación frente al tratamiento de referencia en los resultados comunicados por las pacientes (RCP).
    5. Evaluar la seguridad y la tolerabilidad del tratamiento en investigación frente al tratamiento de referencia correspondiente.
    6. Identificar biomarcadores de la respuesta o la resistencia a los tratamientos del estudio.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed Informed Consent Form prior to any study-specific procedure.
    2. Female patients.
    3. Post-menopausal status and age ≥18 years. Post-menopausal status is defined as:
     Age ≥ 60 years or
     Age < 60 years and 12 months of amenorrhea plus follicle stimulating hormone (FSH) and plasma estradiol levels within post-menopausal range by local laboratory assessment or
     Prior bilateral oophorectomy (≥ 28 days prior to Day 1 of treatment).
    4. Histologically confirmed invasive breast carcinoma, with all the following characteristics:
     Primary tumor ≥ 2cm in largest diameter as measured by breast MRI
     Stage I to stage IIIA breast cancer
     No evidence of distant metastasis (M0)
    5. Breast cancer eligible for primary surgery.
    6. Available pre-treatment FFPE core (Tru-cut) biopsy evaluable for PAM50 or possibility to obtain one. Minimal sample requirements are to have at least 2 tumor cylinders with a minimal tissue surface of 10 mm2 tissue, containing at least 10% tumor cells and having enough tissue to do at least 2 cuts of 10 m each.
    7. Luminal B subtype as per PAM50 analysis of pre-treatment sample.
    8. ER-positive and/or PgR-positive and HER2-negative tumor by ASCO/CAP guidelines assessed locally.
    9. In the case of a multifocal tumor (defined as the presence of two or more foci of cancer within the same breast quadrant), the largest lesion must be ≥ 2 cm and designated the “target” lesion for all subsequent tumor evaluations and HR+/HER2-negative status must be documented in all the tumor foci.
    10. ECOG performance status of 0 or 1.
    11. Adequate hematological, renal and hepatic function, as follows:
     Absolute neutrophil count (ANC) ≥1.5 x 109/L
     Platelets count ≥100 x 109/L
     Hemoglobin ≥10 g/dL
     Alkaline phosphatase (AP) ≤2.5x upper limit of normal (ULN)
     Total bilirubin < ULN. Patients with known Gilbert syndrome may be enrolled with total bilirubin ≤3 x ULN or direct bilirubin ≤1.5 x ULN.
     Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5x ULN
     Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥60 mL/min
     Potassium, total calcium (corrected for serum albumin), magnesium, sodium and phosphorus within institutional normal limits or corrected to within normal limits with supplements before first dose of study medication
    12. Ability and willingness to comply with study visits, treatment, testing and to comply with the protocol.
    1. Firma del documento de consentimiento informado antes de realizar cualquier procedimiento específico del estudio.
    2. Pacientes de sexo femenino.
    3. Estado posmenopáusico y edad ≥ 18 años. El estado posmenopaúsico se define como:
     Edad ≥ 60 años o
     Edad < 60 años y 12 meses de amenorrea más hormona folitropina (FSH) y concentraciones plasmáticas de estradiol dentro del intervalo de valores posmenopáusicos en la evaluación del laboratorio local u
     Ovariectomía bilateral previa (≥ 28 días antes del día 1 de tratamiento).
    4. Carcinoma de mama invasivo con confirmación histológica y todas las características siguientes:
     Tumor primario ≥ 2 cm en su diámetro mayor medido en la RM de mama
     Cáncer de mama en estadio I a estadio IIIa
     Ausencia de indicios de metástasis a distancia (M0).
    5. Cáncer de mama susceptible de cirugía primaria.
    6. Disponibilidad de una biopsia con aguja gruesa (Tru-cut) FFIP obtenida antes del tratamiento y evaluable para PAM50 o posibilidad de obtener una. Los requisitos mínimos que deben cumplir las muestras es disponer de al menos 2 cilindros tumorales con una superficie mínima de tejido de 10 mm2 que contenga al menos un 10% de células tumorales y suficiente cantidad de tejido como para obtener al menos 2 cortes de 10 μm cada uno.
    7. Subtipo luminal B conforme al análisis PAM50 de la muestra obtenida antes del tratamiento.
    8. Tumor positivo para RE y/o positivo para RPg y negativo para HER2 conforme a las directrices de la ASCO/CAP según la evaluación local.
    9. En el caso de un tumor multifocal (definido como la presencia de dos o más focos de cáncer en el mismo cuadrante de la mama), la lesión más grande debe ser ≥ 2 cm y designarse como lesión “de referencia” en todas las evaluaciones posteriores del tumor y el estado HR+ y HER2 negativo deberá documentarse en todos los focos tumorales.
    10. Estado funcional según el ECOG de 0 o 1.
    11. Función hematológica, renal y hepática adecuada, como sigue:
     Recuento absoluto de neutrófilos (RAN) ≥ 1,5 x 109/l
     Recuento de plaquetas ≥ 100 x 109/l
     Hemoglobina ≥ 10 g/dl
     Fosfatasa alcalina (FA) ≤ 2,5 veces el límite superior de la normalidad (LSN).
     Bilirrubina total < LSN Las pacientes con síndrome de Gilbert confirmado podrán participar con una bilirrubina total ≤ 3 veces el LSN o una bilirrubina directa ≤ 1,5 veces el LSN.
     Alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST) < 2,5 veces el LSN.
     Creatinina sérica ≤ 1,5 mg/dl o aclaramiento de creatinina calculado ≥ 60 ml/min.
     Potasio, calcio total (corregido para tener la cuenta de la albúmina en suero), magnesio, sodio y fósforo dentro de los límites normales del centro o corregidos hasta quedar dentro de los límites normales con suplementos antes de la administración de la primera dosis de medicación del estudio.
    12. Capacidad y voluntad de cumplir con las visitas del estudio, el tratamiento, los análisis y el protocolo.
    E.4Principal exclusion criteria
    1. Any prior treatment for primary invasive breast cancer.
    2. Inoperable locally advanced or inflammatory (i.e., inoperable Stage III) breast cancer.
    3. Metastatic (Stage IV) breast cancer.
    4. Bilateral invasive breast cancer.
    5. Multicentric breast cancer, defined as the presence of two or more foci of cancer in different quadrants of the same breast.
    6. Patients who have undergone sentinel lymph node biopsy prior to study treatment.
    7. Inability or unwillingness to swallow pills.
    8. Malabsorption syndrome or other condition that would interfere with enteric absorption of study drugs.
    9. Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer.
    10. Patient with a Child-Pugh score B or C.
    11. Patient has active cardiac disease or a history of cardiac dysfunction including any of the following:
     History of acute coronary syndromes or symptomatic pericarditis within 12 months prior to screening.
     History of documented congestive heart failure (NYHA functional classification III-IV).
     Documented cardiomyopathy.
     Patient has a Left Ventricular Ejection Fraction (LVEF) < 50%.
     Clinical 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 or any of the following:
    o Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure or history of clinically significant/symptomatic bradycardia
    o QTc> 500 msec or conduction abnormality in the previous 12 months.
     On screening 12-lead ECG, any of the following cardiac parameters (defined as the mean of triplicate ECGs: bradycardia (resting heart rate < 50), tachycardia (resting heart rate > 90), PR interval > 220 msec, QRS interval >109 msec, or QTcF interval ≥450 msec (using Fridericia’s correction).
    12. Uncontrolled hypertension (Systolic blood pressure >160 mmHg or <90 mmHg and/or diastolic >100 mmHg).
    13. Active infection requiring intravenous (IV) antibiotics.
    14. Symptomatic hypercalcemia despite adequate management.
    15. Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis.
    16. Known human immunodeficiency virus (HIV) infection.
    17. Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may compromise compliance with the protocol, that may affect the interpretation of the results, or renders the patients at high risk from treatment complications.
    18. Significant traumatic injury within 3 weeks prior to initiation of study treatment.
    19. Major surgical procedure (not including minor procedures such as lymph node biopsy, tumor core biopsy, fine needle aspiration) within 4 weeks prior to initiation of study treatment or not fully recovered from any side effects of previous procedures.
    20. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
    21. History of other malignancy within 5 years prior to screening, except for appropriately treated basal or squamous cell carcinoma, carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer.
    22. Hormone replacement therapy stopped less than 2 weeks before treatment start.
    23. Currently receiving or has received systemic corticosteroids until 2 weeks before treatment start or who have not fully recovered from side effects of such treatment. Following corticosteroid uses 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)
    24. Known hypersensitivity to any of the excipients of ribociclib, letrozole, doxorubicin, cyclophosphamide or paclitaxel.
    25. Patients currently on following medications, which cannot be interrupted 7 days prior treatment start:
     Any prohibited medication as per letrozole, doxorubicin, cyclophosphamide, or paclitaxel label.
     Herbal preparations/medications, dietary supplements.
     Medications that have a known risk to prolong the QT interval or cause Torsades de Pointe.
     Medications with a narrow therapeutic window and predominantly metabolized through CYP3A4/5.
     Strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit and Seville oranges.
     Warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin or fondaparinux is allowed.
    1. Cualquier tratamiento previo para el cáncer de mama invasivo primario.
    2. Cáncer de mama inoperable localmente avanzado o inflamatorio.
    3. Cáncer de mama metastásico.
    4. Cáncer de mama invasivo bilateral.
    5. Cáncer de mama multicéntrico.
    6. Pacientes sometidos a una biopsia del ganglio linfático centinela antes del tratamiento del estudio
    7. Incapacidad o falta de disposición a tragar píldoras.
    8. Síndrome de malabsorción u otros trastornos que interferirían con la absorción intestinal de los fármacos del estudio.
    9. Participación en un estudio de investigación previo en los 30 días anteriores al reclutamiento o en las 5 semividas del producto en investigación.
    10. Pacientes con una puntuación B o C de Child-Pugh.
    11. Pacientes con cardiopatía activa o con antecedentes de disfunción cardíaca como:
     Antecedentes de síndromes coronarios agudos o pericarditis sintomática en los 12 meses previos a la selección.
     Antecedentes de insuficiencia cardíaca congestiva documentada (clase funcional III-IV de la NYHA).
     Miocardiopatía documentada.
     Pacientes con una fracción de eyección del ventrículo izquierdo (VEFI) < 50%.
     Arritmias cardíacas clínicamente significativas, bloqueo completo de rama izquierda, bloque AV de alto grado.
     Síndrome de QT prolongado o antecedentes familiares de muerte súbita idiopática o síndrome congénito de QT prolongado o alguno de los siguientes:
    o Factores de riesgo de taquicardia helicoidal, incluidos antecedentes de hipopotasemia o hipomagnesemia no corregidas, antecedentes de insuficiencia cardíaca o antecedentes de bradicardia clínicamente significativa o sintomática.
    o QTc> 500 ms o anomalía de la conducción en los 12 meses previos.
     En el ECG de 12 derivaciones realizado en la selección, alguno de los parámetros cardíacos siguientes (definidos como la media de ECG realizados por triplicado: bradicardia, taquicardia, intervalo PR > 220 ms, intervalo QRS > 109 ms o intervalo QTcF ≥ 450 ms.
    12. Hipertensión no controlada.
    13. Infección activa que precise antibióticos intravenosos (IV)
    14. Hipercalcemia sintomática a pesar de un tratamiento adecuado.
    15. Antecedentes clínicamente importantes de hepatopatía.
    16. Infección conocida por el virus de la inmunodeficiencia humana (VIH).
    17. Cualquier otra enfermedad, disfunción pulmonar activa o no controlada, disfunción metabólica, sospecha de una enfermedad o un trastorno que suponga una contraindicación para el uso de un fármaco en investigación, que pueda comprometer el cumplimiento con el protocolo, que pueda afectar a la interpretación de los resultados o que ponga a las pacientes en un riesgo elevado de presentar complicaciones del tratamiento.
    18. Lesión traumática importante en las 3 semanas previas al inicio del tratamiento del estudio.
    19. Procedimiento de cirugía mayor (no se incluyen procedimientos de cirugía menor como biopsia de ganglios linfáticos, biopsia tumoral con aguja gruesa o aspiración con aguja fina) en las 4 semanas previas al inicio del tratamiento del estudio o recuperación incompleta de algún efecto secundario de procedimientos previos.
    20. Cualquier condicionante psicológico, familiar, sociológico o geográfico que pueda dificultar el cumplimiento con el protocolo del estudio y el calendario de seguimiento.
    21. Antecedentes de otras neoplasias malignas en los 5 años previos a la selección, excepto carcinoma basocelular o epidermoide tratado debidamente, carcinoma in situ de cuello uterino, carcinoma de piel distinto del melanoma o cáncer de útero en estadio I.
    22. Tratamiento hormonal sustitutivo interrumpido menos de 2 semanas antes del inicio del tratamiento.
    23. Administración actual o previa de corticosteroides sistémicos hasta 2 semanas antes del inicio del tratamiento o recuperación incompleta de los efectos secundarios de dicho tratamiento. Se permiten los siguientes usos de los corticosteroides: dosis únicas, aplicaciones tópicas, aerosoles inhalados, colirios o inyecciones locales.
    24. Hipersensibilidad conocida a algunos de los excipientes de ribociclib, letrozol, doxorubicina, ciclofosfamida o paclitaxel.
    25. Pacientes tratadas actualmente con los medicamentos siguientes y que no puedan interrumpir su administración 7 días antes del inicio del tratamiento del estudio:
     Cualquier medicamento prohibido según las fichas técnicas de letrozol, doxorubicina, ciclofosfamida o paclitaxel.
     Preparados y medicamentos de herbolario, suplementos dietéticos.
     Medicamentos con un riesgo conocido de prolongar el intervalo QT o causar taquicardia helicoidal.
     Medicamentos con un margen terapéutico estrecho y metabolizados principalmente a través de CYP3A4/5.
     Inductores o inhibidores potentes de CYP3A4/5, como zumo de pomelo, híbridos de pomelo, fruta estrella y naranjas amargas.
     Warfarina y otros anticoagulantes cumarínicos para tratamiento, profilaxis u otros usos. Se permite el tratamiento con heparina, heparina de bajo peso molecular o fondaparinux.
    E.5 End points
    E.5.1Primary end point(s)
    Rate of residual cancer burden (RCB) score 0 or 1 (RCB0/1) after neoadjuvant treatment, according to the MD Anderson Cancer Center procedures, as per central assessment.
    Tasa de puntuación de 0 o 1 de la carga de cáncer residual (CCR) (CCR0/1) después del tratamiento neoadyuvante, conforme a los procedimientos del MD Anderson Cancer Center, según una evaluación centralizada.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After surgery.
    Después de la cirugía.
    E.5.2Secondary end point(s)
    1.1 Tumor overall objective response rate (ORR), defined as the sum of Partial Responses (PR) and Complete Responses (CR) according to RECIST v1.1, as per Investigator’s assessments by breast MRI.
    1.2 ORR by physical examination, mammography and breast US, if available.
    1.3 pCR in the breast (pCRB) defined as the complete absence of invasive carcinoma in the breast on histological examination at the time of definitive surgery, irrespective of in situ carcinoma in the breast.
    1.4 pCR in the breast and axillary lymph nodes (pCRBL) after completion of study treatment, defined as the complete absence of invasive carcinoma in the breast and axillary lymph nodes on histological examination at the time of definitive surgery, irrespective of in situ carcinoma in the breast.
    1.5 Rate of residual cancer burden (RCB) score 0 or 1 (RCB0/1) after neoadjuvant treatment, according to the MD Anderson Cancer Center procedures, as per local assessment.
    1.6 Preoperative endocrine prognostic index (PEPI) score in the ribociclib plus letrozole treatment arm compared to historical values.
    2.1 Rate of breast conserving surgery (BCS): patients to whom a BCS was recommended from the beginning plus patients who were supposed to undergo a mastectomy but after neoadjuvant therapy became suitable for a BCS approach versus patients who underwent a mastectomy.
    3.1 Decrease in Ki67 from baseline to week 2, from baseline to surgery, from week 2 to surgery and from baseline to progression (in those patients who consent for early termination biopsy). To be assessed in both treatment arms.
    3.2 Rates of Luminal A disease (at surgery) in patients with residual disease in the breast at surgery.
    3.3 Change to Luminal A or ROR-low disease from baseline to week 2, from baseline to surgery, from week 2 to surgery and from baseline to progression (in those patients who consent for early termination biopsy).
    4.1 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30), version 3.
    4.2 EORTC QLQ-BR23 (breast cancer-specific questionnaire).
    5.1 Incidence, duration and severity of Adverse Events (AEs) assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 4, including dose reductions, delays and treatment discontinuations.
    6.1 Correlation of clinical benefit endpoints and specific alterations or patterns at the immunological, genomic, genetic, epigenomic, and gene expression levels.
    1.1 Tasa global de respuesta objetiva (TRO) del tumor, definida como la suma de las respuestas parciales (RP) y las respuestas completas (RC) conforme a los criterios RECIST v1.1, según las evaluaciones del investigador basadas en una RM de mama.
    1.2 TRO mediante exploración física, mamografía y ecografía de mama, si se dispone de ella.
    1.3 RCap en la mama (RCapM), definida como la ausencia completa de carcinoma invasivo en la mama según el examen histológico realizado en el momento de la intervención quirúrgica definitiva, independientemente de la presencia de carcinoma in situ en la mama.
    1.4 RCap en la mama y los ganglios linfáticos de la axila (RCapMG) después de finalizar el tratamiento del estudio, definida como la ausencia completa de carcinoma invasivo en la mama y los ganglios linfáticos de la axila según el examen histológico realizado en el momento de la intervención quirúrgica definitiva, independientemente de la presencia de carcinoma in situ en la mama.
    1.5 Tasa de puntuación de 0 o 1 de la carga de cáncer residual (CCR) (CCR0/1) después del tratamiento neoadyuvante, conforme a los procedimientos del MD Anderson Cancer Center, según una evaluación local.
    1.6 Puntuación del índice pronóstico endocrino prequirúrgico (PEPI) en el grupo tratado con ribociclib más letrozol en comparación con los valores históricos.
    2.1 Tasa de cirugía con conservación de la mama (CCM): pacientes a las que se recomendó CCM desde el principio más pacientes que se suponía que iban a someterse a una mastectomía, pero que después de recibir tratamiento neoadyuvante se convirtieron en candidatas adecuadas para una estrategia de CCM, frente a las pacientes sometidas a una mastectomía.
    3.1 Disminución de la proteína Ki67 desde el momento basal hasta la semana 2, desde el momento basal hasta la intervención quirúrgica, desde la semana 2 hasta la intervención quirúrgica y desde el momento basal hasta la progresión de la enfermedad (en las pacientes que otorguen su consentimiento para una biopsia en caso de finalización prematura). Se evaluará en los dos grupos de tratamiento.
    3.2 Tasa de enfermedad de tipo luminal A (en el momento de la intervención quirúrgica) en pacientes con enfermedad residual en la mama en el momento de la intervención quirúrgica.
    3.3 Cambio a enfermedad de tipo luminal A o a enfermedad con bajo riesgo de recidiva (RDR) desde el momento basal hasta la semana 2, desde el momento basal hasta la intervención quirúrgica, desde la semana 2 hasta la intervención quirúrgica y desde el momento basal hasta la progresión de la enfermedad (en las pacientes que otorguen su consentimiento para una biopsia en caso de finalización prematura).
    4.1 Puntuación obtenida en el Cuestionario de calidad de vida C30 de la Organización Europea para la Investigación y el Tratamiento del Cáncer (QLQ-C30 de la EORTC), versión 3.
    4.2 Puntuación obtenida en el Cuestionario QLQ-BR23 de la EORTC (cuestionario específico sobre el cáncer de mama).
    5.1 Incidencia, duración e intensidad de los acontecimientos adversos (AA), evaluados utilizando la versión 4 de los Criterios terminológicos comunes para la clasificación de acontecimientos adversos (CTCAE), incluidas reducciones de dosis, retrasos e interrupciones del tratamiento.
    6.1 Correlación entre los criterios de valoración del beneficio clínico y alteraciones o patrones específicos de tipo inmunológico, genómico, genético, epigenómico y de expresión génica.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Before and after surgery.
    Antes y después de la cirugía.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned20
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    UVUP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 94
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 94
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state94
    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)
    None
    Ninguno
    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 Decision2017-03-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-07-01
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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