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    Summary
    EudraCT Number:2018-001702-28
    Sponsor's Protocol Code Number:MedOPP199
    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:2018-10-25
    Trial results View 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 number2018-001702-28
    A.3Full title of the trial
    Neoadjuvant Letrozole and Palbociclib in patients with Stage II-IIIb breast cancer, HR (+) / HER2 (-) phenotype and Intermediate (18-25) or High (>25) Recurrence-Score by Oncotype-DX; analysis of RS and pathological changes at surgery.
    Neoadyuvancia con Letrozol y Palbociclib en pacientes con cáncer de mama estadíos II-IIIb, Fenotipo RH (+) / HER2 (-) y Recurrence Score (Oncotype-Dx) Intermedio (18-25) o Alto (>25) con análisis de cambios en el RS a la cirugía.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment with Letrozol and Palbociclib combination in early Breast Cancer HR(+) / HER2(-)
    Tratamiento con la combinación Letrozol y Palbociclib en cáncer de mama HR (+) / HER2(-) en estadío temprano
    A.3.2Name or abbreviated title of the trial where available
    DxCARTES
    DxCARTES
    A.4.1Sponsor's protocol code numberMedOPP199
    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 SponsorMedica Scientia Innovation Research (MEDSIR)
    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 supportLaboratorios Pfizer, S.L.U.
    B.4.2CountrySpain
    B.4.1Name of organisation providing supportGenomic Health
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedica Scientia Innovation Research (MedSIR)
    B.5.2Functional name of contact pointLaura Calabuig
    B.5.3 Address:
    B.5.3.1Street AddressRambla Cataluña, 2-4, 2D
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08007
    B.5.3.4CountrySpain
    B.5.4Telephone number34932214135
    B.5.5Fax number34932992382
    B.5.6E-maillaura.calabuig@medsir.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 IBRANCE
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    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.3.4Pharmaceutical 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 INNPALBOCICLIB
    D.3.9.1CAS number 571190-30-2
    D.3.9.4EV Substance CodeSUB177204
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    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 IBRANCE
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    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.3.4Pharmaceutical 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 INNPALBOCICLIB
    D.3.9.1CAS number 571190-30-2
    D.3.9.4EV Substance CodeSUB177204
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 IBRANCE
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    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.3.4Pharmaceutical 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 INNPALBOCICLIB
    D.3.9.1CAS number 571190-30-2
    D.3.9.4EV Substance CodeSUB177204
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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.2.1.1.1Trade name LETROZOL KERN PHARMA
    D.2.1.1.2Name of the Marketing Authorisation holderKern Pharma S.L.
    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.3.4Pharmaceutical 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 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.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
    Early HR(+)/HER2(-) Breast Cancer
    Cáncer de mama HR(+) / HER2(-) en estadío temprano
    E.1.1.1Medical condition in easily understood language
    Early HR(+)/HER2(-) Breast Cancer
    Cáncer de mama HR(+) / HER2(-) en estadío temprano
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10006187
    E.1.2Term Breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To explore after 6 months of treatment the ability of palbociclib in combination with letro-zole to induce global molecular changes measured by either the Oncotype DX Breast Recurrence Score® (the “Assay”) test result at surgery (post-treatment Recurrence Score® (RS) result), or pathological Complete Response (pCR) in patients with aggres-sive luminal tumors (pre-treatment RS result 18-25 or 26-100, and Ki67>20).
    Explorar la capacidad del palbociclib en combinación con letrozol para inducir variaciones moleculares globales medidas mediante el resultado de la prueba Oncotype DX Breast Recurrence Score® (en adelante, RS) en la intervención quirúrgica (resultado de la puntuación de recurrencia posterior al tratamiento, RS2) o la respuesta completa patológica (RCp) en pacientes con tumores luminales agresivos (resultado de RS intermedio o alto previo al tratamiento y Ki67 > 20%) después de 6 meses de tratamiento.
    E.2.2Secondary objectives of the trial
    -Explore ability of palbociclib plus letrozole to induce global molecular changes post-treatment RS result after treatment
    -Explore ability of combination to induce global molecular reduction measured by either the post-treatment RS result, and/or Residual Cancer Burden (RCB), and/or Ki67 after treatment.
    -Verify ability to induce global molecular reduction (measured as either post-treatment RS≤25 or RCB score of 0-I) in >35% in cohort B and ability to induce increase in RS result (measured as post-treatment RS 26-100) in <3% in cohort A
    -Concordance rate between the RCB score (0-I vs.II-III) and the post-treatment RS result. Concordance rate between the preoperative endocrine prognostic index (PEPI) score and post-treatment RS result
    -Concordance rate between the pCR and the post-treatment RS result
    -Determine the Overall Response Rate, Duration of Response, Time to Response, Clinical Benefit Rate and Maximum Tumor Shrinkage
    -Safety and tolerability of palbociclib plus letrozole
    -Capacidad del palbociclib más letrozol para inducir variaciones moleculares globales en RS post-tratamiento.
    -Capacidad para inducir una reducción molecular global mediante el resultado RS post-tratamiento y/o carga del cáncer residual (RSB, recurrence Score Burden) y/o Ki67
    -Capacidad de inducir una reducción molecular global (RS2 <25 o puntuación de la CCR de 0-l) en >35 % en cohorte B
    y de inducir un aumento del resultado de RS (medido como RS > 25 posterior al tratamiento) en <3 % en cohorte A
    -Tasa concordancia entre RCB (0-l frente a ll-lll) y RS2 posterior al tratamiento.
    -Evaluar tasa concordancia entre la puntuación del índice de pronóstico endocrino preoperatorio (PEPI) y resultado de RS posterior al tratamiento y Tasa concordancia entre la RCp y RS posterior a tratamiento en ambas cohortes
    -Respuesta global, duración de respuesta, tiempo transcurrido hasta respuesta,Tasa beneficio clínico, máxima reducción del tamaño tumoral
    -Seguridad y tolerabilidad a tratamiento
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Female patients over 18 years of age.
    2. Patients have been informed about the nature of study, have agreed to participate in the study, and have signed the informed consent form prior to participation in any study-related activities.
    3. Premenopausal and postmenopausal women. Premenopausal women must be treated with LHRH analogue since patient pre- registration. Premenopausal or postmeno-pausal status should have been established before starting study treatment with letrozole plus palbociclib based on the following classification:
    a) Postmenopausal status is defined as either:
    o Prior bilateral oophorectomy;
    Or
    o Age>60 years;
    Or
    o Age<60 years and amenorrhoeic for 12 months in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression, and follicle-stimulating hormone (FSH) and estradiol in postmenopausal range.
    b) Premenopausal status is defined as all those women who do not meet any of above criteria.
    4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
    5. HR-positive (estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive) EBCs (breast cancers that have at least 1% of cells staging positive for ER and PgR should be considered ER-positive and PgR-positive according to the National Compre-hensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guide-lines). ER and/or PgR status must be centrally confirmed by using immunohistochemistry (IHC) testing and Allred score of 6-8.
    6. Patients with HER2-negative breast cancer through in situ hybridization test (fluores-cence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], or silver en-hanced in situ hybridization [SISH]) or negative immunohistochemical status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required. HER2 status must be centrally confirmed.
    7. Ki67 levels ≥ 20% confirmed by IHC testing in a central laboratory.
    8. Tumor size >2,0 cm (T2-4 according to TNM staging system, but always >2,0 cm).
    9. Limited node involvement (N0-2, according to TNM staging system), as assessed by a sentinel lymph node biopsy, an axillary dissection, or both, and as defined by the Sixth Edition of the American Joint Committee on Cancer (AJCC) staging criteria.
    10. No metastatic disease (M0, according to TNM staging system).
    11. Available pre-treatment tissue sample (biopsy) material (formalin- fixed paraffin-embedded (FFPE)) for RS central evaluation by the Assay.
    12. Patients agree to collection of tissue biopsy from the primary breast cancer at the time of study inclusion (screening), at Cycle 1 Day 14 of treatment, and after 24 weeks, or if experience intolerable side effects, disease progression, or withdraw during 24 weeks of study treatment.
    13. Patients must have biopsable and measurable disease (according to RECIST criteria v.1.1).
    14. No prior chemotherapy, endocrine or radiation therapy for current disease.
    15. Adequate organ function:
    a) Hematological: White blood cell (WBC) count ≥ 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5x 109/L, platelet count ≥ 75.0 x109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L).
    b) Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (x ULN) (or total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN in patients with well-documented Gilbert's syndrome); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transami-nase (ALT) ≤ 3 times ULN.
    c) Renal: Serum creatinine ≤ 1.5 x ULN.
    16. Resolution of all acute toxic effects of prior surgical proce-dures to grade ≤1 as determined by the NCI CTCAE v.5.0.
    1. Mujeres mayores de 18 años.
    2. Las pacientes han sido informadas de la naturaleza del estudio, han accedido a participar y han firmado el formulario de consentimiento informado antes de realizar ninguna actividad relacionada con el estudio.
    3. Mujeres premenopáusicas y posmenopáusicas. Las mujeres premenopáusicas deben recibir tratamiento con un análogo de LHRH desde el registro previo de la paciente. El estado de premenopáusica o posmenopáusica debe establecerse antes de iniciar el tratamiento del estudio con letrozol más palbociclib, basándose en la siguiente clasificación:
    a) El estado posmenopáusico se define por:
    o Ooforectomía bilateral previa;
    o
    o Edad > 60 años;
    o
    o Edad < 60 años y con amenorrea durante 12 meses en ausencia de quimioterapia, tamoxifeno, toremifeno o supresión ovárica, y folitropina (FSH) y estradiol dentro del intervalo posmenopáusico.
    b) El estado premenopáusico se define como todas las mujeres que no cumplan con los criterios anteriores.
    4. Estado funcional del Eastern Cooperative Oncology Group (ECOG) ≤ 1.
    5. Cánceres de mama incipientes (CMI) positivos para RH (positivos para el receptor de estrógenos [RE] y/o positivos para el receptor de progesterona [RPg]) (los cánceres de mama con al menos un 1 % de las células positivas para el RE y el RPg deben considerarse positivos para el RE y el RPg de conformidad con las pautas de la National Comprehensive Cancer Network [NCCN] y la American Society of Clinical Oncology [ASCO]). El estado de RE y/o RPg debe confirmarse centralmente mediante pruebas de inmunohistoquímica (IHQ) y una puntuación de Allred de 6-8.
    6. Pacientes con cáncer de mama negativo para HER2 a través de pruebas de hibridación in situ (hibridación por fluorescencia in situ [FISH], hibridación cromogénica in situ [CISH] o hibridación in situ con plata [SISH]) o estado inmunohistoquímico negativo de 0, 1+ o 2+. Si la IHQ es 2+, se requiere una prueba de hibridación in situ (FISH, CISH o SISH) negativa. El estado de HER2 debe confirmarse centralmente.
    7. Niveles de Ki67 ≥ 20 % confirmados por pruebas de IHQ en un laboratorio central.
    8. Tamaño tumoral > 2,0 cm (T2-4 según el sistema de estadificación TNM, pero siempre > 2,0 cm).
    9. Afectación ganglionar limitada (N0-2, según el sistema de estadificación TNM), evaluada mediante una biopsia del ganglio centinela, una disección axilar, o ambas, y según la definición de la sexta edición de los criterios de estadificación del American Joint Committee on Cancer (AJCC).
    10. Ausencia de enfermedad metastásica (M0, según el sistema de estadificación TNM).
    11. Material (biopsia) disponible de muestra tisular previa al tratamiento (fijado en formol e incluido en parafina [FFIP]) para la evaluación central de la RS mediante la Prueba.
    12. Las pacientes deben aceptar la obtención de una biopsia tumoral en el momento de la inclusión, en el día 14 del ciclo 1 del tratamiento, después de 24 semanas, o si presentan efectos secundarios intolerables, progresión de la enfermedad o se retiran durante 24 semanas del tratamiento del estudio.
    13. Las pacientes deben presentar enfermedad biopsiable y mensurable (según los criterios RECIST, v. 1.1).
    14. Sin quimioterapia, hormonoterapia ni radioterapia previas para la enfermedad actual.
    15. Función orgánica aceptable:
    a) Parámetros hematológicos: Recuento de leucocitos ≥ 3,0 × 109/l, recuento absoluto de neutrófilos (RAN) ≥ 1,5 × 109/l; recuento de plaquetas ≥ 75,0 × 109/l y hemoglobina ≥ 10,0 g/dl (≥ 6,2 mmol/l).
    b) Parámetros hepáticos: Bilirrubina ≤ 1,5 veces el límite superior de la normalidad (LSN) (o bilirrubina total ≤ 3,0 veces el LSN o bilirrubina directa ≤ 1,5 veces el LSN en pacientes con síndrome de Gilbert bien documentado); fosfatasa alcalina (FA) ≤ 2,5 veces el LSN; aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) ≤ 3 veces el LSN.
    c) Parámetros renales: Creatinina sérica ≤ 1,5 veces el LSN.
    16. Resolución de todos los efectos tóxicos agudos de los procedimientos quirúrgicos previos hasta grado ≤ 1 según lo determinado por los CTCAE del NCI, v. 5.0.
    E.4Principal exclusion criteria
    1. Metastatic progression (M1, according to TNM staging system).
    2. Substantial nodal involvement (N>2, according to TNM staging system).
    3. Non-large tumor (T0-1, according to TNM staging system).
    4. Bilateral breast carcinoma.
    5. Inflammatory carcinoma (T4d, according to TNM staging system).
    6. Patients with exclusive non-measurable/evaluable disease.
    7. Known hypersensitivity to any palbociclib excipients.
    8. Known hypersensitivity to any letrozole excipients.
    9. Formal contraindication to endocrine therapy.
    10. Patients unable to swallow tablets.
    11. Other malignancies within the past five years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix.
    12. Previous radiotherapy on the ipsilateral chest wall for the treatment of any other malignance.
    13. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within four weeks of start of study treatment, or patients who have not recovered from the side effects of any major surgery, or patients that may require major surgery during the course of the study.
    14. Have a serious concomitant systemic disorder (i.e., active infection including HIV, or cardiac disease) incompatible with the study (at the discretion of investigator).
    15. Patients with an active bleeding diathesis, previous history of bleeding diathesis, or anti-coagulation treatment (the use of low molecular weight heparin is allowed as soon as it is used as prophylaxis intention).
    16. History of malabsorption syndrome or other condition that would interfere with enteral absorption.
    17. Chronic daily treatment with corticosteroids with a dose of ≥ 10 mg/day methylpredniso-lone equivalent (excluding inhaled steroids).
    18. QTc interval > 480 msec on basal assessments, personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
    19. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (i.e., hypocalcemia, hypokalemia, or hypomagnesemia).
    20. Participation in the treatment phase of an interventional trial within 30 days prior to study treatment start.
    1. Progresión metastásica (M1, según el sistema de estadificación TNM).
    2. Afectación ganglionar sustancial (N>2, según el sistema de estadificación TNM).
    3. Tumor no grande (T0-1, según el sistema de estadificación TNM).
    4. Carcinoma mamario bilateral.
    5. Carcinoma inflamatorio (T4d, según el sistema de estadificación TNM).
    6. Pacientes con enfermedad no mensurable/evaluable exclusiva.
    7. Hipersensibilidad conocida a cualquier excipiente del palbociclib.
    8. Hipersensibilidad conocida a cualquier excipiente del letrozol.
    9. Contraindicación formal a la hormonoterapia.
    10. Pacientes incapaces de tragar comprimidos.
    11. Otra neoplasia maligna en los últimos cinco años, excepto carcinoma basocelular o espinocelular, o carcinoma cervicouterino in situ, tratados de forma apropiada.
    12. Radioterapia previa en la pared torácica homolateral para el tratamiento de cualquier otra neoplasia maligna.
    13. Pacientes con una cirugía mayor (definida como la que precisa anestesia general) o lesión traumática significativa en las cuatro semanas previas al inicio de la administración del tratamiento del estudio, o pacientes que no se hayan recuperado de los efectos secundarios de alguna cirugía mayor o pacientes que quizá la necesiten durante el transcurso del estudio.
    14. Pacientes con un trastorno sistémico concomitante grave (p. ej., infección activa, incluido el VIH, o cardiopatía) incompatible con el estudio (a criterio del investigador).
    15. Pacientes con diátesis hemorrágica activa, antecedentes de diátesis hemorrágica o tratamiento anticoagulante (se permite el uso de heparina de bajo peso molecular siempre que se utilice como profilaxis).
    16. Antecedentes de síndrome de malabsorción u otras enfermedades que pudieran interferir en la absorción intestinal.
    17. Tratamiento diario prolongado con corticosteroides a una dosis ≥ 10 mg/día de metilprednisolona o equivalente (excepto corticosteroides inhalados).
    18. Intervalo QTc > 480 ms en las evaluaciones basales, antecedentes personales de síndrome de QT corto o prolongado, síndrome de Brugada o antecedentes conocidos de prolongación del QTc o Torsade de Pointes (TdP).

    19. Desequilibrios electrolíticos no controlados que puedan agravar los efectos de un fármaco que prolongue el intervalo QTc (p. ej., hipocalcemia, hipopotasemia o hipomagnesemia).
    20. Participación en la fase de tratamiento de un estudio intervencionista en los 30 días previos al inicio del tratamiento del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    1. The percentage of patients in cohort A that experience a stable RS result as measured by the Assay after 6 months of treatment: from pre-treatment RS 18-25 to post-treatment RS≤25; or (*)
    2. The percentage of patients in cohort B that experience a change in RS result after 6 months of treatment: from pre-treatment RS 26-100 to post-treatment RS≤25; or (*)
    (*) The percentage of patients with pre-treatment RS 18-25 or 26-100 that experience a biological response after 6 months of treatment defined by pCR (invasive) or microscop-ic residual infiltration where the post-treatment RS result is not feasible (reviewed by an independent pathologist).
    1. El porcentaje de pacientes de riesgo intermedio (cohorte A) que presenten un resultado de PR estable, medido por la Prueba tras 6 meses de tratamiento: desde una RS de 18-25 previa al tratamiento hasta una RS ≤ 25 posterior al tratamiento; o (*)
    2. El porcentaje de pacientes de alto riesgo (cohorte B) que presenten un cambio en el resultado de RS tras 6 meses de tratamiento: desde una RS > 25 previa al tratamiento hasta una RS ≤ 25 posterior al tratamiento.
    (*)
    (*) El porcentaje de pacientes de riesgo intermedio o alto que presentan una respuesta biológica tras 6 meses de tratamiento, definido por la RCp (invasiva) o la infiltración residual microscópica cuando el resultado de la RS posterior al tratamiento no es factible (según la revisión de un anatomopatólogo independiente)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline up to surgery (maximum 26 Weeks since treatment start)
    Desde inicio tratamiento hasta cirugía (máximo 26 semanas desde inicio tratamiento)
    E.5.2Secondary end point(s)
    BIOLOGY
    o The percentage of patients that experience a biological response after 6 months of treatment defined by any of the three following parameters:
    - Change in RS result: from pre-treatment RS 18-25 to post-treatment RS 0-17 for patients in cohort A and from pre-treatment RS 26-100 to post-treatment RS≤25 for patients in cohort B;
    And/Or
    - Change in RCB score, which is calculated combining pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size): from pre-treatment score of II-III to post-treatment score of 0-I for both cohorts of pa-tients;
    And/Or
    - Change in Ki67: from Ki67 >20 to <2.7 for both cohorts of patients evaluated on surgical resected sample post-treatment (reviewed by an independent pathologist).
    o Rate of patients in cohort B for whom the RS result decreases (from pre-treatment RS 26-100 to post-treatment RS≤25) and RCB score (from score II-III to 0-I);
    o Rate of patients in cohort A for whom the RS result increases (from pre-treatment RS 18-25 to post-treatment RS 26-100);
    o The concordance rate among post-treatment RS, pCR (lack of signs of cancer), RCB, and PEPI scores; the latter is calculated combining assessment of tumor size, nodal involvement, HR status and Ki67 levels.
    o Percentage of patients with Ki67 >10% and Ki67 <2.7 evaluated on tissue biopsy at 14 days.
    Median absolute value or median percentage of change in RS result from pre-treatment to post-treatment RS results in both cohorts of patients after 6 months of treatment.
    EFFICACY
    o ORR, defined as the number of patients with complete response (CR) and partial response (PR) divided by the number of patients in the analysis population. Tumor re-sponse will be defined as best response, based on local investigator’s assessment ac-cording to RECIST v.1.1.
    o DoR, defined as the time from documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurs first, as assessed by the Investigator per RECIST v.1.1.
    o TTR: is defined as the time from study initiation to the first overall tumor response (tumor shrinkage of ≥30%) observed for patients who achieved a CR or PR. The CBR is defined as the percentage of patients who experience a CR, PR or stable disease for at least 24 weeks and assessed by RECIST v1.1.
    o CBR as best response, defined as the percentage of patients who experience a CR, PR or SD for at least 24 weeks and assessed by the Investigator per RECIST v.1.1.
    o Maximum Tumor Shrinkage defined as the percentage of tumor shrinkage from baseline, based on local investigator’s assessment according to RECIST v1.1.

    SAFETY
    AEs, which will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. Grade 3 and 4 AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability of the drug combination.
    BIOLOGÍA
    o El porcentaje de pacientes que presentan una respuesta biológica tras 6 meses de tratamiento, definido por cualquiera de los tres parámetros siguientes:
    - Cambio en el resultado de la RS: desde la RS de 18-25 previa al tratamiento hasta la RS ≤ 18 posterior al tratamiento en las pacientes con un riesgo intermedio (cohorte A) y desde la RS > 25 previa al tratamiento hasta la RS ≤ 25 posterior al tratamiento en las pacientes con un riesgo alto (cohorte B);
    y/o
    - Cambio en la puntuación de la RSB, que se calcula combinando las mediciones patológicas del tumor primario (tamaño y celularidad) y las metástasis ganglionares (número y tamaño): desde la puntuación previa al tratamiento de ll-lll hasta la puntuación posterior al tratamiento de 0-l para ambas cohortes de pacientes;
    y/o
    - Cambio en Ki67: desde una Ki67 > 20% hasta una Ki67 < 2,7 para las dos cohortes de pacientes evaluadas en una muestra quirúrgica resecada posterior al tratamiento (según la revisión de un anatomopatólogo independiente).
    o La tasa de pacientes de alto riesgo (cohorte B), en los que el resultado de la RS disminuye (desde una RS > 25 previa al tratamiento hasta una RS ≤ 25 posterior al tratamiento) y puntuación de la RSB (desde la puntuación ll-lll hasta la 0-l).
    o La tasa de pacientes de riesgo intermedio (cohorte A), en los que el resultado de la RS aumenta (desde una RS de 18-25 previa al tratamiento hasta una RS > 25 posterior al tratamiento).
    o La tasa de concordancia entre las puntuaciones posteriores al tratamiento de RS, RCp (ausencia de signos de cáncer), RSB y PEPI; la última se calcula combinando la evaluación del tamaño del tumor, la afectación ganglionar, el estado de los receptores hormonales (RH) y los niveles de Ki67.
    o El valor absoluto de la mediana o el porcentaje de la mediana del cambio en el resultado de la RS desde los resultados de la RS previos al tratamiento hasta los posteriores al tratamiento en ambas cohortes de pacientes después de 6 meses de tratamiento.

    EFICACIA
    o La Tasa de Respuesta Global, definida como el número de pacientes con respuesta completa (RC) y respuesta parcial (RP) dividido entre el número de pacientes en la población de análisis. La respuesta tumoral, definida como la mejor respuesta, según la evaluación del investigador local de acuerdo con los criterios RECIST, v. 1.1.
    o La Duración de la Respuesta, definida como el tiempo desde la documentación de la respuesta tumoral objetiva (RC o RP) hasta la primera documentación de progresión de la enfermedad o muerte por cualquier causa, lo que ocurra primero, según lo evaluado por el investigador conforme a los criterios RECIST, v. 1.1.
    o El Tiempo Transcurrido hasta la Respuesta, definido como el tiempo desde el inicio del estudio hasta la primera respuesta tumoral global (reducción del tumor del ≥ 30 %) observada en las pacientes que alcanzaron RC o RP. La TBC, definida como el porcentaje de pacientes con RC, RP o enfermedad estable durante un mínimo de 24 semanas, según la evaluación mediante los criterios RECIST, v. 1.1.
    o La Tasa de Beneficio Clínico, según la mejor respuesta, definida como el porcentaje de pacientes que experimentan una RC, RP o EE durante al menos 24 semanas según la evaluación del investigador conforme a los criterios RECIST, v. 1.1.
    o La máxima reducción del tamaño tumoral, definida como el porcentaje de reducción del tamaño del tumor respecto al inicio, según la evaluación del investigador local de acuerdo con los criterios RECIST, v. 1.1.
    SEGURIDAD
    Los AA, que se evaluarán mediante los Criterios terminológicos comunes para acontecimientos adversos (CTCAE) del Instituto Nacional del Cáncer (NCI), v. 5.0. Los AA de grado 3 y 4 y los acontecimientos adversos graves (AAG) se evaluarán para determinar la seguridad y la tolerabilidad de la combinación farmacológica.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline up to surgery (maximum 26 Weeks since treatment start)
    Desde inicio tratamiento hasta cirugía (máximo 26 semanas desde inicio tratamiento)
    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 No
    E.6.11Pharmacogenomic No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 Yes
    E.8.1.7.1Other trial design description
    Diseño Simon de dos etapas
    Simon's two stage design
    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.8.3 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 concerned17
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 26
    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 state49
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 17
    F.4.2.2In the whole clinical trial 66
    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)
    Standard of Care
    Práctica clínica habitual
    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 Decision2018-11-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-10-29
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