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    Summary
    EudraCT Number:2012-004601-27
    Sponsor's Protocol Code Number:A5481008
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2013-05-16
    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 number2012-004601-27
    A.3Full title of the trial
    A RANDOMIZED, MULTICENTER, DOUBLE-BLIND PHASE 3 STUDY OF PD-0332991 (ORAL CDK 4/6 INHIBITOR) PLUS LETROZOLE VERSUS PLACEBO PLUS LETROZOLE FOR THE TREATMENT OF POSTMENOPAUSAL WOMEN WITH ER (+), HER2 (-) BREAST CANCER WHO HAVE NOT RECEIVED ANY PRIOR SYSTEMIC ANTI-CANCER TREATMENT FOR ADVANCED DISEASE
    ENSAYO CLÍNICO EN FASE 3, ALEATORIZADO, MULTICÉNTRICO, DOBLE CIEGO CON PD0332991 (INHIBIDOR ORAL DE CDK 4/6) EN COMBINACIÓN CON LETROZOL COMPARADO CON PLACEBO MÁS LETROZOL EN EL TRATAMIENTO DE PACIENTES POSMENOPÁUSICAS CON CÁNCER DE MAMA RE (+), HER2 (-) QUE NO HAN RECIBIDO TRATAMIENTO SISTÉMICO PREVIO PARA LA ENFERMEDAD AVANZADA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of PD-0332991 + letrozole vs. letrozole for treatment of posmenopausal women with ER+/HER2- advanced breast cancer.
    Estudio con PD-0332991 + letrozol comparado con letrozol para el tratamiento de mujeres posmenopáusicas con cáncer de mama avanzado RE (+), HER2 (-).
    A.4.1Sponsor's protocol code numberA5481008
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01740427
    A.5.4Other Identifiers
    Name:TRIO-022Number:TRIO-022
    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 SponsorPfizer Inc 235 East 42nd Street, New York, NY10017
    B.1.3.4CountryUnited States
    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 supportPfizer Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc
    B.5.2Functional name of contact pointClinical Trials.gov Call Center
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018007181021
    B.5.5Fax number0013037391119
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code PD-0332991
    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 INNNA
    D.3.9.1CAS number 571190-30-2
    D.3.9.2Current sponsor codePD-0332991
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    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 RoleComparator
    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 Letrozole
    D.2.1.1.2Name of the Marketing Authorisation holderActavis Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.9.3Other descriptive nameLetrozole
    D.3.9.4EV Substance CodeSUB08444MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code PD-0332991
    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 INNNA
    D.3.9.1CAS number 571190-30-2
    D.3.9.2Current sponsor codePD-0332991
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    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: 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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code PD-0332991
    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 INNNA
    D.3.9.1CAS number 571190-30-2
    D.3.9.2Current sponsor codePD-0332991
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    "Estrogen receptor-positive (ER+), HER2 negative (HER2-) Advanced Breast Cancer (ABC)"
    Cáncer de mama avanzado (CMA) positivo para el receptor estrogénico RE(+) y negativo para HER2 (HER2(-)).
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10072737
    E.1.2Term Advanced breast cancer
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10070575
    E.1.2Term Estrogen receptor positive 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 demonstrate that the combination of PD-0332991 with letrozole is superior to placebo plus letrozole in prolonging PFS in postmenopausal women with ER(+)/HER2 (-) advanced breast cancer who have not received any prior systemic anti-cancer therapies for their advanced/metastatic disease.
    Demostrar que la combinación de PD-033299 y letrozol es superior a placebo más letrozol para prolongar la supervivencia libre de progresión (SLP) en pacientes posmenopáusicas con cáncer de mama avanzado RE(+) / HER2(-) que no han recibido tratamiento sistémico previo para la enfermedad avanzada.
    E.2.2Secondary objectives of the trial
    - To compare measures of tumor control duration and overall survival between the treatment arms;
    - To compare safety and tolerability between the treatment arms;
    - To compare health related quality of life between the treatment arms;
    - To characterize the effects of PD-0332991 at therapeutic doses in combination with letrozole on QTc interval in this patient population;
    - To determine trough PD-0332991 plasma concentration in this patient population and explore correlations between exposure and response and/or safety findings;
    - To characterize alterations in genes, proteins, and RNAs relevant to the cell cycle (eg, CCND1 amplification, CDKN2A deletion), drug targets (eg, CDK 4/6), and tumor sensitivity and/or resistance (eg, Ki67, pRb) in tumor tissues.
    - Comparar la duración del control tumoral y la supervivencia global entre los brazos de tratamiento.
    - Comparar la seguridad y la tolerabilidad entre los brazos de tratamiento.
    - Comparar la calidad de vida entre los brazos de tratamiento.
    - Caracterizar los efectos de PD-0332991 a dosis terapéuticas en combinación con letrozol sobre el intervalo QT en esta población de pacientes.
    - Determinar la concentración plasmática de PD-0332991 en esta población de pacientes y explorar la correlación entre la exposición y la respuesta y/o los hallazgos de seguridad.
    - Caracterizar las alteraciones en los genes, las proteínas y el ARN que son importantes para el ciclo celular (p. ej., amplificación de la CCND1, delección en el CDKN2A), las dianas del fármaco (p. ej., CDK 4/6) y la sensibilidad y/o la resistencia del tumor (p. ej., Ki67, pRb) en muestras de tejido tumoral.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    - Optional Tumor Tissue Biopsy for Molecular Profiling, Section
    7.5.1 of protocol
    - Additional Pharmacogenomic Research, Section 7.6.2 of protocol
    - ECG/PK sub-study, Sections 7.2.2 and 7.3 of protocol
    - Biopsia opcional de tejido tumoral para perfil Molecular, Sección 7.5.1 del protocolo
    - Investigación Farmacogenómica adicional, Sección 7.6.2 del protocolo
    - ECG / PK sub-estudio, Secciones 7.2.2 y 7.3 del protocolo
    E.3Principal inclusion criteria
    Patient eligibility should be reviewed and documented by an appropriately qualified member
    of the investigator?s study team before patients are included in the study.
    Patients must meet all of the following inclusion criteria to be eligible for enrollment into the
    study:
    1. Adult women (>= 18 years of age) with proven diagnosis of adenocarcinoma of the breast
    with evidence of locoregionally recurrent or metastatic disease not amenable to resection
    or radiation therapy with curative intent and for whom chemotherapy is not clinically
    indicated.
    2. Documentation of histologically or cytologically confirmed diagnosis of
    estrogen-receptor positive (ER+) breast cancer based on local laboratory results.
    3. Previously untreated with any systemic anti-cancer therapy for their locoregionally
    recurrent or metastatic ER+ disease.
    4. Postmenopausal women defined as women with:
    - Prior bilateral surgical oophorectomy, or
    - Medically confirmed post-menopausal status defined as spontaneous cessation of regular menses for at least 12 consecutive months with no alternative pathological or
    physiological cause.
    5. Measurable disease as defined per RECIST v.1.1 or bone-only disease.
    Tumor lesions previously irradiated or subjected to other locoregional therapy will only
    be deemed measurable if disease progression at the treated site after completion of
    therapy is clearly documented.
    6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
    7. Adequate organ and marrow function defined as follows:
    - ANC >=1,500/mm3 (1.5 x 109 /L);
    - Platelets >=100,000/mm3 (100 x 109 /L);
    - Hemoglobin >=9 g/dL (90 g/L);
    - Serum creatinine ?1.5 x ULN or estimated creatinine clearance >= 60 mL/min as
    calculated using the method standard for the institution;
    - Total serum bilirubin =<1.5 x ULN (=<3.0 x ULN if Gilberts disease);
    - AST and/or ALT =<3 x ULN (=<5.0 x ULN if liver metastases present);
    - Alkaline phosphatase =<2.5 x ULN (=<5.0 x ULN if bone or liver metastases present).
    8. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.0 Grade =<1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
    9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
    10. Willingness and ability to provide tumor tissues (ie, archived formalin fixed paraffin embedded tissues [block or 12 unstained slides]), which will be used for centralized retrospective confirmation of ER status and to evaluate correlation between genes, proteins, and RNAs relevant to the cell cycle pathways and sensitivity/resistance to the investigational agents. If tumor tissue is not available, then a fresh biopsy will be required for patient participation.
    11. Evidence of a personally signed and dated informed consent document indicating that the
    patient (or a legal representative) has been informed of all pertinent aspects of the study
    before any study-specific activity is performed.
    La elegibilidad de cada paciente debe revisarse y documentarse por parte de un miembro cualificado del equipo de investigación antes de incluir a la paciente en el ensayo clínico.
    Para participar en este estudio las pacientes deben reunir los siguientes criterios de inclusión:
    1. Ser mujer mayor de edad (>= 18 años) con diagnóstico confirmado de adenocarcinoma de mama con evidencia de enfermedad locorregional recurrente o de enfermedad metastásica no tributaria de resección quirúrgica ni de radioterapia con intención curativa y para la cual la quimioterapia no está indicada. 2. Documentación del diagnóstico confirmado histológica o citológicamente de cáncer de mama con receptor estrogénico positivo (RE+) mediante los resultados de las pruebas de laboratorio local.
    3. Sin tratamiento sistémico previo para la enfermedad locorregional recurrente o metastásica RE+.
    4. Mujer posmenopausica, definida como:
    - Ovariectomía quirúrgica bilateral realizada con anterioridad, o
    - Estado posmenopáusico médicamente confirmado, que se define como el cese espontáneo de la menstruación regular durante un mínimo de 12 meses consecutivos sin que existan causas patológicas o fisiológicas alternativas.
    5. Enfermedad medible, tal como se define en los RECIST v.1.1 (véase el Apéndice 7) o enfermedad que afecta únicamente al hueso. Las lesiones tumorales irradiadas con anterioridad o sometidas anteriormente a otra modalidad de tratamiento locorregional se considerarán medibles únicamente si se documenta claramente la progresión de la enfermedad en el sitio tratado después de la terminación del tratamiento.
    6. Puntuación en la escala del estado general (EG) del Eastern Cooperative Oncology Group (ECOG) de entre 0 y 2 (véase el Apéndice 1).
    7. Funcionamiento adecuado de los órganos y de la médula ósea, que se define como sigue:
    RAN >=1.500/mm3 (1,5 x 109 /l);
    Plaquetas >=100.000/mm3 (100 x 109 /l);
    Hemoglobina >=9 g/dl (90 g/l);
    Creatinina sérica =<1,5 x LSN o aclaramiento estimado de creatinina >= 60 ml/min calculado mediante el método habitual que se utilice en el centro participante en el ensayo clínico; Bilirrubina total sérica =<1,5 x LSN (=<3,0 x LSN si hay enfermedad de Gilbert);
    - AST y/o ALT =<3 x LSN (=<5,0 x LSN si hay metástasis hepáticas);
    - Fosfatasa alcalina =<2,5 x LSN (=<5,0 x LSN si hay metástasis óseas o hepáticas).
    8. Resolución de todos los efectos tóxicos producidos por los tratamientos anteriores del cáncer o los procedimientos quirúrgicos a un Grado =<1 según los criterios NCI CTCAE versión 4.0 (excepto la alopecia u otros efectos tóxicos que no supongan un riesgo para la seguridad de la paciente según el criterio del investigador).
    9. Disposición y capacidad para cumplir con las visitas programadas en el protocolo, con el plan de tratamiento, con las pruebas de laboratorio y con los demás procedimientos del estudio.
    10. Disposición y capacidad para proporcionar tejido tumoral (es decir, tejido fijado en formalina y embebido en parafina [bloque o 12 laminillas sin teñir]), que se utilizará para la confirmación centralizada retrospectiva del estado con respecto al RE y para evaluar la correlación entre los genes, las proteínas y el ARN relevantes para el ciclo celular y la resistencia/sensibilidad a los fármacos en investigación. Si no se dispone de tejido tumoral, para la participación de la paciente se requiere una biopsia de novo en fresco.
    11. Evidencia de la existencia del documento del consentimiento informado firmado y fechado personalmente como prueba de que la paciente (o su representante legal) ha sido informada de todos los aspectos relevantes del estudio antes de realizar cualquiera de los procedimientos del mismo.
    E.4Principal exclusion criteria
    Patients presenting with any of the following will not be included in the study:
    1. HER2-positive tumor as defined by documentation of erbB-2 gene amplification by FISH (as defined by a HER2/CEP17 ratio >=2) or chromogenic in situ hybridization (CISH, as defined by the manufacturer?s kit instruction) or documentation of HER2-overexpression by IHC (defined as IHC3+, or IHC2+ with FISH or CISH confirmation) based on local laboratory results utilizing one of the sponsor-approved assays. If HER2 status is unavailable or was determined using a test other than a sponsor-approved
    assay, then testing must be performed/repeated using one of these assays prior to randomization.
    2. Patients with advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions
    [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement).
    3. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are
    eligible if they have been definitively treated with local therapy (eg, radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization.
    4. Prior neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor (ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of completing treatment.
    5. Prior treatment with any CDK4/6 inhibitor.
    6. Patients treated within the last 7 days prior to randomization with: - Food or drugs that are known to be CYP3A4 inhibitors (ie, amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice); - Drugs that are known to be CYP3A4 inducers (ie, carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. Johns wort). - Drugs that are known to prolong the QT interval.
    7. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anti-cancer therapy within 2 weeks before randomization. Patients who received prior radiotherapy to >=25% of bone marrow are not eligible independent of when it was received.
    8. Diagnosis of any other malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
    9. QTc >480 msec (based on the mean value of the triplicate ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
    10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (eg, hypocalcemia, hypokalemia, hypomagnesemia).
    11. Any of the following within 6 months of randomization: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade >=2, atrial fibrillation of any grade, coronary/peripheral artery bypass
    graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.
    12. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection.
    13. Known hypersensitivity to letrozole, or any of its excipients, or to any PD-0332991/placebo excipients.
    14. Known human immunodeficiency virus infection.
    15. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the
    judgment of the investigator, would make the patient inappropriate for entry into this study.
    16. Patients who are investigational site staff members or relatives of those site staff members or patients who are Pfizer employees directly involved in the conduct of the trial.
    17. Participation in other studies within 4 weeks before randomization.
    18. Recent or active suicidal ideation or behavior.
    1.Tumor HER2 positivo tal como se demuestra por la confirmación de la amplificación del gen erbB-2 mediante FISH (definido por un cociente HER2/CEP17 >=2) o mediante hibridización cromogénica in situ o por la documentación de la sobreexpresión de HER2 mediante IHQ según los resultados obtenidos en el laboratorio del centro participante en el estudio clínico utilizando uno de los métodos analíticos autorizados por el promotor del estudio.Si no se conoce el estado de HER2 o se ha determinado utilizando un método analítico no autorizado por el promotor del estudio, debe llevarse a cabo/repetirse la prueba antes de la aleatorización utilizando uno de los métodos analíticos autorizados. 2.Extensión visceral avanzada sintomática, que pueden dar lugar a complicaciones que pueden poner en riesgo la vida de la paciente a corto plazo.3.Metástasis conocidas activas, sintomáticas o no controladas en el SNC,meningitis carcinomatosa o enfermedad leptomeníngea,indicado por la presencia de síntomas clínicos, edema cerebral y/o crecimiento progresivo. Las pacientes con antecedentes de metástasis en el SNC o de compresión de la médula espinal pueden participar en el estudio siempre y cuando hayan sido definitivamente tratadas con un tratamiento local, estén clínicamente estables y no hayan sido tratadas con anticonvulsivos ni corticoesteroides durante al menos las 4 semanas anteriores a la aleatorización.4.Tratamiento anterior neoadyuvante o adyuvante con un inhibidor de la aromatasa no esteroideo con recidiva de la enfermedad durante el tratamiento o dentro de los 12 meses siguientes a la terminación de este. 5.Tratamiento anterior con algún inhibidor de CDK4/6.
    6. Pacientes tratadas en los últimos 7 días antes de la aleatorización con: Alimentos o fármacos que se sabe que son inhibidores de CYP3A4 (es decir, amprenavir, atazanavir, boceprevir, claritromicina, conivaptán, delavirdina, diltiazem, eritromicina, fosamprenavir, indinavir, itraconazol, ketoconazol, lopinavir, mibefradil, miconazol, nefazodona, nelfinavir, posaconazol, ritonavir, saquinavir, telaprevir, telitromicina, verapamilo, voriconazol y pomelo o zumo de pomelo); Fármacos que se sabe que son inductores de CYP3A4 (es decir, carbamazepina, felbamato, nevirapina, fenobarbital, fenitoína, primidona, rifabutina, rifampina, rifapentina y hierba de San Juan). Fármacos que se sabe que producen una prolongación de intervalo QT.7.Cirugía mayor, quimioterapia, radioterapia, agentes en investigación u otros tratamientos para la enfermedad en las 2 semanas anteriores a la aleatorización. Las pacientes que hayan recibido radioterapia anteriormente que ha afectado a >=25% de la médula ósea no pueden participar en este ensayo clínico con independencia de cuándo hayan sido tratadas.8.Diagnóstico de cualquier otro cáncer en los 3 años anteriores a la aleatorización, excepto cáncer epidermoide y carcinoma basocelular de la piel o carcinoma de cérvix adecuadamente tratados. 9. QTc >480 mseg, antecedentes personales o familiares de síndrome del intervalo QT largo o corto, de síndrome de Brugada o antecedentes conocidos de prolongación de QTc o de Torsade de Pointes (TdP). 10. Alteraciones de los electrólitos no controladas que pudieran agravar el efecto de la prolongación de QTc provocado por el fármaco en investigación.11. Cualquiera de los siguientes problemas en los 6 meses anteriores a aleatorización: infarto de miocardio, angina de pecho grave o inestable, arritmia cardíaca no resuelta de Grado 2 o superior según los criterios NCI CTCAE versión 4.0, fibrilación auricular de cualquier grado, revascularización coronaria o periférica, insuficiencia cardíaca congestiva sintomática, accidente cerebrovascular, incluido el ataque isquémico transitorio, o embolia pulmonar sintomática. 12. Enfermedad intestinal inflamatoria activa o diarrea crónica, síndrome del intestino corto o cualquier tipo de resección quirúrgica de la parte superior del aparato digestivo, incluida la resección gástrica. 13. Hipersensibilidad conocida al letrozol o a alguno de sus excipientes, o a algunos de los excipientes de PD-0332991/placebo. 14. Infección conocida por el virus de la inmunodeficiencia humana (VIH). 15. Otras dolencias médicas o psiquiátricas crónicas o agudas o resultados anormales en las pruebas de laboratorio que pudieran producir un aumento de los riesgos asociados con la participación en el ensayo clínico o con la administración del producto en investigación o interferir en la interpretación de los resultados del estudio, y, a juicio del investigador, hacen que fuese desaconsejable incluir a la paciente en el estudio. 16. Ser miembro o pariente del equipo investigador del centro o ser empleado de Pfizer y estar directamente implicado en este ensayo clínico. 17. Haber participado en otro estudio en las 4 semanas anteriores a la aleatorización. 18. Ideas suicidas o intento de suicidio reciente o activo.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-Free Survival (PFS).
    Median time from the first dose of study treatment to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first.
    Supervivencia libre de progresión (SLP).
    Mediana de tiempo desde la primera dosis del tratamiento de estudio hasta la primera documentación de progresión objetiva del tumor o la muerte por cualquier causa, lo que ocurra primero.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Disease assessment every 12 weeks
    Baseline up to 2.5 years.
    Evaluación de la enfermedad cada 12 semanas.
    Desde la visita basal hasta a los 2,5 años
    E.5.2Secondary end point(s)
    - Overall Survival (OS);
    - 1-year, 2-year, and 3-year survival probabilities;
    - Objective Response (OR: Complete Response or Partial Response);
    - Duration of Response (DR);
    - Disease Control (DC: CR+PR+Stable disease ?24 weeks);
    - Corrected QT interval (QTc);
    - Tumor tissue biomarkers, including genes (eg, copy numbers of CCND1, CDKN2A), proteins (eg, Ki67, pRb), and RNA expression (eg, cdk4, cdk6);
    - Trough plasma concentration of PD-0332991;
    - EuroQol (EQ-5D) Score;
    - Functional Assessment of Cancer Therapy - Breast (FACT-B);
    - Type, incidence, severity (as graded by NCI CTCAE v4.0),seriousness and relationship to study medications of adverse events (AE) and any laboratory abnormalities.
    - Supervivencia global (SG).
    - Probabilidad de supervivencia a 1 año, a 2 años y a 3 años.
    - Respuesta objetiva (RO: respuesta completa o respuesta parcial).
    - Duración de la respuesta (DR).
    - Control de la enfermedad (CE: RC+RP+enfermedad estable ?24 semanas).
    - Intervalo QT corregido (QTc).
    - Biomarcadores del tejido tumoral, incluidos los genes (p. ej., número de copias de CCND1, CDKN2A), las proteínas (p. ej., Ki67, pRb) y la expresión del ARN (p. ej., cdk4, cdk6).
    - Concentracion plasmática mínima de PD-0332991.
    - Puntuación en el EuroQol (EQ-5D).
    - Evaluación Funcional del Tratamiento del Cáncer ? Mama (FACT-B).
    - Tipo, incidencia, intensidad (graduada mediante los NCI CTCAE v4.0), gravedad y relación con la medicación del estudio de los acontecimientos adversos (AA) y de los valores anormales de las pruebas de laboratorio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Disease assessment every 12 weeks
    Evaluación de la enfermedad cada 12 semanas
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic 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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned22
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA117
    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
    Australia
    Belgium
    Brazil
    Canada
    China
    Czech Republic
    European Union
    France
    Germany
    Hungary
    Ireland
    Italy
    Japan
    Korea, Republic of
    New Zealand
    Poland
    Russian Federation
    South Africa
    Spain
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of Trial in all participating countries is defined as Last Patient Last Visit.
    El Fin de Ensayo en todos los países participantes se define como la Última Visita del Último Paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    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 months1
    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: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 150
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 212
    F.4.2.2In the whole clinical trial 450
    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
    Tratamiento habitual
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation ICORG
    G.4.3.4Network Country Ireland
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation GEICAM
    G.4.3.4Network Country Spain
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-06-06
    P. End of Trial
    P.End of Trial StatusOngoing
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