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    Summary
    EudraCT Number:2014-003878-16
    Sponsor's Protocol Code Number:B7391003
    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:2015-06-15
    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 number2014-003878-16
    A.3Full title of the trial
    A Phase 3 randomized, double-blind study of PF-06439535 plus Paclitaxel-Carboplatin and Bevacizumab plus Paclitaxel-Carboplatin for the first-line treatment of patients with advanced non-squamous non-small cell lung cancer.
    ESTUDIO EN FASE III, ALEATORIZADO Y DOBLE CIEGO DE PF-06439535 MÁS PACLITAXEL-CARBOPLATINO Y BEVACIZUMAB MÁS PACLITAXEL-CARBOPLATINO PARA EL TRATAMIENTO DE PRIMERA LÍNEA DE PACIENTES CON CÁNCER DE PULMÓN NO ESCAMOCELULAR NO MICROCÍTICO AVANZADO
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to test if PF-06439535 plus Paclitaxel-Carboplatin compared to Bevacizumab plus Paclitaxel-Carboplatin is an effective treatment in patients with advanced non-squamous non-small cell lung cancer.
    Un estudio para probar si PF-06439535 más paclitaxel-carboplatino comparado con Bevacizumab más Paclitazel-Carboplatino es un tratamiento efectivo en pacientes con cáncer de pulmón no escamolecular no microcítico avanzado
    A.4.1Sponsor's protocol code numberB7391003
    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, NY 10017
    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. 235 East 42nd Street, New Yor, NY 10017
    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 number0113037391119
    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.3.1Product nameBevacizumab-Pfizer
    D.3.2Product code PF-06439535
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBEVACIZUMAB
    D.3.9.2Current sponsor codePF-06439535
    D.3.9.4EV Substance CodeSUB16402MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/l milligram(s)/litre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeBiosimilar medicinal product
    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 Avastin 100mg/4ml & 400mg/16ml concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameAvastin
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.4EV Substance CodeSUB16402MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Advanced non-squamous non-small cell lung cancer.
    Cáncer de pulmón no escamolecular no microcítico avanzado
    E.1.1.1Medical condition in easily understood language
    Advanced non-squamous non-small cell lung cancer.
    Cáncer de pulmón no escamolecular no microcítico avanzado
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10061873
    E.1.2Term Non-small cell lung 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
    The primary objective of this study is to compare the confirmed objective response rate (ORR) by Week 19 following treatment with bevacizumab-Pfizer in combination with paclitaxel and carboplatin to bevacizumab-EU plus paclitaxel and carboplatin in patients who have not received previous treatment for advanced non-squamous non-small cell lung cancer (NSCLC).
    El objetivo principal de este estudio es comparar la tasa de respuesta objetiva (TRO) confirmada en la semana 19 tras el tratamiento con bevacizumab-Pfizer en combinación con paclitaxel y carboplatino con bevacizumab-EU más paclitaxel y carboplatino en pacientes que no han recibido tratamiento previo para el cáncer de pulmón no escamocelular no microcítico avanzado (NSCLC).
    E.2.2Secondary objectives of the trial
    To evaluate the safety of bevacizumab-Pfizer plus paclitaxel and carboplatin and
    bevacizumab-EU plus paclitaxel and carboplatin;

    To evaluate secondary measures of tumor control;

    To evaluate the population pharmacokinetics (PK) of bevacizumab-Pfizer and
    bevacizumab-EU;

    To evaluate the immunogenicity of bevacizumab-Pfizer and bevacizumab-EU.
    ? Evaluar la seguridad de bevacizumab-Pfizer más paclitaxel y carboplatino y bevacizumab-EU más paclitaxel y carboplatino;
    ? Evaluar las mediciones secundarias de control del tumor;
    ? Evaluar la farmacocinética (FC) poblacional de bevacizumab-Pfizer y bevacizumab-EU;
    ? Evaluar la inmunogenicidad de bevacizumab-Pfizer y bevacizumab-EU.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patient eligibility should be reviewed and documented by an appropriate 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. Male and female patients age ?18 years of age, or ? age of consent in the region.
    2. Newly diagnosed Stage IIIB or IV non-small cell lung cancer (according to Revised International System for Staging Lung Cancer criteria of 2010) or recurrent non-small cell lung cancer (NSCLC) for which they had not received chemotherapy for
    metastatic disease.
    3. Histologically or cytologically confirmed diagnosis of predominately non-squamous NSCLC.
    4. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
    5. For patients with recurrent disease, at least 6 months must have elapsed since completing adjuvant or neoadjuvant treatment.
    6. Patients must have had a baseline scan (computed tomography [CT] or magnetic resonance imaging [MRI]) of the chest, abdomen, and other disease sites, as clinically indicated, to assess disease burden performed within 28 days prior to randomization.
    7. Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
    8. Screening laboratory values within the following limits (where deviation of up to 10% is acceptable for any single value if in the investigator?s opinion the patient does not have an increased safety risk):

    Bone Marrow Function

    a. Absolute neutrophil count (ANC) ?1.5 x 10x9 cells/L (1500/mm3);
    b. Platelet count ?100 x 10x9 cells/L (100,000/mm3);
    c. Hemoglobin ?9.0 g/dL (90 g/L);

    Renal Function

    d. Serum creatinine ?1.5 x upper limit of normal (ULN);
    e. Urine dipstick proteinuria <2+ (ie, either 0, trace, or 1+). If urine dipstick is >1+ then a 24 hour urine for protein must have demonstrated urinary excretion of ?500 mg of protein per day;

    Liver Function
    f. Total bilirubin ?1.5 x ULN (<3 ULN if Gilbert?s disease);

    g. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ?3 x ULN (?5 x ULN if liver metastases are present).

    9. Recovery (to Grade 1 or baseline) from all clinically significant adverse effects of prior therapies (excluding alopecia).
    10. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
    11. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
    12. Be eligible to receive study treatment of bevacizumab, paclitaxel and carboplatin based on local standard of care, for the treatment of
    advanced or metastatic non-squamous NSCLC.
    13. Male and female subjects of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of contraception throughout the study and for at least 6 months after the last dose of assigned treatment (bevacizumab-Pfizer or
    bevacizumab-EU).

    Female subjects who are not of childbearing potential (ie, meet at least 1 of the following criteria):

    ? Have undergone a documented hysterectomy and/or bilateral oophorectomy;
    ? Have medically confirmed ovarian failure; or
    ? Achieved postmenopausal status, defined as follows: cessation of regular menses
    for at least 12 consecutive months with no alternative pathological or
    physiological cause; and have a serum follicle stimulating hormone (FSH) level within the laboratory?s reference range for postmenopausal women.
    Un miembro adecuado del equipo del estudio del investigador debe analizar y documentar la idoneidad de los pacientes antes de su inclusión en el estudio.
    Los pacientes deben satisfacer todos los siguientes criterios de inclusión para que se pueda considerar su inscripción en el estudio:
    1. Pacientes de ambos sexos, de >18 de edad o con la > edad de consentimiento en la región.
    2. Recientemente diagnosticados con cáncer de pulmón no microcítico en estadio IIIB o IV (según los criterios del sistema internacional revisado de estadiaje de cáncer de pulmón de 2010) o cáncer de pulmón no microcítico (NSCLC) recurrente para el que no hayan recibido quimioterapia para la patología metastásica.
    3. Diagnóstico confirmado histológica o citológicamente de NSCLC predominantemente no escamocelular.
    4. Presentar al menos una lesión medible, según la definición de los criterios de evaluación de respuesta en tumores sólidos (RECIST v1.1).
    5. En los pacientes con enfermedad recurrente, deben haber transcurrido al menos 6 meses desde que finalizó el tratamiento adyuvante o neoadyuvante.
    6. Se debe haber realizado al paciente una exploración de referencia (basal), sea tomografía computarizada (TC) o resonancia magnética nuclear (RMN) del tórax, el abdomen y otras localizaciones de la enfermedad, según indicación clínica, para evaluar la carga de la enfermedad, en los 28 días anteriores a la aleatorización.
    7. Estado 0 ó 1 del Grupo Oncológico Cooperativo del Este (ECOG).
    8. Valores analíticos del laboratorio dentro de los siguientes límites (donde la desviación de hasta el 10% es aceptable para cualquier valor si, en opinión del investigador, el paciente no presenta mayores riesgos de seguridad):
    Función de la médula ósea
    a. Recuento absoluto de neutrófilos (RAN) ?1,5 x 109 células/L (1500/mm3);
    b. Recuento de plaquetas ?100 x 109 células/L (100.000/mm3);
    c. Hemoglobina ?9,0 g/dl (90g/L);
    Función renal
    d. Creatinina sérica ?1,5 x el límite superior de la normalidad (LSN);
    e. Proteinuria medida en orina con tira reactiva <2+ (esto es, 0, vestigial, o 1+). Si la tira reactiva de orina es >1+, la proteína en orina de 24 horas debe haber demostrado una excreción urinaria de ?500 mg de proteína por día;
    Función hepática
    f. Bilirrubina total ?1,5 x LSN (<3 LSN en caso de enfermedad de Gilbert);
    g. Aspartato aminotransferasa (AST) y/o la alanina aminotransferasa (ALT) ?3 x LSN (?5 x LSN si hay metástasis hepáticas).
    9. Recuperación (al grado 1 o a los valores de referencia) de todos los efectos adversos clínicamente significativos de tratamientos previos (excluyendo alopecia).
    10. Prueba documental firmada y fechada personalmente del consentimiento informado, indicando que el paciente ha sido informado de todos los aspectos relevantes del estudio.
    11. Los pacientes deben estar dispuestos y ser capaces de cumplir con las visitas programadas, el plan de tratamiento, las pruebas de laboratorio y otros procedimientos del estudio.
    12.Ser aptos para recibir el tratamiento en estudio de bevacizumab, paclitaxel y carboplatino en función desegún la norma asistencial local, para el tratamiento del NSCLC no escamocelular avanzado o metastásico.
    13. Los pacientes de ambos sexos en edad fértil y con riesgo de embarazo deben acceder a utilizar dos métodos altamente eficaces de contraconcepción durante todo el estudio y durante al menos 6 meses después de recibir la última dosis del tratamiento asignado (bevacizumab-Pfizer o bevacizumab-EU).
    Pacientes de sexo femenino que no estén en edad fértil (es decir, que satisfagan al menos 1 de los siguientes criterios):
    ? Haber sido sometida a una histerectomía y/u ooforectomía bilateral documentadas;
    ? Padecer de insuficiencia ovárica confirmada médicamente; o
    ? Ser menopáusica, definido por: cese de las menstruaciones regulares durante al menos 12 meses consecutivos sin otra etiología patológica o fisiológica; tener un nivel de la hormona foliculoestimulante (FSH) en suero dentro del intervalo de referencia del laboratorio para mujeres posmenopáusicas.
    E.4Principal exclusion criteria
    1. Small cell lung cancer (SCLC) or combination SCLC and NSCLC. Squamous-cell tumors and mixed adenosquamous carcinomas of predominantly squamous nature.
    2. Evidence of a tumor that compresses or invades major blood vessels or tumor cavitation.
    3. Known sensitizing EGFR mutations (for example, deletion 19 or L858R) or EML4-ALK translocation positive mutations.
    4. History of other cancer within 5 years prior to screening for this study, with the exception of adequately treated ductal carcinoma in situ of the breast, cervical carcinoma in situ, or basal or squamous cell skin cancer.
    5. Prior systemic therapy for metastatic disease.
    6. History of hemoptysis (>2.5 mL per event) in the last 3 months or severe bleeding. Evidence of current thrombotic or bleeding disorders. Systemic anticoagulation or chronic therapy with prescription non-steroidal anti-inflammatory drugs (NSAIDs), aspirin >325 mg, or other non-selective NSAIDs above the maximum allowed over
    the counter (OTC) dose, and/or coagulation abnormalities (eg, INR >1.5 and aPTT greater than ULN within 1 week prior to randomization). [Some NSAIDs have effects on platelet function (see Prescribing Information for the specific NSAID). In the event that a patient?s NSAID therapy exceeds the maximum dose of OTC medication, the investigator should contact the Sponsor for approval of patient inclusion. Approval will be based on the type of NSAID therapy, the dose, and the patient?s other known risk factors.]
    7. Medically uncontrolled hypertension or systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg.
    8. Peripheral motor or sensory neuropathy with value of ?2.
    9. Major surgery, radiotherapy, or any investigational agents, within 4 weeks before the administration of the first dose of study treatment. Planned major surgery during the treatment period.
    10. Any unhealed wound or bone fracture.
    11. Infection requiring a course of systemic anti-infective agents within 3 weeks prior to randomization. Patients must be off of antibiotics for 7 days.
    12. Comorbities that would increase the risk of toxicity as per the investigator?s discretion.
    13. Concurrent administration of other anticancer therapies. Bisphosphonate or Rank-Ligand inhibitor therapy for pre-existing bone metastases or osteoporosis is allowed.
    14. Known central nervous system (CNS) metastases, as evidenced by appropriate scans, clinical symptoms, cerebral edema, and/or progressive growth.
    15. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (CHF) New York Heart Association (NYHA) functional classification of ?3, unstable angina, or myocardial infarction within 12 months before first dose of study treatment. Clinically significant cardiovascular disease, peripheral vascular disease, transient ischemic attack, cerebrovascular accident.
    16. History of severe hypersensitivity reaction to any of the products to be administered during the study, including mammalian cell derived drug products, taxanes, bevacizumab, murine proteins, or excipients in their formulations.
    17. Clinical contraindication to treatment with steroids preventing use as part of paclitaxel premedication.
    18. Pregnant female patients; breastfeeding female patients; male patients with partners currently pregnant; male and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in this protocol from at least 19 days prior to the first dose of study medication, for the duration of the study, and for at least 6 months after the last dose of investigational product (bevacizumab-Pfizer or bevacizumab-EU).
    Note: For female patients of childbearing potential, to exclude the possibility of pregnancy, a serum or urine pregnancy test with sensitivity of at least 25 mIU/mL will be performed by the local certified laboratory, and 2 negative tests are required before receiving the first dose of investigational product. The second negative test should be at least 19 days after the first, and should be done during the first 5 days of the menstrual period, immediately preceding the first dose of the investigational product. In the absence of regular menstrual bleeding, the patient should have used 2 different methods of contraception for at least 1 month before the second pregnancy test. A patient is of childbearing potential if, in the opinion of the investigator, she is biologically capable of having children and is sexually active. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives.
    19. Immunocompromised patients, including known seropositivity for human immunodeficiency virus (HIV).

    Please see the protocol for exclusion criterias 20-23.
    1. Cáncer microcítico de pulmón (SCLC) o combinación de SCLC y NSCLC. Tumores escamocelulares y carcinomas adenoescamosos mixtos de naturaleza predominantemente escamosa.
    2. Evidencia de un tumor que comprime o invade vasos sanguíneos importantes o cavitación tumoral.
    3. Mutaciones sensibilizantes del EGFR conocidas o mutaciones de translocación positiva de EML4-ALK.
    4. Antecedentes de otro tipo de cáncer en los 5 años anteriores a la selección para este estudio, a excepción del carcinoma ductal de mama in situ adecuadamente tratado, carcinoma cervical in situ, o cáncer de piel basal o escamocelular.
    5. Tratamiento sistémico previo para una patología metastásica.
    6. Antecedentes de hemoptisis en los últimos 3 meses o hemorragia importante. Evidencia de trastornos trombóticos o hemorrágicos actuales. Tratamiento anticoagulación sistémico o crónico con prescripción de fármacos antiinflamatorios no esteroideos, aspirina >325 mg, u otros AINE no selectivos por encima del máximo permitido sin receta, y/o anomalías de la coagulación. [Algunos AINE tienen efectos sobre la función plaquetaria. En caso de que el tratamiento con AINE del paciente supere la dosis de un medicamento sin receta, el investigador debe ponerse en contacto con el patrocinador para obtener su aprobación. La aprobación se basará en el tipo de tratamiento con AINE, la dosis, y otros factores de riesgo conocidos del paciente.]
    7. Hipertensión no controlada médicamente o presión arterial sistólica de >150 mmHg o diastólica de >100 mmHg.
    8. Neuropatía periférica motora o sensorial con un valor de>2.
    9. Cirugía importante, radioterapia, o cualquier agente en investigación, en las 4 semanas anteriores a la administración de la primera dosis del tratamiento del estudio. Cirugía importante programada durante el período de tratamiento.
    10. Cualquier herida o una fractura ósea sin curar.
    11. Infección que requiera agentes antiinfecciosos sistémicos en las 3 semanas anteriores a la aleatorización. Los pacientes no deben haber tomado antibióticos durante 7 días.
    12. Comorbilidades que incrementarían el riesgo de toxicidad según el criterio del investigador.
    13. Administración concomitante de otras terapias contra el cáncer. Se permite el tratamiento con bisfosfonato o inhibidor de ligando de receptor activador para el factor nuclear K (Rank) para metástasis óseas previas u osteoporosis.
    14. Metástasis conocidas del sistema nervioso central, demostradas mediante las exploraciones adecuadas, los síntomas clínicos, el edema cerebral, y/o el crecimiento progresivo.
    15. Patologías cardíacas activas no controladas, incluyendo cardiomiopatía, insuficiencia cardiaca congestiva, clasificación funcional de ?3 según la Asociación del Corazón de Nueva York, angina de pecho inestable o infarto de miocardio en los 12 meses previos a la primera dosis del tratamiento del estudio. Patologías cardiovasculares de importancia clínica, patología vascular periférica, ataque isquémico transitorio, accidente cerebrovascular.
    16. Antecedentes de reacción de hipersensibilidad importante a cualquiera de los productos que se administran durante el estudio, incluyendo productos farmacológicos obtenidos de células de mamíferos, taxanos, bevacizumab, proteínas murinas, o excipientes en sus formulaciones.
    17. Contraindicación clínica al tratamiento con esteroides que impida su uso como parte de la medicación previa con paclitaxel.
    18. Mujeres embarazadas; mujeres en lactancia; varones con pareja actualmente embarazada; pacientes de ambos sexos en edad fértil que no quieran o no puedan utilizar 2 métodos altamente eficaces de contracepción según se describe en este protocolo de por lo menos 19 días antes de la primera dosis de la medicación del estudio, durante la duración del estudio, y por lo menos 6 meses después de la última dosis del producto en investigación (bevacizumab-Pfizer o bevacizumab-EU).
    Nota: en mujeres fértiles, a fin de excluir la posibilidad de embarazo, el laboratorio local certificado realizará una prueba de embarazo en suero con una sensibilidad de al menos 25 mUI/ml, y se requerirán 2 resultados negativos antes de recibir la primera dosis del producto en investigación. La segunda prueba negativa debe haberse realizado al menos 19 días después de la primera, durante los primeros 5 días del período menstrual, justo antes de la primera dosis del producto en investigación. En ausencia de sangrado menstrual regular, la paciente debe haber usado 2 métodos anticonceptivos diferentes durante al menos 1 mes antes de la segunda prueba de embarazo. Una paciente se considera fértil si, en opinión del investigador, es biológicamente capaz de tener hijos y es sexualmente activa. Esto incluye a mujeres que usan anticonceptivos o cuyas parejas sexuales son estériles o usan anticonceptivos.
    19. Pacientes inmunocomprometidos, incluyendo seropositividad conocida para el virus del VIH.
    Por favor refiérase al Protocolo para los criterios de exclusión 20-23
    E.5 End points
    E.5.1Primary end point(s)
    Objective Response Rate (ORR), evaluating the best response achieved by Week 19 and subsequently confirmed by 6 weeks thereafter, in accordance with Response Evaluations Criteria in Solid Tumors (RECIST) version 1.1.
    Tasa de respuesta objetiva (TRO), evaluando la mejor respuesta obtenida hasta la semana 19 y confirmada 6 semanas después, de acuerdo con los criterios de evaluación de respuesta en tumores sólidos (RECIST) versión 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At Week 19 and subsequently confirmed by 6 weeks thereafter.
    Hasta la semana 19 y confirmada 6 semanas después
    E.5.2Secondary end point(s)
    ? Safety characterized by type, incidence, severity, timing, seriousness, and relationship to study therapy of adverse events, including cardiotoxicity and infusion-related reactions, and laboratory abnormalities;

    ? Duration of response (DOR), 1 year progression-free survival (PFS) rate and 1-year survival rate;

    ? Peak and trough bevacizumab-Pfizer and bevacizumab-EU concentrations at selected cycles;

    ? Incidence of anti-drug (bevacizumab) antibodies (ADA), including neutralizing antibodies (NAb).
    ? Seguridad, caracterizada por tipo, incidencia, importancia, momento, gravedad y relación con los acontecimientos adversos del tratamiento en estudio, incluida la cardiotoxicidad, las reacciones relacionadas con la infusión y las analíticas anómalas del laboratorio;
    ? Duración de la respuesta (DR), tasa de supervivencia sin progresión (SSP) a 1 año y tasa de supervivencia a 1 año;
    ? Concentraciones pico y más bajas de bevacizumab-Pfizer y bevacizumab-EU en ciclos seleccionados;
    ? Incidencia de los anticuerpos antifármaco (ADA) (bevacizumab), incluyendo anticuerpos neutralizantes (NAb).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1 Year
    1 año
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    Inmunogenicidad
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group 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 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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA128
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Belarus
    Belgium
    Brazil
    Bulgaria
    Canada
    Chile
    Croatia
    Czech Republic
    Denmark
    Egypt
    Finland
    France
    Germany
    Greece
    Hong Kong
    Hungary
    India
    Italy
    Japan
    Korea, Republic of
    Latvia
    Lebanon
    Malaysia
    Mexico
    Netherlands
    New Zealand
    Norway
    Peru
    Philippines
    Poland
    Portugal
    Romania
    Russian Federation
    Serbia
    Singapore
    Slovakia
    South Africa
    Spain
    Sweden
    Taiwan
    Thailand
    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 a Member State of the European Union is defined as the time at which it is deemed that a sufficient number of patients have been recruited and completed the study as stated in the regulatory application.

    End of trial in all other participating countries is defined as the time at which the last patient has completed the last study visit (LSLV) and data from those visits have been reviewed by the investigator or designee.
    La finalización del ensayo en un Estado miembro de la Unión Europea se define como el momento en el que se considera que un número suficiente de pacientes se han inscrito y han finalizado el estudio como se indica en la solicitud normativa.

    La finalización del ensayo en el resto de países participantes se define como el momento en el que el último paciente ha finalizado la última visita del estudio (UVUP) y los datos de esas visitas han sido revisados por el investigador o su delegado.
    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 months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    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: 439
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 359
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state29
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 324
    F.4.2.2In the whole clinical trial 798
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients who discontinue all study treatment should be evaluated for safety for at least 28 (+7) days after last dose.
    After discontinuation of treatment, patient survival status will be collected by telephone contact every 2 months ± 14 days until death or 1 year from patient randomization and at least 6 months following receipt of the last dose of study treatment, which ever is longer.
    Information on subsequent anti-cancer treatments received will be collected during long-term follow-up.
    La seguridad de los pacientes que interrumpan su participación debe ser evaluada durante al menos 28(+7)después de la última dosis.Después de la interrupción del tratamiento, se obtendrá el estatus de supervivencia por contacto telefónico cada 2 meses ±14 días, hasta fallecimiento o 1 año después de la asignación al azary 6 meses mínimo después de la última dosis, lo que suceda más tarde.Información de tratamientos contra el cáncer post recibidos se recogerán duranteseguimientolargo plazo
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-06-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-12-12
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