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    Summary
    EudraCT Number:2012-000128-16
    Sponsor's Protocol Code Number:2011-003
    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:2012-05-29
    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 number2012-000128-16
    A.3Full title of the trial
    A Randomized, Open-label, Phase 3 Study of Carfilzomib Plus Dexamethasone vs Bortezomib Plus Dexamethasone in Patients With Relapsed Multiple Myeloma
    Estudio de fase 3 aleatorizado y abierto de carfilzomib y dexametasona en comparación con bortezomib y dexametasona en pacientes con mieloma múltiple en recidiva
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 3 study with carfilzomib and dexamethasone versus velcade and dexamethasone for relapsed multiple myeloma patients
    Estudio de fase 3 con carfilzomib y dexametasona en comparación con velcade y dexametasona en pacientes con mieloma múltiple en recidiva
    A.4.1Sponsor's protocol code number2011-003
    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 SponsorOnyx Therapeutics, Inc.
    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 supportOnyx Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOnyx Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointHeidi Gillenwater, Clinical Science
    B.5.3 Address:
    B.5.3.1Street Address249 East Grand Avenue
    B.5.3.2Town/ citySouth San Francisco
    B.5.3.3Post codeCA 94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number0014349781494
    B.5.6E-mailhgillenwater@onyx.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/08/548
    D.3 Description of the IMP
    D.3.1Product nameCarfilzomib
    D.3.2Product code PR-171
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCarfilzomib
    D.3.9.1CAS number 868540-17-4
    D.3.9.2Current sponsor codePR-171
    D.3.9.3Other descriptive nameFP-101; 506160
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 Velcade
    D.2.1.1.2Name of the Marketing Authorisation holderJANSSEN-CILAG INTERNATIONAL NV
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 nameVelcade
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBORTEZOMIB
    D.3.9.1CAS number 179324-69-7
    D.3.9.4EV Substance CodeSUB20020
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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
    Multiple myeloma
    Mieloma múltiple
    E.1.1.1Medical condition in easily understood language
    Bone marrow cancer
    Cáncer de médula ósea
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare progression-free survival (PFS) in patients with multiple myeloma relapsed after 1 to 3 prior therapies treated with either carfilzomib plus dexamethasone (Cd) or bortezomib (Velcade®) plus dexamethasone (Vd).
    Comparar la supervivencia sin progresión (SSP) en pacientes con mieloma múltiple en recidiva después de entre 1 y 3 tratamientos previos con carfilzomib y dexametasona (Cd) o bortezomib (Velcade®) y dexametasona (Vd).
    E.2.2Secondary objectives of the trial
    To compare the following between the treatment groups:
    - Overall Survival (OS)
    - Overall Response Rate (ORR) [defined as the proportion of best
    overall response of stringent Complete Response (sCR), Complete
    Response (CR), Very Good Partial Response (VGPR), and Partial
    Response (PR)]
    - Duration of Response (DOR)
    - Neuropathy Events (defined from Grade 2 or higher peripheral
    neuropathy incidence, and FACT/GOG-NTx [version 4; "Additional Concerns" questionnaire] score)
    - Health-related quality of life (HR-QOL) (measured by European
    Organization for Research and Treatment of Cancer [EORTC] Core
    Module [QLQ-C30] and Multiple Myeloma Module [QLQ-MY20)]
    questionnaires)
    - Safety and Tolerability
    Comparar lo siguiente entre los grupos de tratamiento: supervivencia general (SG),tasa de resp general (TRG) definida como proporción de mejor respuesta gen de respuesta completa estricta (RCe),respuesta completa (RC),respuesta parcial muy buena (RPMB) y respuesta parcial (RP)]-duración de respuesta (DOR, Duration of Response)acontecimientos de neuropatía(definidos como incidencia de neuropatía periférica de grado2o superior y puntuación de Subescala de neurotoxicidad de evaluación funcional del grupo oncología ginecol del tratamiento contra cáncer (Neurotoxicity Subscale of Gynecol Onc Group?s Functional Assess of Cancer Therapy) FACT/GOG-NTx [ver 4;cuestionario de ?Preocupaciones adicionales?])-la calidad de vida relacionada con salud (CVRS) medida por cuestionarios del Módulo Principal [QLQ-C30] de Organización Europea para Inv y Tratamiento del Cáncer [EORTC, European Org for Research and Treatment of Cancer] y Módulo del Mieloma Múltiple [QLQ-MY20]) seguridad y tolerabilidad
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetic sub-study:
    Blood samples will be collected from approximately 100 patients in the Cd arm for measurement of plasma carfilzomib concentrations and subsequent estimation of a number of pharmacokinetic parameters.

    Pharmacodynamics and Biomarkers sub-study:
    Pharmacodynamics in the form of proteasome inhibition will be measured in whole blood and isolated peripheral blood mononuclear cells collected from at least 15 patients per treatment arm. Analysis of biomarkers predictive of response to proteasome inhibitors will also be performed on these samples, as will genomic and proteomic analyses in an attempt to determine biomarkers that predict for response metrics and safety signals.

    ECHO sub-study:
    A transthoracic ECHO to assess LVEF will be conducted on all patients at screening, within 21 days prior to randomization. A subset of patients from both arms (a minimum of 100 patients and a maximum of 300 patients total; 50 to 150 patients per treatment arm, depending on input from the data monitoring committee [DMC]) will be assessed for LVEF with transthoracic ECHO every 12 weeks and at end of treatment
    Subestudio farmacocinético:Se recogerán muestras de sangre de aproximadamente 100 pacientes en el grupo de tratamiento de Cd para la evaluación de la concentración de carfilzomib en plasma y la posterior estimación de una serie de parámetros farmacocinéticos.
    Subestucio de farmacodinámica y marcadores biológicos:
    Se medirá la farmacodinámica en forma de inhibición del proteosoma en sangre completa y en células mononucleares aisladas de sangre periférica recogidas de al menos 15 pacientes por grupo de tratamiento. El análisis de los biomarcadores que predicen la respuesta tras el tratamiento con inhibidores del proteosoma también se realizará en dichas muestras, así como los análisis genómico y proteómico en un intento de determinar los biomarcadores que predicen la métrica de la respuesta y las señales de seguridad.
    Subestudio ECO:Se realizará una ECO transtorácica para evaluar la FEVI en todos los pacientes en la visita basal, en los 21 días previos a la aleatorización. Se evaluará un subconjunto de pacientes de ambos grupos de tratamiento (un mínimo de 100 pacientes y un máximo de 300 pacientes en total; entre 50 y 150 pacientes por grupo de tratamiento, dependiendo de la entrada del comité de monitorización de datos [CMD]) para obtener información sobre la FEVI mediante ECO transtorácica cada 12 semanas y al final del estudio.
    E.3Principal inclusion criteria
    1.Multiple myeloma with relapsing or progressing disease at study entry.
    2.Patients must have evaluable multiple myeloma with, at least one of the following (assessed within 21 days prior to randomization):
    ?Serum M-protein ? 0.5 g/dL, or
    ?Urine M-protein ? 200 mg/24 hour, or
    ?In patients without detectable serum or urine M-protein, serum free light chain (FLC) > 100 mg/L (involved light chain) and an abnormal ?/? ratio (>4:1 or <2:1), or
    ?For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ? 750 mg/dL (0.75 g/dL).
    3.Patients must have documented at least PR to at least 1 line of prior therapy. PR documentation can be based on Investigator assessment.
    4. Received at least 1, but no more than 3 prior treatment regimens or lines of therapy for
    multiple myeloma. (Induction therapy followed by stem cell transplant and
    consolidation/maintenance therapy will be considered as one line of therapy).
    5. Prior therapy with Velcade is allowed as long as the patient had at least a PR to prior
    Velcade therapy, was not removed from Velcade therapy due to toxicity, and will have at
    least a 6 month Velcade treatment-free interval from last dose received until first study
    treatment. (Patients may receive maintenance therapy with drugs that are not in the
    proteasome inhibitor class during this 6 month Velcade treatment-free interval).
    6. Prior therapy with carfilzomib is allowed as long as the patient had at least a PR to prior carfilzomib therapy, was not removed from carfilzomib therapy due to toxicity, and had at least a 6-month carfilzomib treatment-free interval from last dose received until first study treatment. (Patients may receive maintenance therapy with drugs that are not in the proteasome inhibitor class during this 6 month carfilzomib treatment-free interval). The exception to this are patients randomized or previously randomized in any other Onyx-Sponsored Ph 3 trial
    7.Males and females ? 18 years of age.
    8. ECOG Performance Status of 0 to 2.
    9. Adequate hepatic function within 21 days prior to randomization, with bilirubin
    < 1.5 times the ULN, and AST and ALT < 3 times the ULN.
    10. LVEF ? 40%. 2-D transthoracic ECHO is the preferred method of evaluation. MUGA is acceptable if ECHO is not available.
    11. ANC ? 1000/mm3 within 21 days prior to randomization. Screening ANC should be independent of growth factor support for ? 1 week.
    12. Hemoglobin ? 8.0 g/dL within 21 days prior to randomization. Use of erythropoietic stimulating factors and RBC transfusions per institutional guidelines is allowed, however most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.
    13. Platelet count ? 50,000/mm3 (? 30,000/mm3 if myeloma involvement in the bone marrow is > 50%) within 21 days prior to randomization. Patients should not have received
    platelet transfusions for at least 1 week prior to obtaining the screening platelet count.
    14. Calculated or measured CrCl of ? 15 mL/min within 21 days prior to randomization. Calculation should be based on standard formula such as the Cockcroft and Gault: [(140 ? Age) ? Mass (kg) / (72 ? Creatinine mg/dL)]; multiply result by 0.85 if female.
    15. Written informed consent in accordance with federal, local, and institutional guidelines.
    16. FCBP must have a negative serum pregnancy test within 21 days prior to randomization and agree to use an effective method of contraception during and for 3 months following
    last dose of drug (more frequent pregnancy tests may be conducted if required per local regulations). Postmenopausal females (> 45 years old and without menses for > 1 year)
    and surgically sterilized females are exempt from a pregnancy test.
    17. Male patients must agree to use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a female of child-bearing potential.
    1MIELOMA MÚLTIPLE CON RECIDIVA O ENFERMEDAD EN PROGRESIÓN EN LA VISITA BASAL DEL ESTUDIO. 2LOS PACIENTES DEBEN TENER MIELOMA MÚLTIPLE EVALUABLE CON AL MENOS UNO DE LOS SIGUIENTES (EVALUADO EN EL PLAZO DE LOS 21 DÍAS ANTES DE LA ALEATORIZACIÓN):-PROTEÍNA M EN SUERO ? 0,5 G/DL, O-PROTEÍNA M EN ORINA ? 200 MG/24 HORAS, O-EN PACIENTES SIN PROTEÍNA M DETECTABLE EN SUERO U ORINA, CADENA LIGERA LIBRE EN SUERO (CLLS) > 100 MG/L (CADENA LIGERA INVOLUCRADA) Y UNA RELACIÓN CAPPA/ GAMMAANORMAL (> 4:1 O < 2:1), OPARA LOS PACIENTES CON IGA CUYA ENFERMEDAD ÚNICAMENTE SE PUEDA MEDIR DE FORMA FIABLE MEDIANTE LA INMUNOGLOBULINA CUANTITATIVA EN SUERO (QIGA) ? 750 MG/DL (0,75 G/DL) 3LOS PACIENTES DEBEN TENER DOCUMENTADA UNA RP A AL MENOS 1 LÍNEA DE TRATAMIENTO PREVIO. LA DOCUMENTACIÓN DE LA RP SE PUEDE BASAR EN LA EVALUACIÓN DEL INVESTIGADOR.4HABER RECIBIDO 1, PERO NO MÁS DE 3 REGÍMENES DE TRATAMIENTO PREVIO O LÍNEAS DE TRATAMIENTO PARA EL MIELOMA MÚLTIPLE. (SE CONSIDERARÁ EL TRATAMIENTO DE INDUCCIÓN SEGUIDO POR EL TRASPLANTE DE CÉLULAS MADRE Y EL TRATAMIENTO DE CONSOLIDACIÓN/MANTENIMIENTO COMO UNA LÍNEA DE TRATAMIENTO).5EL TRATAMIENTO PREVIO CON VELCADE ESTÁ PERMITIDO SIEMPRE Y CUANDO EL PACIENTE TUVIESE AL MENOS UNA RP AL TRATAMIENTO PREVIO CON VELCADE, NO SE LE HUBIESE RETIRADO DEL TRATAMIENTO CON VELCADE DEBIDO A TOXICIDAD Y TUVIESE AL MENOS UN INTERVALO SIN TRATAMIENTO CON VELCADE DE 6 MESES DESDE LA ÚLTIMA DOSIS RECIBIDA HASTA EL PRIMER TRATAMIENTO DEL ESTUDIO. (LOS PACIENTES PUEDEN RECIBIR TRATAMIENTO DE MANTENIMIENTO CON FÁRMACOS QUE NO PERTENECEN A LA CLASE DE INHIBIDORES DEL PROTEOSOMA DURANTE ESTE INTERVALO DE 6 MESES SIN TRATAMIENTO CON VELCADE)6EL TRATAMIENTO PREVIO CON CARFILZOMIB ESTÁ PERMITIDO SIEMPRE Y CUANDO EL PACIENTE TUVIESE AL MENOS UNA RP AL TRATAMIENTO PREVIO CON CARFILZOMIB, NO SE LE HUBIESE RETIRADO DEL TRATAMIENTO CON CARFILZOMIB DEBIDO A TOXICIDAD Y TUVIESE AL MENOS UN INTERVALO SIN TRATAMIENTO CON CARFILZOMIB DE 6 MESES DESDE LA ÚLTIMA DOSIS RECIBIDA HASTA EL PRIMER TRATAMIENTO DEL ESTUDIO. (LOS PACIENTES PUEDEN RECIBIR TRATAMIENTO DE MANTENIMIENTO CON FÁRMACOS QUE NO PERTENECEN A LA CLASE DE INHIBIDORES DEL PROTEOSOMA DURANTE ESTE INTERVALO DE 6 MESES SIN TRATAMIENTO CON CARFILZOMIB). SE EXCEPTUARÁ A LOS PACIENTES ALEATORIZADOS O ALEATORIZADOS PREVIAMENTE EN CUALQUIER OTRO ENSAYO DE FASE 3 PROMOVIDO POR ONYX7HOMBRES Y MUJERES ? 18 AÑOS DE EDAD8ESTADO FUNCIONAL DE ENTRE 0 Y 2, SEGÚN EL GRUPO ONCOLÓGICO COOPERATIVO DEL ESTE (ECOG, EASTERN COOPERATIVE ONCOLOGY GROUP)9FUNCIÓN HEPÁTICA CORRECTA EN LOS 21 DÍAS PREVIOS A LA ALEATORIZACIÓN, CON LA BILIRRUBINA < 1,5 VECES EL LÍMITE SUPERIOR DEL INTERVALO NORMAL (LSN), Y LA ASPARTATO AMINOTRANSFERASA (AST) Y LA ALANINA AMINOTRANSFERASA (ALT) < 3 VECES EL LSN10FEVI ? 40 %. LA ECOCARDIOGRAFÍA TRANSTORÁCICA 2D (ECO) ES EL MÉTODO DE EVALUACIÓN PREFERIDO. LA VENTRICULOGRAFÍA NUCLEAR (VRN) ES UNA TÉCNICA ACEPTABLE SI NO SE DISPONE DE ECO11EL RECUENTO ABSOLUTO DE NEUTRÓFILOS (RAN) ? 1.000/MM3 EN LOS 21 DÍAS PREVIOS A LA ALEATORIZACIÓN. EL RAN EN LA SELECCIÓN DEBE SER INDEPENDIENTE DEL APOYO DEL FACTOR DE CRECIMIENTO PARA ? 1 SEMANA12HEMOGLOBINA ? 8,0 G/DL EN LOS 21 DÍAS PREVIOS A LA ALEATORIZACIÓN. SE PERMITE EL USO DE FACTORES ESTIMULADORES DE LA ERITROPOYESIS Y TRANSFUSIONES DE HEMATÍES (HEM) SEGÚN DIRECTRICES INSTITUCIONALES; SIN EMBARGO, LA TRANSFUSIÓN MÁS RECIENTE DE HEM NO DEBE HABERSE REALIZADO EN LOS 7 DÍAS PREVIOS A LA OBTENCIÓN DE LA HEMOGLOBINA EN LA VISITA DE SELECCIÓN13RECUENTO DE PLAQUETAS ? 50.000/MM3 (? 30.000/MM3 SI LA IMPLICACIÓN DEL MIELOMA EN LA MÉDULA ÓSEA ES > 50 %) EN LOS 21 DÍAS PREVIOS A LA ALEATORIZACIÓN. LOS PACIENTES NO DEBEN HABER RECIBIDO TRANSFUSIONES DE PLAQUETAS DURANTE AL MENOS 1 SEMANA ANTES DE LA OBTENCIÓN DEL RECUENTO DE PLAQUETAS EN LA VISITA DE SELECCIÓN14ACLARAMIENTO DE CREATININA (ACR) CALCULADO O MEDIDO DE ? 15 ML/MIN EN LOS 21 DÍAS PREVIOS A LA ALEATORIZACIÓN. EL CÁLCULO SE DEBE BASAR EN UNA FÓRMULA CLÁSICA, COMO POR EJEMPLO, LA DE COCKCROFT Y GAULT:
    [(140 ? EDAD) ? MASA (KG) / (72 ? CREATININA MG/DL)]; MULTIPLICAR EL RESULTADO POR 0,85 EN CASO DE SER MUJER15CONSENTIMIENTO INFORMADO POR ESCRITO DE ACUERDO CON LAS DIRECTRICES ESTATALES, LOCALES E INSTITUCIONALES16LAS MUJERES EN EDAD FÉRTIL (MEF) DEBEN DAR NEGATIVO EN UNA PRUEBA DE EMBARAZO EN SUERO EN LOS 21 DÍAS PREVIOS A LA ALEATORIZACIÓN Y ACEPTAR EL USO DE UN MÉTODO ANTICONCEPTIVO EFICAZ DURANTE Y HASTA 3 MESES DESPUÉS DE LA ÚLTIMA DOSIS DEL FÁRMACO (SE REALIZARÁN PRUEBAS DE EMBARAZO CON MÁS FRECUENCIA SI LO EXIGEN LAS NORMATIVAS LOCALES). LAS MUJERES POSTMENOPÁUSICAS (> 45 AÑOS DE EDAD Y SIN MENSTRUACIÓN DURANTE > 1 AÑO) Y ESTERILIZADAS QUIRÚRGICAMENTE ESTÁN EXENTAS DE LA PRUEBA DE EMBARAZO.17LOS VARONES DEBEN UTILIZAR UN MÉTODO DE BARRERA EFICAZ PARA LA CONTRACEPCIÓN DURANTE EL ESTUDIO Y DURANTE LOS 3 MESES POSTERIORES A LA ÚLTIMA DOSIS SI SON SEXUALMENTE ACTIVOS CON UNA MUJER EN EDAD FÉRTIL.
    E.4Principal exclusion criteria
    1. Multiple myeloma of IgM subtype.
    2. Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 14 days prior to randomization.
    3. POEMS syndrome.
    4. Plasma cell leukemia or circulating plasma cells ? 2 × 109/L.
    5. Waldenstrom?s Macroglobulinemia.
    6. Patients with known amyloidosis.
    7. Chemotherapy with approved or investigational anticancer therapeutics within 21 days prior to randomization.
    8. Patients randomized or previously randomized in any other Onyx-sponsored Phase 3 trial.
    9. Focal radiation therapy within 7 days prior to randomization. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to randomization (i.e., prior radiation must have been to less than 30% of the bone marrow).
    10. Immunotherapy within 21 days prior to randomization.
    11. Major surgery (except kyphoplasty) within 28 days prior to randomization.
    12. Active congestive heart failure (NYHA Class III to IV; refer to Appendix H), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within four months prior to randomization.
    13. Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to randomization.
    14. Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B SAg or core antibody receiving and responding to antiviral therapy directed at hepatitis B: these patients are allowed).
    15. Patients with known cirrhosis.
    16. Second malignancy within the past 3 years except:
    - adequately treated basal cell or squamous cell skin cancer
    - carcinoma in situ of the cervix
    - prostate cancer < Gleason Score 6 with stable PSA over the past 12 months
    - breast carcinoma in situ with full surgical resection
    - treated medullary or papillary thyroid cancer
    17. Patients with myelodysplastic syndrome.
    18. Significant neuropathy (Grades 3 to 4, or Grade 2 with pain) within 14 days prior to randomization.
    19. Female patients who are pregnant or lactating.
    20. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
    21. Patients with hypersensitivity to carfilzomib, Velcade, boron, or mannitol.
    22. Patients with contraindication to dexamethasone.
    23. Contraindication to any of the required concomitant drugs or supportive treatments,including hypersensitivity to antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment.
    24. Ongoing graft-vs-host disease.
    25. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization.
    26. Any other clinically significant medical disease or psychiatric condition that, in the Investigator?s opinion, may interfere with protocol adherence or a patient?s ability to give informed consent.
    1Mieloma múltiple de subtipo IgM.2Tratamiento con glucocorticoides (prednisona > 30 mg/día o equivalente) en los 14 días previos a la aleatorización.3Síndrome de polineuropatía, organomegalia, endocrinopatía, proteína monoclonal y cambios epiteliales (POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).4Leucemia de células plasmáticas o células plasmáticas circulantes ? 2 × 109/l.5Macroglobulinemia de Waldenstrom6Pacientes con amiloidosis conocida7Quimioterapia con tratamientos contra el cáncer, aprobados o en investigación, en los 21 días previos a la aleatorización.8Pacientes aleatorizados o previamente aleatorizados en cualquier otro ensayo de fase 3 promovido por Onyx9Radioterapia focal en los 7 días previos a la aleatorización. Radioterapia en un campo amplio que incluya un volumen significativo de la médula ósea en los 21 días previos a la aleatorización (es decir, la radioterapia previa debe haber afectado a menos del 30 % de la médula ósea)10nmunoterapia en los 21 días previos a la aleatorización.11Cirugía mayor (con exclusión de la cifoplastia) en los 28 días previos a la aleatorización12Insuficiencia cardíaca congestiva activa (de clase III o IV según la New York Heart Association [NYHA]), isquemia sintomática o alteraciones en la conducción que no han podido controlarse mediante intervención convencional. Infarto de miocardio en los cuatro meses previos a la aleatorización13nfección aguda activa que necesite antibióticos sistémicos, fármacos antivirales (excepto tratamiento antiviral contra la hepatitis B) o agentes antifúngicos en los 14 días previos a la aleatorización14Seropositivo conocido frente al VIH, infección conocida por hepatitis C y/o hepatitis B (excepto para pacientes que reciban antígeno de superficie para la hepatitis B [SAg] o anticuerpo del núcleo y respondan al tratamiento antiviral contra la hepatitis B: estos pacientes están permitidos)15Pacientes con cirrosis conocida16Segunda neoplasia maligna en los últimos 3 años, excepto: -carcinoma basocelular o de las células escamosas de la piel tratado adecuadamente-carcinoma in situ del cuello uterino-cáncer de próstata con puntuación Gleason < 6 con antígeno prostático específico (PSA, prostate-specific antigen) estable durante 12 meses-carcinoma mamario in situ con resección quirúrgica completa-cáncer de tiroides medular o papilar tratado17Pacientes con síndrome mielodisplásico.8Neuropatía significativa (de grados 3 a 4, o grado 2 con dolor) en los 14 días previos a la aleatorización19Pacientes embarazadas o en periodo de lactancia.20Antecedentes conocidos de alergia al Captisol® (un derivado de la ciclodextrina utilizado para solubilizar el carfilzomib)21Pacientes con hipersensibilidad al carfilzomib, Velcade, boro o manitol22Pacientes con contraindicación a la dexametasona.23Contraindicación a cualquiera de los fármacos concomitantes o tratamientos de apoyo necesarios, que incluya la hipersensibilidad a fármacos antivirales o intolerancia a la hidratación debido a insuficiencia cardíaca o pulmonar preexistente.24Enfermedad injerto contra huésped en curso25Pacientes con derrames pleurales que necesiten toracocentesis o ascitis que necesite paracentesis en los 14 días previos a la aleatorización26Cualquier otra enfermedad médica clínicamente significativa o trastorno psiquiátrico que, en opinión del investigador, pueda interferir con el cumplimiento del protocolo o con la capacidad del paciente para dar el consentimiento informado.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is PFS by Independent Review Committee (IRC)
    El criterio de valoración principal es la SSP por parte de un comité de revisión independiente (CRI).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Study is expected to have required number of PFS events approximately 8 months after enrollment is complete
    Se espera que el estudio tenga el número requerido de acontecimientos de SSP aproximadamente 8 meses después de finalizar la inclusión
    E.5.2Secondary end point(s)
    The secondary endpoints are:
    ?Overall survival
    ?Overall Response Rate (defined as the proportion of best overall response of sCR, CR, VGPR, and PR); by IRC
    ?Duration of Response; by Independent Review Committee
    ?Neuropathy Events (defined from Grade 2 or higher peripheral neuropathy incidence, and FACT/GOG-NTx [version 4; "Additional Concerns" questionnaire] score)
    ?HR-QOL (assessed by EORTC QLQ-C30 and QLQ-MY20 questionnaires)
    ?Safety and Tolerability
    Los criterios de valoración secundarios son:
    ? SG
    ? TRG (definida como la proporción de la mejor respuesta general de
    la RCe, RC, RPMB y RP), por parte del CRI
    ? DOR, por parte del CRI
    ? acontecimientos de neuropatía (definidos como incidencia de la
    neuropatía periférica de grado 2 o superior y puntuación de la
    Subescala de neurotoxicidad de la evaluación funcional del grupo
    de oncología ginecológica del tratamiento contra el cáncer
    (Neurotoxicity Subscale of the Gynecologic Oncology Group?s
    Functional Assessment of Cancer Therapy) FACT/GOG-NTx
    [versión 4; cuestionario de ?Preocupaciones adicionales?])
    ? CVRS (evaluada por los cuestionarios QLQ-C30 y QLQ-MY20 de
    la EORTC)
    ? seguridad y tolerabilidad
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary end points are to be evaluated at the time of the final OS analysis when the required number of events have been reached, estimated at approximately 78 months after the enrollment start.
    Las variables secundarias se evaluarán en el momento del análisis de la SG final cuando se haya alcanzado el número requerido de acontecimientos, estimado aproximadamente 78 meses después del comienzo del reclutamiento.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA84
    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
    Bulgaria
    Canada
    Czech Republic
    France
    Germany
    Greece
    Hungary
    India
    Israel
    Italy
    Korea, Republic of
    New Zealand
    Poland
    Romania
    Russian Federation
    Slovakia
    Taiwan
    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 the study defined as when the final OS analysis takes place
    Se definirá el final del estudio como el momento en que tenga lugar el análisis final de la SG
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    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: 592
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 296
    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 state45
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 888
    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)
    Not applicable
    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 Decision2012-07-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-07-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-02-05
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