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    Summary
    EudraCT Number:2017-003838-88
    Sponsor's Protocol Code Number:M13-494
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2018-10-09
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-003838-88
    A.3Full title of the trial
    A Phase 3, Multicenter, Randomized, Open Label Study of Venetoclax and Dexamethasone Compared with Pomalidomide and Dexamethasone in Subjects with t(11;14)-Positive Relapsed or Refractory Multiple Myeloma
    Estudio fase 3, multicéntrico, aleatorizado y abierto de venetoclax y dexametasona en comparación con pomalidomida y dexametasona en sujetos con mieloma múltiple en recidiva o refractario con t(11;14)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 3 Study of Venetoclax and Dexamethasone Compared with Pomalidomide and Dexamethasone in Subjects with t(11;14)-Positive Relapsed or Refractory Multiple Myeloma
    Estudio fase 3 de Venetoclax y Dexametasona en comparacion con Pomalidomida y Dexametasona en sujetos con Mieloma Múltiple con t(11;14) positiva en recidiva o refractarios.
    A.4.1Sponsor's protocol code numberM13-494
    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 SponsorAbbVie Deutschland GmbH & Co. KG
    B.1.3.4CountryGermany
    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 supportAbbVie Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAbbVie Ltd.
    B.5.2Functional name of contact pointEU Clinical Trials Helpdesk
    B.5.3 Address:
    B.5.3.1Street AddressAbbVie House, Vanwall Business Park, Vanwall Road
    B.5.3.2Town/ cityMaidenhead, Berkshire
    B.5.3.3Post codeSL6 4UB
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+34901200103
    B.5.6E-mailabbvie_reec@abbvie.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 Yes
    D.2.1.1.1Trade name Venclyxto
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1767
    D.3 Description of the IMP
    D.3.1Product nameVenetoclax
    D.3.2Product code ABT-199 (GDC-0199)
    D.3.4Pharmaceutical form Film-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 INNVenetoclax
    D.3.9.2Current sponsor codeABT-199 (GDC-0199)
    D.3.9.4EV Substance CodeSUB176260
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Imnovid
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/09/672
    D.3 Description of the IMP
    D.3.1Product nameImnovid
    D.3.2Product code pomalidomide
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpomalidomide
    D.3.9.1CAS number 19171-19-8
    D.3.9.3Other descriptive namePOMALIDOMIDE
    D.3.9.4EV Substance CodeSUB33379
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Imnovid
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/09/672
    D.3 Description of the IMP
    D.3.1Product nameImnovid
    D.3.2Product code pomalidomide
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpomalidomide
    D.3.9.1CAS number 19171-19-8
    D.3.9.3Other descriptive namePOMALIDOMIDE
    D.3.9.4EV Substance CodeSUB33379
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Imnovid
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/09/672
    D.3 Description of the IMP
    D.3.1Product nameImnovid
    D.3.2Product code pomalidomide
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpomalidomide
    D.3.9.1CAS number 19171-19-8
    D.3.9.3Other descriptive namePOMALIDOMIDE
    D.3.9.4EV Substance CodeSUB33379
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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
    R/R Multiple Myeloma
    Mieloma Múltiple en recidiva o refractario (R/R)
    E.1.1.1Medical condition in easily understood language
    Subjects with a type of blood cancer (multiple myeloma) that is either relapsed (comes back) or refractory (did not get better) after prior treatment.
    Sujetos con una tipo de cáncer de la sangre (mieloma múltiple) que sea recidivante (que recaen) o refractario (que no mejoran) después del tratamiento previo.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.2System Organ Class 100000004864
    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 subjects with t(11;14)-positive MM treated with venetoclax in combination with dexamethasone versus pomalidomide in combination with dexamethasone.
    - Comparar la supervivencia sin progression (SSP) en sujetos con MM con t(11;14) tratados con venetoclax en combinación con dexametasona frente a pomalidomida en combinación con dexametasona.
    E.2.2Secondary objectives of the trial
    - To compare, between treatment arms (where applicable), the following:
    ● rate of very good partial response (VGPR) or better;
    ● overall response rate (ORR);
    ● patient reported outcomes (PRO) including Fatigue (Patient Reported Outcomes Measurement Information System
    [PROMIS] Fatigue Short Form 7a), Worst Pain (Brief Pain Inventory – Short Form [BPI-SF]), Physical
    Functioning (EORTC QLQ-C30), and Global Health Status/Quality of Life (EORTC QLQ-C30);
    ● overall survival (OS);
    ● duration of response (DOR);
    ● time to disease progression (TTP);
    ● time to response (TTR);
    ● minimal residual disease (MRD) negativity rate;
    ● pharmacokinetics of venetoclax,
    ● safety
    - Comparar entre los grupos de tratamiento (si procede) lo siguiente:
    • Tasa de respuesta parcial muy buena (RPMB) o mejor
    • Tasa de respuesta global (TRG)
    • Resultados comunicados por los pacientes: cansancio (cuestionario abreviado SF 7a sobre el cansancio del Patient Reported Outcomes Measurement Information System [PROMIS]), peor dolor (Inventario Abreviado del Dolor versión corta [BPI SF]), función física (QLQ C30 de la EORTC) y estado de salud general/calidad de vida (QLQ C30 de la EORTC).
    • Supervivencia global (SG);
    • Duración de la respuesta (DR);
    • Tiempo hasta la progresión de la enfermedad (THP);
    • Tiempo hasta la respuesta (THR);
    • Tasa de negatividad de la enfermedad residual mínima (ERM);
    • Farmacocinética de venetoclax;
    • Seguridad
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Subjects must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
    - Adult male or female subjects ≥ 18 years old.
    - Subjects should have laboratory values meeting the following criteria within the screening period prior to the first dose of study drug:
    • Absolute neutrophil count (ANC) ≥ 1000/μL; subject may use growth factor support to achieve ANC eligibility criteria;
    • Platelets: ≥ 50,000/mm3. For subjects with > 50% myeloma involvement in the marrow, a platelet count of ≥ 30,000 mm3. Subjects may not have received a platelet transfusion within 72 hours prior to the platelet count used for eligibility;
    • Hemoglobin ≥ 8.0 g/dL; subject may receive red blood cell (RBC) transfusions in accordance with institutional guidelines to meet this criteria;
    • AST and ALT ≤ 3 × upper limit of normal (ULN);
    • Total bilirubin ≤ 1.5 x ULN (subjects with documented Gilbert's syndrome, may have bilirubin > 1.5 × ULN);
    • Creatinine clearance ≥ 30 mL/min, measured by 24-hour urine collection or calculated using the Cockcroft-Gault formula);
    • Serum calcium corrected for albumin ≤ 14.0 mg/dL (≤ 3.5 mmol/L).
    - Subjects should be willing or able to comply with procedures required in this protocol.
    - Subjects should be willing and able to receive antithrombotic prophylactic treatment.
    - Documented diagnosis of multiple myeloma based on standard IMWG criteria.
    - Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
    - Subject has documented disease progression on or within 60 days of completion of their last therapy.
    - Subject has received at least 2 prior lines of therapy.
    • A line of therapy consists of at least 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens.
    - Subject must have received at least 2 consecutive cycles of lenalidomide and be refractory to lenalidomide as defined by one of the following:
    • Subject experienced PD on or within 60 days of completing treatment.
    • Subject exhibited PR or better but relapsed within 6 months after stopping treatment.
    - Subject must have received at least 2 consecutive cycles of a proteasome inhibitor (bortezomib, carfilzomib or ixazomib).
    - Subject has measurable disease at Screening, defined by at least 1 of the following:
    • Serum M-protein ≥ 1.0 g/dL (≥ 10 g/L); OR
    • Urine M-protein ≥ 200 mg/24 hours; OR
    • Serum immunoglobulin free light chain (FLC) ≥ 10 mg/dL (100 mg/L), provided serum FLC ratio is abnormal
    - Subject has MM positive for t(11;14) as determined by an analytically validated FISH assay per centralized laboratory testing.
    - A negative serum pregnancy test for all female subjects (except those of non-childbearing potential) within 10 to 14 days prior to initiating therapy and a negative urine pregnancy test within 24 hours for all female subjects (except those of non-childbearing potential) at baseline prior to the first dose of study drug.
    - If female, subject must be either postmenopausal, OR permanently surgically sterile OR for women of childbearing potential practicing at least 2 protocol-specified methods of birth control that are effective from at least 30 days before starting study drugs through at least 30 days after the last dose of any study drug.
    - If male, and subject is sexually active with female partner(s) of childbearing potential, he must agree, from Study Day 1 through 30 days after the last dose of study drug, to practice the protocol-specified contraception.
    - Los sujetos deben firmar y fechar voluntariamente el consentimiento informado, aprobado por un Comité de Ética Independiente (CEI)/ Junta de Revisión Institucional (JRI), antes de iniciar cualquier procedimiento específico de selección o del estudio.
    - Adultos hombres o mujeres ≥ 18 años.
    - Los sujetos deberán tener unos valores analíticos que cumplan los siguientes criterios:
    • Recuento de Neutrófilos Absolutos (ANC) ≥ 1000/µL; los sujetos pueden usar el apoyo de factores de crecimiento para cumplir el criterio de ANC;
    • Plaquetas: ≥ 50.000/mm3. En Sujetos con >50% de afectación de la médula por el mieloma, recuento plaquetario de ≥ 30.000 mm3. No se permitirán las transfusiones de plaquetas ≤72 horas antes del recuento de plaquetas de la selección
    • Hemoglobina ≥ 8.0 g/dL; los sujetos podrán recibir transfusiones de glóbulos rojos de acuerdo con las normas del centro para cumplir este criterio;
    • AST y ALT ≤ 3 veces el límite superior de la normalidad (LSN);
    • Bilirrubina total ≤1,5 x LSN (podrán participar sujetos con síndrome de Gilbert documentado si la bilirrubina total es >1,5 x LSN);
    • Aclaramiento de creatinina ≥30 ml/min, medido mediante la recogida de la orina hace 24 horas o calculado con la fórmula de Cockcroft Gault;
    • Calcio sérico corregido para la albúmina ≤14,0 mg/dl (≤3,5 mmol/l)
    - Los sujetos deben estar dispuestos o ser capaces de cumplir con los procedimientos requeridos en el protocolo.
    - Los sujetos deben estar dispuestos y ser capaces para recibir tratamiento profiláctico antitrombótico.
    - Diagnóstico documentado de MM según los criterios normalizados del IMWG.
    - El sujeto debe tener un ECOG ≤ 2.
    - El sujeto debe presentar progresión de la enfermedad documentada durante o en los 60 días después de haber completado el último tratamiento.
    - Sujetos que hayan recibido al menos 2 líneas de tratamiento previas
    • Una línea de tratamiento consiste en al menos un ciclo completo de un único agente, un régimen que consiste en una combinación de varios medicamentos, o una terapia secuencial planificada de varios regímenes.
    - Los sujetos deben haber recibido al menos 2 ciclos consecutivos con Lenalidomida y ser refractarios a la lenalidomida, lo que se define por uno de los siguientes:
    • El sujeto presenta PE durante o en los 60 días después de haber completado el tratamiento.
    • El sujeto presenta RP o mejor pero recae dentro de los 6 meses después de haber parado el tratamiento.
    - El sujeto debe haber recibido al menos dos ciclos consecutivos con un inhibidor del proteasoma (bortezomib, carfilzomib or ixazomib).
    - El sujeto tiene enfermedad medible durante la selección, definida por al menos 1 de los siguientes puntos:
    • Proteína M en suero ≥1,0 g/dl (≥10 g/l); O
    • Proteína M en orina ≥200 mg/24 horas; O
    • Cadenas ligeras libres (CLL) en suero ≥10 mg/dl (100 mg/l), siempre que el cociente de FLC en suero sea anómalo
    - Sujetos que presenten la t (11;14), identificada mediante un análisis por FISH validado analíticamente conforme a los análisis de laboratorio central.
    - Una prueba de embarazo en suero negativa para todas las mujeres (excepto las que no tienen posibilidad de tener hijos) entre 10 y 14 días antes de iniciar el tratamiento y una prueba de embarazo en orina negativa 24 horas antes de la primera dosis del tratamiento para todas las mujeres (excepto las que no tienen posibilidad de tener hijos)
    -Si es mujer , debe ser postmenopáusica o quirúrgicamente estéril o bien mujeres estériles que utilicen dos métodos anticonceptivos especificados en el protocolo que sean efectivos al menos 30 días antes de empezar con el medicamento de estudio y hasta al menos 30 días después de la última dosis de estudio.
    - Si es hombre, y es sexualmente activo con pareja(s) de sexo femenino que pueda quedarse embarazada, debe acordar, desde el día uno de estudio hasta 30 días después de la última dosis del medicamento de estudio, utilizar el método anticonceptivo especificado en protocolo.
    E.4Principal exclusion criteria
    - Subject has history of treatment with venetoclax or another BCL-2 inhibitor or pomalidomide.
    - Subject has a history of other active malignancies, including myelodysplastic syndromes (MDS), within
    the past 3 years with the following exceptions:
    • Adequately treated in situ carcinoma of the cervix uteri or the breast;
    • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
    • Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment; or
    • Previous malignancy with no current evidence of disease, and which was confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study.
    - Subject has evidence of ongoing graft-versus-host disease (GvHD) if prior stem cell transplant (SCT).
    - Subject must not have received any live vaccines within 8 weeks prior to randomization
    - Subject has had prior treatment with the following:
    • Allogeneic or syngeneic SCT within 16 weeks prior to randomization; or
    • Autologous SCT within 12 weeks prior to randomization
    - Subject has known meningeal involvement of multiple myeloma.
    - Subject has a history of clinically significant renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, pulmonary or hepatic disease within the last 6 months that, in the opinion of the investigator, would adversely affect participation in this study.
    - Subject has a history of known allergies, hypersensitivities, or intolerance to any of the study drug or
    excipients, or thalidomide derivatives.
    - Subject has the following conditions:
    • Nonsecretory multiple myeloma;
    • Active plasma cell leukemia i.e., either 20% of peripheral white blood cells or > 2.0 × 109/L circulating plasma cells by standard differential;
    • Waldenström's macroglobulinemia;
    • Primary amyloidosis;
    • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes);
    • Known human immunodeficiency virus (HIV) infection;
    • Active hepatitis B or C infection based on screening blood testing;
    • Significant cardiovascular disease, including uncontrolled angina, arrhythmia, recent myocardial infarction within 6 months of first dose, congestive heart failure NYHA Class ≥ 3;
    • Major surgery within 4 weeks prior to first dose or planned during study participation;
    • Acute infections within 14 days prior to first dose requiring parenteral therapy (antibiotic, antifungal, or antiviral);
    • Uncontrolled diabetes or hypertension within 14 days prior to first dose; or
    • Peripheral neuropathy ≥ Grade 3 or ≥ Grade 2 with pain within 2 weeks prior to first dose.
    - Female who is pregnant, breastfeeding, or considering becoming pregnant during the study and for at least 30 days after the last dose of study drug.
    - Male who is considering fathering a child or donating sperm during the study and for at least 30 days after the last dose of study drug.
    - Subject who have been treated with any systemic anti-myeloma therapies within 5 half-lives or 2 weeks prior to randomization, whichever is longer (or 2 weeks if half-life unknown), and through the last dose of any study drug.
    - Subject who have been treated with anti-myeloma radiotherapy within 2 weeks prior to randomization.
    - Subject who have received corticosteroid therapy at a dose equivalent to > 4 mg daily of dexamethasone or a single dose of corticosteroid equivalent dose > 40 mg of dexamethasone within 2 weeks prior to randomization.
    - Subject who have used systemic strong or moderate inhibitor or inducer of cytochromeP450 (CYP)3A within 1 week prior to the first dose of study drugs.
    - Subject who have used systemic strong inhibitor of CYP1A2 within 1 week before the first dose of study drugs.
    - Subject who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or starfruit within 3 days prior to the first dose of study drugs.
    - Subject who anticipate the use of prohibited medications or foods during study participation.
    -Sujetos que presenten historial de tratamiento con venetoclax u otro inhibidor de BCL-2 o pomalidomida.
    -Sujetos que presentan historia de otras malignidades activas, incluyendo síndromes mielodisplásicos (MDS) en los últimos 3 años con las siguientes excepciones:
    • Carcinoma de cuello uterino o mama tratado in situ adecuadamente;

    • Carcinoma de células basales de la piel o células escamosas localizadas de la piel;


    • Cáncer de próstata grado 6 o menor en la escala de Gleason y con antígeno prostático específico (PSA) con niveles estables de tratamiento; o

    • Previas malignidades sin evidencia actual de enfermedad, la cual fue confinada y quirúrgicamente extirpada (o tratada con otras modalidades) con intento curativo pero con pocas probabilidades de supervivencia durante la duración del estudio.
    - Sujetos con evidencia de Enfermedad de injerto contra huésped en curso, con previo trasplante de células madre.
    -El sujeto no debe haber recibido ningún tipo de vacuna de virus vivo en las últimas 8 semanas previas a la aleatorización.
    - El sujeto ha tenido previo tratamiento con:
    • Trasplante de células madre alogénico o singénico en las últimas 16 semanas previas a la aleatorización; o

    • Trasplante de células madre autólogo en las últimas 12 semanas previas a la aleatorización.
    -Sujetos con conocida afectación meníngea con mieloma múltiple.
    - Sujetos con historia clínica de enfermedad clínica renal, neurológica, psiquiátrica, endocrinológica, metabólica, inmunológica, cardiovascular, pulmonar, o hepática relevante en los últimos 6 meses que, en opinión del investigador, podrían afectar a la participación del sujeto en el estudio.
    -Sujetos con historia clínica de alergias, hipersensibilidad o intolerancia a alguna de las medicaciones de estudio o sus excipientes, o derivados de la talidomida.
    -Los sujetos cumplen las siguientes condiciones:
    • Mieloma múltiple no secretor

    • Leucemia activa de células plasmáticas, es decir, bien 20% de glóbulos blancos periféricos o > 2,0 × 109/ l de células plasmáticas circulantes por diferencial estándar.

    • Macroglobulinemia de Waldenstöm.

    • Amiloidosis primaria.

    • Síndrome POEMS (polineuropatía, organomegalia, endocrinopatía, proteína monoclonal y cambios en la piel);

    • Infección por virus de inmunodeficiencia humana(VIH);

    • Hepatitis B o C activa basado en un análisis de sangre en la selección.

    • Enfermedad cardiovascular significante, incluyendo angina incontrolada, arritmia, infarto de miocardio reciente en los últimos 6 meses previos a la primera dosis de tratamiento, insuficiencia cardiaca congestivo NYHA de clase ≥ 3;
    • Cirugía importante en los últimos 4 semanas previas a la primera dosis o planeada durante el estudio;

    • Infección aguda durante los últimos 14 días previos a la primera dosis de tratamiento del estudio que requiera tratamiento parenteral ( antibiótico, antifúngico o antivírico)

    • Diabetes incontrolada o hipertensión en los últimos 14 días previos a la primera dosis; o

    • Neuropatía periférica ≥ Grado 3 o ≥ Grado 2 con dolor en la últimas dos semanas a la primera dosis de tratamiento.
    - Mujeres embarazadas, en periodo de lactancia o que se considera que pueda quedarse embarazada durante el estudio y durante al menos los 30 días posteriores a la última dosis del tratamiento con la medicación de estudio.
    - Hombres que consideran ser padres o donar esperma durante el estudio y durante al menos 30 días después de la última dosis de tratamiento con la medicación de estudio.
    -Sujetos que han sido tratados con cualquier tratamiento sistémica anti –mieloma en las últimas 5 semividas o 2 semanas previas a la aleatorización, lo que sea más largo ( o dos semanas si la semivida es desconocida), y hasta la última dosis de cualquiera de las medicaciones del estudio.
    -Sujetos que hayan sido tratados con radioterapia anti-mieloma en las últimas dos semanas previas a la aleatorización.
    -Sujetos que hayan recibido corticosteroides en una dosis equivalente a > 4 mg diarios de dexametasona o una sola dosis de corticosteroide equivalente a > 40 mg de dexametasona en las últimas dos semanas previas a la aleatorización.
    - Sujetos que hayan utilizado algún inhibidor o inductor fuerte del citocromoP450 (CYP3A) durante una semana previa a la primera dosis de tratamiento con medicación del estudio.
    - Sujetos que hayan utilizado un inhibidor fuerte del CYP1A2 una semana previa a la primera dosis de tratamiento con la medicación de estudio.
    -Sujetos que hayan consumido zumo de pomelo, productos con zumo de pomelo, naranjas de Sevilla (incluyendo mermelada que contenga naranjas de Sevilla), o fruta de estrella en los últimos 3 días previos a la primera dosis de tratamiento con la medicación de estudio.
    - Sujetos que anticipan el uso de comida y medicación prohibida en el estudio, durante la participación en el estudio.
    E.5 End points
    E.5.1Primary end point(s)
    - The primary efficacy endpoint is progression-free survival (PFS) per Independent Review Committee (IRC) which is defined as the time in days from subject randomization to the date of the first documented progressive disease (PD) or death due to any cause, whichever occurs first.
    - El objetivo primario de eficacia es la supervivencia libre de progresión (SLP) según el comité de revisión independiente, que está definido como el tiempo en días desde la aleatorización hasta la fecha documentada en la que haya progresión de la enfermedad (PE) o muerte por alguna causa, la que primero ocurra.
    E.5.1.1Timepoint(s) of evaluation of this end point
    - PFS will be monitored throughout the study for PD or death whichever occurs first.
    - SLP será monitorizada durante el estudio por PE o por muerte, lo que antes suceda.
    E.5.2Secondary end point(s)
    - Secondary Endpoints are:
    • Rate of very good partial response (VGPR) or better
    • Overall response rate (ORR)
    • Patient reported outcomes: Fatigue (PROMIS Fatigue Short Form 7a), Worst Pain (BPI-SF), Physical Functioning (EORTC QLQ-C30), and Global Heath Status/Quality of Life (EORTC QLQ-C30)
    • Overall survival (OS)
    • Duration of response (DOR)
    • Time to disease progression (TTP)
    • Time to response (TTR)
    • Minimal residual disease (MRD) negativity rate
    • Pharmacokinetics of venetoclax
    • Safety
    - Biomarker Samples will be collected to conduct exploratory investigations into known and/or novel biomarkers, including tumor BCL-2 family member expression, chromosomal abnormalities (gains, deletions, and/or mutations) and circulating markers of disease.
    -Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiogram (ECG) variables, and clinical laboratory testing (hematology and chemistry)
    -Los objetivos secundarios son:
    • Tasa de respuesta parcial muy buena (VGPR) o mejor

    • Tasa de respuesta global (ORR)
    • Resultados comunicados por los pacientes: cansancio (cuestionario abreviado SF 7a sobre el cansancio del Patient Reported Outcomes Measurement Information System [PROMIS]), peor dolor (Inventario Abreviado del Dolor versión corta [BPI SF]), función física (QLQ C30 de la EORTC) y estado de salud general/calidad de vida (QLQ C30 de la EORTC).

    • Supervivencia global (OS)

    • Duración de la respuesta (DOR)


    • Tiempo para la progresión de la enfermedad (TTP)

    • Tiempo de respuesta (TTR)


    • Tasa de negatividad de enfermedad residual mínima (MRD)

    • Farmacocinética de venetoclax

    • La seguridad
    - Las muestras de biomarcadores serán recogidas para realizar investigación exploratoria de conocidos y nuevos biomarcadores, incluyendo la expresión de miembros de la familia BCL-2, anormalidades en cromosomas (aumento, eliminación y /o mutaciones) y marcadores circulantes de la enfermedad.
    - Las evaluaciones de seguridad incluyen la monitorización de eventos adversos, examinaciones físicas, medidas de signos vitales, variables de electrocardiograma (ECG), y análisis de laboratorio (hematología y bioquímica).
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Biomarker Research will be collected at specified timepoints and monitored throughout the study.
    - PRO assessments will be collected at specified timepoints throughout the study.
    - Safety evaluations will be monitored for the entire study duration of the study.
    - PK samples for venetoclax will be evaluated for peak (i.e., 6 hour) and trough concentrations (Ctrough).
    - Efficacy endpoints will be evaluated throughout the study.
    -Las muestras de biomarcadores serán recogidas en momentos específicos y monitorizadas durante todo el estudio.
    -Las evaluaciones de PRO serán recogidas en momentos específicos durante todo el estudio.
    - Las evaluaciones de seguridad serán monitorizadas durante toda la duración del estudio.
    - Las muestras de farmacocinética (PK) para venetoclax serán evaluadas por picos (es decir, cada 6 horas) y concentraciones valle (Ctrough)
    -Los objetivos de eficacia serán evaluados durante todo el estudio.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    European Union
    Israel
    Japan
    Korea, Republic of
    Russian Federation
    Singapore
    Turkey
    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
    The end-of-study is defined as the last subject’s last visit, including survival.
    -El final de estudio está definido como la última visita del último paciente, incluyendo supervivencia.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months5
    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: 134
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 110
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 244
    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)
    The full details of the treatment or care after participation can be found in the “M13-494 Treatment After End of Study” document included in the CTA. In summary, the provision of further treatment or care is at the discretion of the subject’s treating physician.
    - Todos los detalles del tratamiento o cuidados después de la participación pueden encontrarse en el documento incluido en el CTA “M13-494 tratamiento después del final del estudio”. En resumen, la previsión de tratamiento o cuidados más allá del estudio es a criterio del médico encargado del tratamiento del paciente.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-10-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-11
    P. End of Trial
    P.End of Trial StatusRestarted
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