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    Summary
    EudraCT Number:2018-003287-31
    Sponsor's Protocol Code Number:M16-104
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-06-11
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2018-003287-31
    A.3Full title of the trial
    A Phase 2, Multicenter, Single Arm, Open Label Study of Venetoclax Plus Lenalidomide and Dexamethasone for the Treatment of Newly Diagnosed t(11;14)-Positive Multiple Myeloma in Subjects Who Are Ineligible for High-Dose Therapy
    Estudio de fase 2, multicéntrico, abierto y de un solo grupo de venetoclax más lenalidomida y dexametasona para el tratamiento del mieloma múltiple positivo para t(11;14), recién diagnosticado en pacientes no aptos para recibir tratamiento en dosis altas
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Investigate the Efficacy of Venetoclax Plus Lenalidomide and Dexamethasone in Participants with Newly Diagnosed t(11;14)-Positive Multiple Myeloma
    Un estudio para investigar la eficacia de Venetoclax más Lenalidomide y Dexametasona en participantes con diagnóstico reciente de mieloma múltiple positivo para t(11; 14)
    A.4.1Sponsor's protocol code numberM16-104
    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 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/3/16/1767
    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.3.9.1CAS number 1257044-40-8
    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 Revlimid 2.5 mg, hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Ltd
    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 nameLenalidomide
    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 INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Revlimid 5 mg, hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Ltd
    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 nameLenalidomide
    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 INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 Revlimid 10 mg, hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Ltd
    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 nameLenalidomide
    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 INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 5
    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 Revlimid 15 mg, hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Ltd
    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 nameLenalidomide
    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 INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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: 6
    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 Revlimid 25 mg, hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Ltd
    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 nameLenalidomide
    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 INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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: 7
    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 Dexamethasone
    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 nameDexamethasone
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDEXAMETHASONE
    D.3.9.3Other descriptive nameDexamethasone
    D.3.9.4EV Substance CodeSUB07017MIG
    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
    Multiple Myeloma
    Mieloma múltiple
    E.1.1.1Medical condition in easily understood language
    New diagnosed t(11;14)-Positive Multiple Myeloma
    Mieloma múltiple de nuevo diagnóstico positive para t(11;14)
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the safety and preliminary efficacy of venetoclax plus lenalidomide and dexamethasone in subjects with newly diagnosed t(11;14)-positive MM who are ineligible for high-dose therapy.
    Investigar la seguridad y eficacia preliminar de venetoclax más lenalidomida y dexametasona para el tratamiento del mieloma múltiple positivo para t(11;14), recién diagnosticado en pacientes no aptos para recibir tratamiento en dosis altas
    E.2.2Secondary objectives of the trial
    - To characterize the plasma pharmacokinetics (PK) of venetoclax and lenalidomide when co-administered in subjects with newly diagnosed t(11;14)-positive MM who are ineligible for high-dose therapy and who are also receiving dexamethasone as part of the treatment regimen.

    - The exploratory objective of this study is to evaluate correlative biomarkers of venetoclax plus lenalidomide and dexamethasone including, but not limited to, BCL-2 family member expression and chromosomal abnormalities.
    -Caracterizar la farmacocinética (FC) plasmática de venetoclax y lenalidomida cuando se administra de forma conjunta en pacientes con mieloma múltiple positivo para t(11;14) con diagnóstico reciente que no son aptos para recibir el tratamiento en dosis altas y que también están recibiendo dexametasona como parte del régimen de tratamiento.
    -El objetivo exploratorio de este estudio es evaluar los biomarcadores correlativos de venetoclax más lenalidomida y desametasona incluyendo, pero no limitados, a la expresión de miembros de la familia BCL-2 y anomalías cromosómicas.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Subject must have documented, confirmed active MM with ≥ 10% clonal bone marrow plasma cells or biopsy-proven bone or extramedullary plasmacytoma and any one or more of the following myeloma-defining events:
    • Evidence of end organ damage attributed to the underlying plasma cell proliferative disorder and satisfying at least one of the CRAB criteria:
    1. Hypercalcemia (serum calcium > 0.25 mmol/L [> 1 mg/dL] higher than the upper limit of normal (ULN) or > 2.75 mmol/L [> 11 mg/dL]);
    2. Renal insufficiency (creatinine clearance [CrCL] < 40 mL/min or serum creatinine > 177 μmol/L [> 2 mg/dL]);
    3. Anemia (hemoglobin > 20 g/L below the lower limit of normal or hemoglobin < 100 g/L);
    4. Bone lesions (one or more osteolytic lesions on skeletal radiography, computed tomography [CT], or positive emission tomography [PET]-CT).
    • Or Any one or more of the following biomarkers of malignancy:
    1. ≥ 60% clonal bone marrow plasma cells;
    2. Involved:uninvolved serum free light chain ratio ≥ 100;
    3. > 1 focal lesions on magnetic resonance imaging (MRI; each focal lesion must be 5 mm or more in size).
    - Subject must have measurable disease defined by at least one of the following criteria:
    • Serum M-protein ≥ 1.0 g/dL (immunoglobulin [Ig]G myeloma) or ≥ 0.5 g/dL (IgA, IgM, IgD, or IgE myeloma);
    • Urine M-protein ≥ 200 mg/24 hours;
    • Serum free light chain (FLC) ≥ 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal.
    - Subject is newly diagnosed and not considered a candidate for high-dose therapy and hematopoietic stem cell transplantation (HSCT) due to:
    • Age ≥ 65 years;
    • Or age less than (<) 65 years with presence of comorbid condition(s) likely to have a negative impact on tolerability of high dose chemotherapy with hematopoietic stem cell transplantation. Sponsor review and approval of participants below 65 years of age is required.
    - Subject must have MM positive for the t(11;14) translocation, as determined by an analytically validated fluorescence in situ hybridization (FISH) assay per central laboratory testing of a bone marrow aspirate sample (enrollment with local t(11;14)-positive FISH results will be considered at the discretion of the therapeutic area medical director or scientific director).
    - Subject must have Eastern Cooperative Oncology Group performance status ≤ 2.
    - Subject must have laboratory values meeting the following criteria within the screening period before the first dose of study drug:
    • Absolute neutrophil count (ANC) ≥ 1000/μL; subject may use growth factor support to achieve ANC eligibility criteria;
    • Platelets: ≥ 75,000/mm3. For subjects with > 50% myeloma involvement in the marrow, a platelet count of ≥ 50,000 mm3 is allowed. 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 transfusions in accordance with institutional guidelines to meet this criteria;
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN);
    • Total bilirubin ≤ 1.5 × ULN (subjects with documented Gilbert's syndrome may have bilirubin > 1.5 × ULN);
    • Corrected serum calcium < 14 mg/dL (< 3.5 mmol/L) or free ionized calcium < 6.5 mg/dL (< 1.6 mmol/L);
    • Creatinine clearance ≥ 30 mL/minute, measured by 24-hour urine collection or calculated using the Cockcroft-Gault
    formula.
    • Subjects or their legally authorized representative 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.
    • Subjects agree to abide by protocol-mandated pregnancy avoidance measures.
    • All subjects enrolled in this trial must be registered and must comply with all requirements of the lenalidomide risk evaluation and mitigation strategies (REMS) program or local equivalent.
    -Pacientes con un MM activo, confirmado y documentado con ≥ 10 % de células plasmáticas clonales en médula ósea o plasmocitoma óseo o extramedular confirmado mediante biopsia y uno o más de los siguientes acontecimientos definitorios de mieloma:
    •Signos de daño orgánico final atribuido al trastorno proliferativo subyacente de las células plasmáticas y cumplimiento de al menos uno de los criterios CRAB:
    1.Hipercalcemia (calcio sérico > 0,25 mmol/l [> 1 mg/dl] superior al límite superior de la normalidad (LSN) o > 2,75 mmol/l [> 11 mg/dl]).
    2.Insuficiencia renal (aclaramiento de creatinina [CrCL] < 40 ml/min o creatinina sérica > 177 µmol/l [> 2 mg/dl]).
    3.Anemia (hemoglobina > 20 g/l por debajo del límite inferior de la normalidad o hemoglobina < 100 g/l).
    4.Lesiones óseas (una o más lesiones osteolíticas en la radiografía ósea, la tomografía computarizada [TC] o la tomografía de emisión positiva [PET]-TC).

    •Uno o más de los siguientes biomarcadores de malignidad:
    1.≥ 60 % de células plasmáticas clonales en médula ósea.
    2.Relación de cadenas ligeras libres en suero afectadas: no afectadas (CLL) ≥ 100.
    3.1 lesión focal en la resonancia magnética (RM; cada lesión focal debe tener un tamaño igual o superior a 5 mm).
    -El paciente debe tener enfermedad medible, definida por al menos uno de los criterios siguientes:
    •Proteína M en suero ≥ 1,0 g/dl (mieloma de inmunoglobulina [Ig]G) o ≥ 0,5 g/dl (mieloma IgA, IgM, IgD o IgE);
    •Proteína M en orina ≥ 200 mg/24 horas
    •Suero ≥10 mg/dl (100 mg/l) siempre que el cociente de CLL en suero sea anómalo
    -El paciente está recién diagnosticado y no se considera candidato a recibir tratamiento en dosis altas y trasplante de células madre hematopoyéticas (TCMH) debido a:
    •Edad ≥ 70 años.
    •O edad inferior (<) a 70 años con presencia de comorbilidades con probable impacto negativo en la tolerabilidad de altas dosis de quimioterapia con trasplante de células madre hematopoyéticas. El promotor debe revisar y autorizar la inclusión de participantes menores de 70 años.
    -El paciente debe tener un MM positivo para la translocación t(11;14), determinado mediante un análisis de hibridación in situ con fluorescencia (FISH) validado analíticamente según el laboratorio central en una muestra de aspirado de médula ósea; O resultados locales de FISH positivos para t(11;14), siempre que se haya enviado una muestra de médula ósea al laboratorio central.El paciente debe tener un estado funcional del Eastern Cooperative Oncology Group ≤ 2.
    -El paciente deberá presentar valores analíticos que cumplan los criterios siguientes en el período de selección antes de la primera dosis del fármaco del estudio:
    •Recuento absoluto de neutrófilos (RAN) ≥ 1000/µl; el paciente podrá utilizar soporte con factores de crecimiento para cumplir los criterios de elegibilidad relativos al RAN.
    •Trombocitos: ≥ 75.000/mm3. Para pacientes con afectación del mieloma > 50 % en la médula, se permite una cifra de trombocitos ≥ 50.000 mm3. Los pacientes no podrán haber recibido una transfusión de trombocitos en las 72 horas previas al recuento de plaquetas utilizado para determinar la idoneidad.
    •Hemoglobina ≥8,0 g/dl; el paciente podrá recibir transfusiones de eritrocitos conforme a las normas del centro para cumplir este criterio.
    •Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) ≤ 3 veces el límite superior de la normalidad (LSN).
    •Bilirrubina total ≤ 1,5 x LSN (los pacientes con síndrome de Gilbert documentado pueden tener bilirrubina > 1,5 x LSN).
    •Calcio sérico corregido < 14 mg/dl (< 3,5 mmol/l) o calcio ionizado libre < 6,5 mg/dl (< 1,6 mmol/l);
    •Aclaramiento de creatinina ≥ 30 ml/min, medida mediante recogida de la orina de 24 horas o calculado con la fórmula de Cockcroft-Gault
    •Los pacientes o su representante legalmente autorizado deben voluntariamente firmar y fechar un consentimiento nformado aprobado por un comité de ética independiente (CEI/IRB), antes del inicio de cualquier screening o cualquier procedimiento específico del estudio.
    •los pacientes acuerdan cumplir con las medidas para evitar el embarazo descritas en el protocolo.
    •Todos los pacientes inscritos en este ensayo deben estar registrados y deben cumplir con todos los requisitos de la evaluación y el programa de mitigación del riesgo de lenalidomida (REMS) o equivalente local.
    E.4Principal exclusion criteria
    • The subject is not naïve to treatment with venetoclax or another BCL-2 inhibitor
    • The subject has been treated or received any of the following:
    o Prior or current systemic therapy or HSCT for MM
    o Radiation therapy within 2 weeks of dosing
    o Plasmapheresis within 4 weeks of dosing
    o Immunization with live vaccine within 8 weeks of dosing
    • The subject has a history of other active malignancies, including myelodysplastic syndromes (MDS) within the past three years except 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 levels off treatment; previous malignancy with no evidence of disease confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study.
    • The subject has known allergies, hypersensitivities, or intolerance to any of the study drug or excipients.
    • El sujeto no es naïve para el tratamiento con venetoclax u otro inhibidor de BCL-2

    • El sujeto ha sido tratado o recibido alguno de los siguientes:
    o Terapia sistémica previa o actual o HSCT para MM
    o Radioterapia dentro de las 2 semanas posteriores a la administración.
    o Plasmaféresis dentro de las 4 semanas de la dosificación.
    o Inmunización con vacuna viva dentro de las 8 semanas de la administración.
    • El sujeto tiene un historial de otros tumores malignos activos, incluyendo síndromes mielodisplásicos (MDS) en los últimos tres años, excepto del carcinoma in situ del cuello uterino, el útero o la mama adecuadamente tratado; carcinoma de células basales de la piel o carcinoma de células escamosas localizado de la piel; Cáncer de próstata Gleason grado 6 o inferior Y con niveles estables de antígeno específico de la próstata fuera del tratamiento; malignidad previa sin evidencia de enfermedad confinada y resecada quirúrgicamente (o tratada con otras modalidades) con intención curativa y con poca probabilidad de afectar la supervivencia durante la duración del estudio.
    • El sujeto tiene alergias, hipersensibilidades o intolerancia conocidas a
    cualquiera de los medicamentos del estudio o excipientes.
    E.5 End points
    E.5.1Primary end point(s)
    - Percent of subjects who achieve a complete response (CR) or better by International Myeloma Working Group (IMWG) criteria.
    - Porcentaje de sujetos que logran una respuesta completa (CR) o mejor por Criterios del Grupo Internacional de Trabajo sobre el Mieloma (IMWG)
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months
    12 meses
    E.5.2Secondary end point(s)
    • Very good partial response (VGPR) or better
    • Overall response rate (ORR) – includes partial response (PR) or better
    • Time to response (TTR)
    • Duration of response (DOR)
    • Progression-free survival (PFS)
    • MRD negativity rate at 12 months
    • Time to disease progression (TTP)
    • Time to next treatment (TTNT)
    • Overall survival (OS)
    • Percent of subjects who achieve minimal residual disease negativity.
    • Muy buena respuesta parcial (VGPR) o mejor
    • Tasa de respuesta general (RG): incluye respuesta parcial (RP) o mejor
    • Tiempo de respuesta (TR)
    • Duración de la respuesta (DOR)
    • Supervivencia libre de progresión (SLP)
    • Tasa de negatividad de MRD a los 12 meses
    • Tiempo hasta la progresión de la enfermedad (TTP)
    • Tiempo para el siguiente tratamiento (TTNT)
    • Supervivencia global (SG)
    • Porcentaje de sujetos que logran mínima enfermedad residual negativa
    E.5.2.1Timepoint(s) of evaluation of this end point
    7 years
    7 años
    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 Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open 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.8.2.4Number of treatment arms in the trial1
    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 EEA5
    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
    Canada
    European Union
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS or the date of last follow-up contact, whichever occurs later.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days28
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days28
    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: 4
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 40
    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)
    Subjects who continue to derive clinical benefit may continue study drug with approval of the Therapeutic Area Medical Director
    Los sujetos que continúan obteniendo beneficios clínicos pueden continuar con el medicamento del estudio con aprobación del Director Médico del Área Terapéutica.
    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 Decision2019-06-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2019-08-21
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