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    Summary
    EudraCT Number:2017-001618-27
    Sponsor's Protocol Code Number:EMN14/54767414MMY3013
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-06-09
    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 number2017-001618-27
    A.3Full title of the trial
    A Phase 3 Study Comparing Pomalidomide and Dexamethasone With or Without Daratumumab in Subjects With Relapsed or Refractory Multiple Myeloma Who Have Received at Least One Prior Line of Therapy With Both Lenalidomide and a Proteasome Inhibitor.
    Estudio en fase III para comparar la administración de pomalidomida y dexametasona con o sin daratumumab en pacientes con mieloma múltiple recurrente o resistente que han recibido al menos una línea de tratamiento previo con lenalidomida y con inhibidor del proteasoma: El estudio APOLLO.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to compare Pomalidomide and Dexamethasone With or Without Daratumumab in Patients With Relapsed or Refractory Multiple Myeloma Who Have Received at Least One Prior Line of Therapy With Both Lenalidomide and a Proteasome Inhibitor.
    Estudio en fase III para comparar la administración de pomalidomida y dexametasona con o sin daratumumab en pacientes con mieloma múltiple recurrente o resistente que han recibido al menos una línea de tratamiento previo con lenalidomida y con inhibidor del proteasoma: El estudio APOLLO
    A.3.2Name or abbreviated title of the trial where available
    The APOLLO Study
    El estudio APOLLO
    A.4.1Sponsor's protocol code numberEMN14/54767414MMY3013
    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 SponsorEuropean Myeloma Network (EMN)
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHealth Data Specialists Ireland LIMITED
    B.5.2Functional name of contact pointHealth Data Specialists Ireland
    B.5.3 Address:
    B.5.3.1Street AddressRBK House, Irishtown
    B.5.3.2Town/ cityAthlone, County Westmeath
    B.5.3.3Post codeN37
    B.5.3.4CountryIreland
    B.5.6E-mailinfo@heads.ie
    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 DARZALEX
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International NV
    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/3/13/1153
    D.3 Description of the IMP
    D.3.1Product namedaratumumab
    D.3.2Product code daratumumab
    D.3.4Pharmaceutical form Concentrate 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 INNDARATUMUMAB
    D.3.9.1CAS number 945721-28-8
    D.3.9.4EV Substance CodeSUB175772
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typehuman monoclonal antibody
    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 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/3/09/672
    D.3 Description of the IMP
    D.3.1Product namepomalidomide
    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.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 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/3/09/672
    D.3 Description of the IMP
    D.3.1Product namepomalidomide
    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: 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 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/3/09/672
    D.3 Description of the IMP
    D.3.1Product namepomalidomide
    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 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: 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 Imnovid
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/09/672
    D.3 Description of the IMP
    D.3.1Product namepomalidomide
    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.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
    Relapsed or Refractory Multiple Myeloma
    Mieloma múltiple resistente o recurrente
    E.1.1.1Medical condition in easily understood language
    Multiple Myeloma
    Mieloma múltiple
    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
    The primary objective of this study is to compare PFS between treatment arms.
    El objetivo principal de este estudio es comparar la supervivencia sin progresión (SSP) entre los grupos de tratamiento.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are the following:
    To compare Overall Response Rates (ORR) between treatment arms; To compare duration of response (DoR) between treatment arms; To compare time to next therapy between treatment arms; To compare Overall Survival (OS) between treatment arms; To assess the safety and tolerability of the investigational combination treatment; To assess the depth of response by analyzing Minimum Residual Disease (MRD) negativity rate for CR or better and for suspected CR; To compare health-related quality of life (HRQoL) and health utility between treatment arms; To evaluate the immunomodulatory effects of daratumumab on T cells; To evaluate daratumumab pharmacokinetics and immunogenicity.
    Los objetivos secundarios son los siguientes:
    Comparar la tasa de respuesta global (TRG) entre los grupos de tratamiento; Comparar la duración de la respuesta (DR) entre los grupos de tratamiento; Comparar el tiempo hasta el siguiente tratamiento entre los grupos de tratamiento; Comparar la supervivencia global (SG) entre los grupos de tratamiento; Evaluar la seguridad y tolerabilidad del tratamiento combinado en fase de investigación; Evaluar la amplitud de respuesta mediante el análisis de la tasa de enfermedad mínima residual (EMR) para los pacientes con respuesta completa (RC) y para pacientes con presunta RC (pRC); Comparar la calidad de vida relacionada con la salud (CVRS) y la utilidad de los estados de salud entre los grupos de tratamiento; Evaluar los efectos inmunomoduladores de daratumumab en los linfocitos T; Evaluar la farmacocinética y la inmunogenia de daratumumab.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Males and females at least 18 years of age;
    2. Voluntary written informed consent before performance of any study-related procedure;
    3. Subject must have measurable disease of MM as defined by the criteria below:
    - IgG multiple myeloma: Serum M protein level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours, or
    - IgA, IgD, IgE, IgM multiple myeloma: Serum M-protein level ≥0.5 g/dL or urine M-protein level ≥200 mg/24 hours; or
    - Light chain multiple myeloma, for subjects without measurable disease in the serum or urine: Serum immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio;
    4. Subjects must have received prior antimyeloma treatment. The prior treatment must have included both a PI- and lenalidomide-containing regimens. The subject must have had a response (ie, PR or better) to prior therapy;
    5. Subjects must have documented evidence of PD as defined by the modified IMWG criteria on or after the last regimen;
    6. Subjects who received only 1 line of prior treatment must have demonstrated PD on or within 60 days of completion of the lenalidomide containing regimen (ie, lenalidomide refractory);
    7. Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2;
    8. Willingness and ability to participate in study procedures;
    9. For subjects experiencing toxicities resulting from previous therapy, the toxicities must be resolved or stabilized to ≤Grade 1;
    10. Any of the following laboratory test results during Screening:
    a) Absolute neutrophil count ≥1.0 × 10^9/L;
    b) Hemoglobin level ≥7.5 g/dL (≥5 mmol/L);
    c) Platelet count ≥75 × 10^9/L in subjects in whom <50% of bone marrow nucleated cells are plasma cells and platelet count ≥50 x 10^9/L in subjects in whom ≥50% of bone marrow nucleated cells are plasma cells;
    d) Alanine aminotransferase (ALT) level ≤2.5 times the upper limit of normal (ULN);
    e) Aspartate aminotransferase (AST) level ≤2.5 x ULN;
    f) Total bilirubin level ≤1.5 x ULN, (except for Gilbert Syndrome: direct bilirubin ≤1.5 × ULN);
    g) Creatinine clearance ≥30 mL/min (Appendix 6);
    h) Serum calcium corrected for albumin ≤14.0 mg/dL (≤3.5 mmol/L), or free ionized calcium ≤ 6.5 mg/dL (≤1.6 mmol/L);
    11. Reproductive Status:
    a) Women of childbearing potential (WOCBP) must have 2 negative serum or urine pregnancy tests, one 10-14 days prior to start of study treatment and one 24 hours prior to the start of study treatment. Females are not of reproductive potential if they have been in natural menopause for at least 24 consecutive months, or have had a hysterectomy and/or bilateral oophorectomy;
    b) Women must not be breastfeeding;
    c) WOCBP must agree to follow instructions for methods of contraception for 4 weeks before the start of study treatment, for the duration of study treatment, and for 3 months after cessation of daratumumab or 4 weeks after cessation of pomalidomide, whichever is longer;
    d) Males who are sexually active must always use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if they have undergone a successful vasectomy. They must also agree to follow instructions for methods of contraception for 4 weeks before the start of study treatment, for the duration of study treatment, and for a total of 3 months post-treatment completion;
    e) Male subjects must not donate sperm for up to 90 days post-treatment completion;
    f) Female subject must not donate eggs for up to 90 days post-treatment completion;
    g) Azoospermic males and WOCBP who are not heterosexually active are exempt from contraceptive requirements. However, WOCBP will still undergo pregnancy testing as described in this section.
    Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. Subjects must agree to the use of 2 methods of contraception, with 1 method being highly effective and the other method being additionally effective.
    1. Hombres y mujeres mayores de 18 años.
    2. Firmar la hoja de consentimiento informado (CI) antes de llevar a cabo ningún procedimiento relacionado con el estudio.
    3. Los pacientes deben presentar mieloma múltiple (MM) medible como se define en los siguientes criterios:
    -Mieloma múltiple IgG: Concentración sérica de la paraproteína monoclonal (Proteína M) ≥1,0 g/dl o concentración de la proteína M en orina ≥200 mg/24 horas, o
    -Mieloma múltiple IgA, IgD, IgE, IgM: Concentración sérica de la proteína M ≥0,5 g/dl o concentración de la proteína M en orina ≥200 mg/24 horas; o
    - Mieloma múltiple de cadenas ligeras, en pacientes con enfermedad no medible en suero ni orina: Concentración de cadenas ligeras libres (CLL) de inmunoglobulina en suero ≥10 mg/dl y cociente anómalo de CLL kappa y lambda en suero.
    4. Los pacientes deben haber recibido tratamiento previo para el mieloma que incluyera pautas con inhibidores del proteasoma (IP) y tratamiento con lenalidomida. El paciente debe haber respondido al tratamiento previo, es decir, RP o mejor.
    5. Los pacientes deben presentar pruebas documentadas de progresión de la enfermedad (PE) tal como se define en los criterios actualizados del IMWG durante o después del último tratamiento.
    6. Los pacientes que recibieron solo una línea de tratamiento previo deben demostrar PE durante o en los 60 días posteriores a finalizar el tratamiento con lenalidomida, es decir, resistencia a la lenalidomida.
    7. Puntuación del estado funcional de la escala ECOG (Eastern Cooperative Oncology Group) ≤ 2.
    8. Voluntad y capacidad de participar en los procedimientos del estudio;
    9. Para los sujetos que experimentan toxicidades resultantes de una terapia anterior, las toxicidades deben resolverse o estabilizarse a ≤ Grado 1;
    10. Cualquiera de los siguientes resultados de las pruebas de laboratorio durante la selección:
    a) Recuento absoluto de neutrófilos ≥ 1,0 × 10^9 / L;
    b) Nivel de hemoglobina ≥7,5 g / dL (≥ 5 mmol / L);
    c) Recuento de plaquetas ≥ 75 × 10^9 / L en sujetos en los que <50% de las células nucleadas de médula ósea son células plasmáticas y recuento de plaquetas ≥ 50 x 10^9 / L en sujetos en los que ≥ 50% de células nucleadas de médula ósea son células plasmáticas;
    d) nivel de alanina aminotransferasa (ALT) ≤ 2,5 veces el límite superior de la normalidad (LSN);
    e) Nivel de aspartato aminotransferasa (AST) ≤2,5 x LSN;
    f) Nivel total de bilirrubina ≤1,5 x ULN, (excepto para el síndrome de Gilbert: bilirrubina directa ≤1,5 x ULN);
    g) Depuración de creatinina ≥ 30 ml / min (Apéndice 6);
    h) Calcio sérico corregido para la albúmina ≤ 14,0 mg / dL (≤ 3,5 mmol / L), o calcio ionizado libre ≤ 6,5 mg / dL (≤ 1,6 mmol / L);
    11. Estado reproductivo:
    a) Las mujeres en edad fértil deben presentar 2 pruebas negativas de embarazo en suero y en orina, una 10-14 días antes de iniciar el tratamiento con los fármacos del estudio y otra 24 horas antes de iniciar el tratamiento del estudio. Las mujeres no están en estado reproductivo si han estado en la menopausia natural durante al menos 24 meses consecutivos, o han tenido una histerectomía y / o ooforectomía bilateral;
    b) Tampoco pueden estar en periodo de lactancia.
    c) Las mujeres en edad fértil deben aceptar seguir las instrucciones de métodos anticonceptivos durante las 4 semanas anteriores a iniciar el tratamiento con los fármacos del estudio, durante todo el periodo de tratamiento del estudio y durante un total de 3 meses después de finalizar el tratamiento con daratumumab.
    d) Los hombres sexualmente activos deben usar siempre preservativos de látex o sintéticos durante las relaciones sexuales con mujeres en edad fértil, incluso si se han sometido a una vasectomía. También deben aceptar seguir las instrucciones para los métodos anticonceptivos durante 4 semanas antes del comienzo del tratamiento del estudio, durante la duración del tratamiento del estudio y durante un total de 3 meses después de la finalización del tratamiento;
    e) Los hombres no deben donar esperma hasta 90 días después del tratamiento;
    f) Las mujeres no deben donar óvulos hasta 90 días después del tratamiento;
    g) Los hombres azoospérmicos y las mujeres en edad fértil que no son heterosexualmente activos están exentos de los requerimientos de anticonceptivos. Sin embargo, las mujeres en edad fértil todavía se someterán a pruebas de embarazo como se describe en esta sección.
    Los métodos anticonceptivos altamente eficaces tienen una tasa de fracaso <1% cuando se usan de forma consistente y correcta. Los sujetos deben acordar el uso de 2 métodos anticonceptivos, con 1 método altamente eficaz y el otro método eficaz.
    E.4Principal exclusion criteria
    1. Previous therapy with any anti-CD38 monoclonal antibody;
    2. Previous exposure to pomalidomide;
    3. Subject has received antimyeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before the date of randomization. The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days) for palliative treatment before Cycle 1, Day 1 (C1D1);
    4. Previous allogenic stem cell transplant; or autologous stem cell transplantation (ASCT) within 12 weeks before C1D1;
    5. History of malignancy (other than MM) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years);
    6. Clinical signs of meningeal involvement of MM;
    7. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal. (Appendix 4);
    8. Clinically significant cardiac disease, including:
    a) Myocardial infarction within 6 months, or unstable or uncontrolled condition (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV);
    b) Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 or higher) or clinically significant electrocardiogram (ECG abnormalities;
    c) Electrocardiogram showing a baseline QT interval as corrected QTc >470 msec;
    9. Known active hepatitis A, B, or C;
    10. Known HIV infection;
    11. Gastrointestinal disease that may significantly alter the absorption of pomalidomide;
    12. Subject has plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström’s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis;
    13. Any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results or that, in the opinion of the investigator, would constitute a hazard for participating in this study;
    14. Ongoing ≥ Grade 2 peripheral neuropathy;
    15. Subject had ≥Grade 3 rash during prior therapy;
    16. Subject has had major surgery within 2 weeks before randomization, or has not fully recovered from an earlier surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration. Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery;
    17. Pregnant or nursing women.
    1. Tratamiento previo con cualquier anticuerpo monoclonal anti-CD38;
    2. Exposición previa a la pomalidomida;
    3. El sujeto ha recibido tratamiento antimieloma dentro de las 2 semanas o 5 semividas farmacocinéticas del tratamiento, lo que sea más largo, antes de la fecha de la randomización. La única excepción es el uso de emergencia de un curso corto de corticosteroides (equivalente a dexametasona 40 mg / día durante un máximo de 4 días) para tratamiento paliativo antes del Ciclo 1, Día 1 (C1D1);
    4. Anterior trasplante de células madre alogénicas; o trasplante autólogo de células madre (ASCT) dentro de 12 semanas antes de C1D1;
    5. Antecedentes de malignidad (con excepción de MM) dentro de los 3 años anteriores a la fecha de la asignación al azar (las excepciones son carcinomas escamosos y basocelulares de la piel, carcinoma in situ del cuello del útero o mama u otra lesión no invasiva que, según la opinión del investigador, en concordancia con el monitor médico del promotor, se considera curado con un riesgo mínimo de recurrencia dentro de los 3 años);
    6. Signos clínicos de compromiso meníngeo de MM;
    7. Enfermedad pulmonar obstructiva crónica (EPOC) con un volumen espiratorio forzado en 1 segundo (FEV1) <50% de la normal prevista. Tenga en cuenta que la prueba de FEV1 es necesaria para los sujetos sospechosos de tener EPOC y los sujetos deben ser excluidos si FEV1 <50% de lo previsto normal. (Apéndice 4);
    8. Enfermedad cardiaca clínicamente significativa, incluyendo:
    A) Infarto de miocardio dentro de los 6 meses, o condición inestable o incontrolada (por ejemplo, Angina inestable, insuficiencia cardiaca congestiva, clase III-IV de la Asociación del Corazón de Nueva York);
    B) Arritmia cardíaca (Criterios Terminológicos Comunes para Eventos Adversos [CTCAE] Grado 3 o superior) o electrocardiograma clínicamente significativo (anomalías ECG;
    C) Electrocardiograma que muestra un intervalo QT basal como QTc corregido> 470 mseg;
    9. Hepatitis activa conocida A, B o C;
    10. Infección conocida del VIH;
    11. Enfermedad gastrointestinal que puede alterar significativamente la absorción de pomalidomida;
    12. El sujeto tiene leucemia de células plasmáticas (> 2,0 × 109 / L de células plasmáticas circulantes por diferencial estándar) o macroglobulinemia de Waldenström o síndrome POEMS (polineuropatía, organomegalia, endocrinopatía, proteína monoclonal y cambios en la piel) o amiloidosis;
    13. Cualquier condición o enfermedad médica o psiquiátrica concurrente (por ejemplo, infección sistémica activa, diabetes no controlada, enfermedad pulmonar infiltrativa difusa aguda) que pueda interferir con los procedimientos o resultados del estudio o que, a juicio del investigador, podrían representar un riesgo para participar en este estudio;
    14. En curso ≥ Neuropatía periférica de grado 2;
    15. El sujeto tuvo erupción cutánea ≥ de grado 3 durante la terapia anterior;
    16. El sujeto ha sido sometido a una cirugía mayor dentro de las 2 semanas antes de la randomización, o no se ha recuperado completamente de una cirugía anterior o se ha planificado la cirugía durante el tiempo en que se espera que el sujeto participe en el estudio o dentro de las dos semanas después de la última dosis administrada del fármaco del estudio. Nota: pueden participar los sujetos con procedimientos quirúrgicos planificados que se lleven a cabo bajo anestesia local. La cifoplastia o la vertebroplastia no se consideran cirugía mayor;
    17. Mujeres embarazadas o lactantes.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this study is PFS (Progression-free survival).
    El criterio de valoración principal de este estudio es SSP (Supervivencia sin progresión).
    E.5.1.1Timepoint(s) of evaluation of this end point
    For the entire duration of the study.
    Durante toda la duración del estudio.
    E.5.2Secondary end point(s)
    Secondary Endpoints:
    - Overall response rate;
    - VGPR or better rate;
    - CR or better rate;
    - MRD negativity rate;
    - Time to response;
    - Duration of response;
    - Time to next therapy;
    - Overall survival;
    - Safety (adverse events);
    - Scale and domain scores of the EORTC QLQ-C30 (global health status, physical functioning, emotional functioning, fatigue, pain) and EORTC QLQ-MY20 (disease symptoms, side effects of treatment);
    - EQ-5D-5L health utility values;
    - Immunomodulatory effects of daratumumab on T cells;
    - Daratumumab pharmacokinetic concentrations;
    - Daratumumab immunogenicity;
    Criterios de valoración secundarios:
    - Tasa de respuesta global;
    - Respuesta parcial muy buena o mejor;
    - RC o mejor;
    - Tasa de negatividad de EMR;
    - Tiempo hasta la respuesta;
    - Duración de la respuesta;
    - Tiempo hasta el siguiente tratamiento;
    - Supervivencia global;
    - Seguridad (efectos adversos);
    - Puntuaciones de la escala y las dimensiones de EORTC QLQ-C30 (estado de salud global, función física, función emocional, fatiga, dolor) y EORTC QLQ-MY20 (síntomas de la enfermedad, efectos secundarios del tratamiento);
    - Valores de utilidad de los estados de salud del EQ-5D-5L;
    - Efectos inmunomoduladores de daratumumab en los linfocitos T;
    - Concentraciones farmacocinéticas de daratumumab;
    - Inmunogenia de daratumumab.
    E.5.2.1Timepoint(s) of evaluation of this end point
    For the entire duration of the study.
    Durante toda la duración del 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 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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity Assessments
    Evaluaciones de inmunogenicidad
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open 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) 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    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
    Belgium
    Czech Republic
    Denmark
    France
    Germany
    Greece
    Italy
    Netherlands
    Serbia
    Spain
    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
    Última visita del último paciente
    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 months0
    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 months0
    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: 106
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 196
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 270
    F.4.2.2In the whole clinical trial 302
    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)
    None
    Ninguno
    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 Decision2017-07-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-22
    P. End of Trial
    P.End of Trial StatusOngoing
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