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    EudraCT Number:2018-004185-34
    Sponsor's Protocol Code Number:54767414MMY2065
    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:2019-05-08
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2018-004185-34
    A.3Full title of the trial
    A Phase 2 Study of Daratumumab Subcutaneous (Dara-SC) Administration in Combination with Carfilzomib and Dexamethasone (DKd) Compared with Carfilzomib and Dexamethasone (Kd) in Participants with Multiple Myeloma who have been Previously Treated with Daratumumab Intravenous (Dara-IV) to Evaluate Daratumumab Retreatment
    Estudio en fase 2 de administración subcutánea de daratumumab (Dara-SC) en combinación con carfilzomib y dexametasona (D-Kd) en comparación con carfilzomib y dexametasona (Kd) en pacientes con mieloma múltiple previamente tratados con daratumumab intravenoso (Dara-IV) para evaluar el retratamiento con daratumumab
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Study of Daratumumab Subcutaneous (Dara-SC) Administration in Combination with Carfilzomib and Dexamethasone (DKd) Compared with Carfilzomib and Dexamethasone (Kd) in Participants with Multiple Myeloma who have been Previously Treated with Daratumumab Intravenous (Dara-IV) to Evaluate Daratumumab Retreatment
    Estudio clínico de administración de Daratumumab subcutáneo (Dara-SC) en combinación con Carfilzomib y Dexametasoona (D-Kd) comparado con Carfilzomib y Dexametasona (Kd) en pacientes con mieloma múltiple previamente tratados con Daratumumab intravenoso (Dara-IV) para evaluar el retratamiento con con Daratumumab.
    A.4.1Sponsor's protocol code number54767414MMY2065
    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 SponsorJanssen-Cilag International N.V.
    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 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 organisationJanssen-Cilag International N.V.
    B.5.2Functional name of contact pointClinical Registry Group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333
    B.5.4Telephone number+31715242166
    B.5.5Fax number+31715242110
    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/3/13/1153
    D.3 Description of the IMP
    D.3.1Product nameDaratumumab
    D.3.2Product code JNJ-54767414
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous 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.3.9.2Current sponsor codeJNJ-54767414
    D.3.9.3Other descriptive nameHuMax-CD38, 3003-005
    D.3.9.4EV Substance CodeSUB175772
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1800
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple Myeloma
    mieloma multiple
    E.1.1.1Medical condition in easily understood language
    Bone marrow cancer
    Cáncer de médula ósea
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 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
    The primary objective is to compare the efficacy (rate of very good partial response [VGPR] or better as best response as defined by the International Myeloma Working Group [IMWG] criteria) of Dara-SC in combination with Kd with the efficacy of Kd in participants with relapsed refractory multiple myeloma who were previously exposed to daratumumab intravenous (Dara-IV) to evaluate daratumumab retreatment.
    El objetivo principal es comparar la eficacia (tasa de respuesta parcial muy buena [RPMB] o mejor como la mejor respuesta, según lo definido por el International Myeloma Working Group [criterios del IMWG]) sobre Dara-SC en combinación con Kd con la eficacia de Kd, en pacientes con mieloma múltiple refractario recidivante que han sido tratados previamente con daratumumab intravenoso (Dara-IV) para evaluar el retratamiento con daratumumab.
    E.2.2Secondary objectives of the trial
    The secondary objectives are:
    • To further characterize the efficacy (progression-free survival [PFS], overall survival [OS], overall response rate [ORR], rate of complete response[CR]/stringent complete response [sCR]) of Dara-SC in combination with Kd
    • To evaluate the minimal residual disease (MRD) negativity rate and durability of MRD negativity status
    • To characterize the safety of Dara-SC in combination with Kd
    • To determine time to next treatment
    • To evaluate the pharmacokinetics (PK)of Dara-SC
    • To determine the immunogenicity of daratumumab recombinant human hyaluronidase PH20 (rHuPH20)
    Caracterizar mejor la eficacia (Supervivencia Libre de Progresión [SLP], supervivencia global [SG], tasa de respuesta global [TRG], tasa de respuesta completa [RC]/respuesta completa rigurosa [RCR]) de Dara-SC en combinación con Kd
    • Evaluar la tasa de negatividad de la enfermedad mínima residual (EMR) y la durabilidad del estado de negatividad de la EMR
    • Caracterizar la seguridad de Dara-SC en combinación con Kd
    • Determinar el tiempo hasta el siguiente tratamiento
    • Evaluar la farmacocinética (FC) de Dara-SC
    • Determinar la inmunogenicidad de daratumumab y la hialuronidasa recombinante humana PH20 (rHuPH20)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each potential participant must satisfy all of the following criteria to be enrolled in the study:
    1. At least 18 years of age.
    2. Documented multiple myeloma as defined by the criteria below:
    Multiple myeloma diagnosis according to the International Myeloma Working Group (IMWG) diagnostic criteria.
    Measurable disease at screening as defined by any of the following: Serum M-protein level ≥1.0 g/dL in participants with immunoglobulin G (IgG) type, or serum M-protein level ≥0.5 g/dL in participants with non- IgG type, or urine M-protein level ≥200 mg/24 hours; or Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.
    3. Evidence of a response (partial response or better based on investigator’s determination of response by IMWG criteria) to daratumumab-containing IV therapy with response duration of at least 4 months.
    4. Relapsed or refractory disease as defined below:
    Relapsed disease is defined as an initial response to previous treatment, followed by confirmed PD by IMWG criteria >60 days after cessation of treatment. Refractory disease is defined as <25% reduction in M-protein or confirmed PD by IMWG criteria during previous treatment or ≤60 days after cessation of treatment. 5. Received 1 or 2 prior line(s) of treatment of which one contained Dara-IV, and completed Dara-IV at least 3 months prior to randomization. A single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of corticosteroids (no more than the equivalent of dexamethasone 40 mg/day for 4 days) would not be considered prior lines of therapy.
    6. ECOG Performance Status score of 0, 1, or 2.
    7. Pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:
    a) hemoglobin ≥8 g/dL (≥5mmol/L) (without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted);
    b) absolute neutrophil count (ANC) ≥1.0 × 10^9/L (prior growth factor support is permitted but must be without support within the 7 days prior to the laboratory test);
    c) platelet count ≥75 ×10^9/L for participants in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count of ≥50×10^9/L. Transfusions are not permitted within 7 days of testing to achieve this minimum platelet count.
    d) aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN);
    e) alanine aminotransferase (ALT) ≤2.5 × ULN;
    f) total bilirubin ≤1.5 × ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤1.5× ULN is required); g) estimated creatinine clearance (CrCl) ≥20mL/min per 1.73m^2. CrCl to be calculated using estimated glomerular filtration rate Modification of Diet in Renal Disease (MDRD) formula.
    h) albumin-corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6mmol/L)
    8. Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy.
    9. Women of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to randomization.
    10. Each participant must sign an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study. Participants must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF
    Cada participante potencial debe satisfacer todos los siguientes criterios para ser inscrito en el estudio:
    1. Tener al menos 18 años de edad.
    2. Mieloma múltiple documentado según se define en los criterios que figuran a continuación:
    Diagnóstico del mieloma múltiple según los criterios de diagnóstico del International Myeloma Working Group (IMWG).
    Enfermedad medible en el momento del cribado, tal como se define en cualquiera de los siguientes términos: Nivel de proteína M en suero ≥1.0 g/dL en participantes con inmunoglobulina G (IgG) tipo, o nivel de proteína M en suero ≥0.5 g/dL en participantes con no tipo IgG, o nivel de proteína M en orina ≥200 mg/24 horas; o mieloma múltiple de cadena ligera sin enfermedad medible en el suero o la orina: Cadena ligera libre de inmunoglobulina en suero (CLL) ≥10 mg/dL y proporción anormal de inmunoglobulina en suero kappa lambda CLL.
    3. Evidencia de una respuesta (respuesta parcial o mejor basada en la determinación de la respuesta por parte del investigador según los criterios de la IMWG) a la terapia intravenosa que contiene daratumumab con una duración de respuesta de al menos 4 meses.
    4. Enfermedad recidivante o refractaria según se define a continuación:
    La enfermedad recidivante se define como una respuesta inicial al tratamiento previo, seguida de la confirmación de la EP según los criterios de la IMWG >60 días después de la interrupción del tratamiento. La enfermedad refractaria se define como una reducción <25% en la proteína M o PD confirmada por los criterios de IMWG durante el tratamiento anterior o ≤60 días después del cese del tratamiento. 5. Recibió 1 o 2 línea(s) de tratamiento anterior(es) de las cuales una contenía Dara-IV, y completó Dara-IV por lo menos 3 meses antes de la asignación al azar. Una sola línea de terapia puede consistir en uno o más agentes, y puede incluir inducción, trasplante de células madre hematopoyéticas y terapia de mantenimiento. La radioterapia, el bifosfonato o un solo ciclo corto de corticosteroides (no más que el equivalente de 40 mg/día de dexametasona durante 4 días) no se considerarían líneas de tratamiento previas.
    6. Puntuación de estado de rendimiento ECOG de 0, 1 ó 2.
    7. Valores de laboratorio clínico de pretratamiento que cumplen los siguientes criterios durante la fase de cribado:
    a) hemoglobina ≥8 g/dL (≥5mmol/L) (sin transfusión previa de glóbulos rojos dentro de los 7 días anteriores a la prueba de laboratorio; se permite el uso de eritropoyetina humana recombinante);
    b) recuento absoluto de neutrófilos (ANC) ≥1.0 × 10^9/L (se permite el apoyo previo al factor de crecimiento, pero debe estar sin apoyo dentro de los 7 días anteriores a la prueba de laboratorio);
    c) recuento de plaquetas ≥75 ×10^9/L para participantes en los que <50% de las células nucleadas en la médula ósea son células plasmáticas; de lo contrario, recuento de plaquetas de ≥50×10^9/L. No se permiten las transfusiones dentro de los 7 días de la prueba para lograr este recuento mínimo de plaquetas.
    d) aspartato aminotransferasa (AST) ≤2.5 × límite superior de normal (ULN);
    e) alanina aminotransferasa (ALT) ≤2.5 × ULN;
    f) bilirrubina total ≤1.5 × ULN; excepto en participantes con bilirrubinemia congénita, como el síndrome de Gilbert (en cuyo caso se requiere bilirrubina directa ≤1.5× ULN); g) depuración estimada de creatinina (CrCl) ≥20mL/min por 1.73m^2. CrCl se calculará utilizando la tasa de filtración glomerular estimada Modificación de la dieta en la fórmula de enfermedad renal (MDRD).
    h) calcio sérico corregido con albúmina ≤14 mg/dL (≤3.5 mmol/L) o calcio ionizado libre ≤6.5 mg/dL (≤1.6mmol/L)
    8. Las mujeres en edad fértil deben comprometerse a abstenerse continuamente de tener relaciones sexuales heterosexuales o a utilizar simultáneamente dos métodos anticonceptivos fiables. Esto incluye una forma altamente efectiva de anticoncepción (ligadura de trompas, dispositivo intrauterino, hormonal (píldoras anticonceptivas, inyecciones, parches hormonales, anillos vaginales o implantes) o vasectomía de la pareja) y un método anticonceptivo efectivo adicional (látex masculino o condón sintético, diafragma o capuchón cervical). La anticoncepción debe comenzar 4 semanas antes de la dosis. La anticoncepción fiable está indicada incluso cuando hay antecedentes de infertilidad, a menos que se deba a una histerectomía.
    9. Las mujeres en edad fértil deben someterse a una prueba de embarazo en orina o suero negativa en el momento de la detección dentro de los 14 días anteriores a la asignación al azar.
    10. Cada participante debe firmar un formulario de consentimiento informado (ICF) (o su representante legalmente aceptado debe firmar) indicando que entiende el propósito y los procedimientos requeridos para el estudio y que está dispuesto a participar en el mismo. Los participantes deben estar dispuestos y ser capaces de adherirse a las prohibiciones y restricciones especificadas en este protocolo, como se menciona en el MCP.
    E.4Principal exclusion criteria
    Any potential participant who meets any of the following criteria will be excluded from participating in the study:
    1. Previous treatment with Dara-SC.
    2. Previoustreatment with carfilzomib.
    3. Previous treatment with daratumumab within the last 3 months prior to randomization.
    4. Discontinuation of Dara-IV due to a daratumumab-related AE.
    5. Allergies, hypersensitivity, or intolerance to daratumumab, hyaluronidase, mAbs, human proteins, or their excipients (refer to the IB), or known sensitivity to mammalian derived products. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
    6. Contraindications to the use of any components of the backbone treatment regimens, per local prescribing information.
    7. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before randomization (except for investigational anti-myeloma treatments, which cannot be taken within 2 weeks or 5PK half-lives of the treatment from the first dose of daratumumab, whichever is longer, before the date of randomization).
    8. Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study intervention.
    9. Plans to father a child while enrolled in this study or within 3 months after the last dose of study intervention.
    10. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
    11. Received anti-myeloma treatment within 2 weeks or 5 PK half-lives of the treatment from the first dose of daratumumab, 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) up to 21 days before treatment. A list of anti-myeloma treatments with the corresponding PK half-lives is provided in the Site Investigational Product Procedures Manual.
    12. Received autologous stem cell transplant within 12 weeks before the date of randomization, or the participant has previously received allogeneic stem cell transplant (regardless of timing).
    13. Plans to undergo a stem cell transplant prior to progression of disease on this study.
    14. Focal radiation therapy within 14 days prior to randomization with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma. Radiotherapy within 14 days prior to randomization on measurable extramedullary plasmacytoma is not permitted even in the setting of palliation for symptomatic management.
    15. Clinical signs of meningeal involvement of multiple myeloma.
    16. Either of the following:
    a) Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) is <50% of predicted normal. Note that FEV1 testing also is required for participants suspected of having COPD and participants must be excluded if FEV1 is <50% of predicted normal.
    b) Known moderate or severe persistent asthma, or a history of asthma within the last 2 years, or currently has uncontrolled asthma of any classification. (Participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.)
    17. Concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease, pulmonary hypertension) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study.
    18. Uncontrolled hypertension, defined as an average systolic blood pressure >159mmHg or diastolic >99 mmHg despite optimal treatment (measured following European Society of Hypertension/European Society of Cardiology 2013 guidelines).
    19. Gastrointestinal disease that may significantly alter the absorption of oral drugs.
    20. Myelodysplastic syndrome, plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström's macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) or amyloidosis.
    21. Not able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder) or the participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
    22. Cirrhosis of the liver.
    23. Intolerance to hydration due to preexisting pulmonary or cardiac impairment

    For full exclusion criteria, refer page no: 35 to 38 of the protocol
    Cualquier participante potencial que cumpla con cualquiera de los siguientes criterios será excluido de participar en el estudio:
    1.Tto previo con Dara-SC.
    2.Tto previo con carfilzomib.
    3.Tto previo con dara en últimos 3 meses antes randomización
    4.Suspensión de Dara-IV debido a un EA relacionado con dara.
    5.Alergias, hipersensibilidad o intolerancia al dara, hialuronidasa, Ac monoclonales, prots humanas o sus excipientes (consulte IB), o sensibilidad conocida a productos derivados de mamíferos.Hª conocida de alergia a Captisol (derivado de ciclodextrina usado para solubilizar carfilzomib).
    6.Contraindicaciones para uso de cualquier componente de regímenes de tto estándar, según información de prescripción local.
    7.Recibió una intervención en investigación (incluidas vacunas) o utilizó dispositivo médico invasivo en investigación dentro de 4 semanas anteriores a la randomización (excepto en el caso de tratamientos anti-mieloma en investigación, que no pueden tomarse dentro de las 2 semanas o 5 semividas PK del tto a partir de la 1ª dosis de dara, lo que sea más largo, antes de la fecha de randomización).
    8.Embarazada, o amamantando, o planeando quedarse embarazada mientras participa en estudio o en los 3 meses posteriores a última dosis
    9.Planes para engendrar un hijo mientras participa en estudio o dentro de los 3 meses posteriores a la última dosis
    10.Cualquier condición para la cual,en opinión del investigador,la participación no sería en el mejor interés del participante (ej. comprometer el bienestar) o que podría prevenir, limitar o confundir las evaluaciones especificadas en el protocolo
    11.Recibió tto contra el mieloma en un plazo de 2 semanas o 5 semividas PK del tratamiento a partir de la 1ª dosis de dara, lo que sea más largo, antes de la fecha de randomización. La única excepción es uso de emergencia de un ciclo corto de corticosteroides (equivalente a 40 mg/día dexametasona durante un máx. 4 días) hasta 21 días antes del tto. En el Manual de Procedimientos del Producto en Investigación se proporciona una lista de ttos contra el mieloma con las correspondientes semividas de PK
    12.Recibió un trasplante autólogo de céls madre dentro de 12 semanas anteriores a la fecha de randomización, o el participante ha recibido previamente un trasplante alogénico de céls madre (sin importar el momento)
    13.Planes para someterse a un trasplante de céls madre antes de la progresión enfermedad en este estudio
    14.Radioterapia focal dentro de 14 días anteriores a randomización, con excepción de radioterapia paliativa para el tto sintomático, pero no para el plasmacitoma extramedular medible. Radioterapia dentro de 14 días anteriores a la randomización en el plasmacitoma extramedular medible no está permitida, ni siquiera en el ámbito paliativo para tto sintomático
    15.Signos clínicos de compromiso meníngeo del mieloma múltiple
    16.Cualquiera de los siguientes:
    a)EPOC conocida con un volumen espiratorio forzado en 1 segundo (VEF1) <50% de lo normal previsto.Prueba de VEF1 también se requiere para los participantes sospechosos de tener EPOC y deben ser excluidos si el VEF1 es <50% de lo que se predice como normal
    b)Asma persistente moderado o severo conocido,o un historial de asma en los últimos 2 años, o actualmente asma no controlado de cualquier clasificación. (A los participantes que actualmente han controlado el asma intermitente o el asma leve persistente, se les permite participar en el estudio)
    17.Condición o enf. médica o psiquiátrica concurrente (ej., infección sistémica activa, diabetes no controlada, enf. pulmonar infiltrativa difusa aguda, hipertensión pulmonar) que probablemente interfiera con los procedimientos o resultados del estudio, o que, en opinión del investigador, constituya un peligro para participar en este estudio
    18.Hipertensión no controlada, definida como una PAS media >159 mmHg o PAD >99 mmHg a pesar del tto óptimo (medido según pautas de SEH/SEC 2013)
    19.Enf. gastrointestinal que puede alterar significativamente la absorción de medicamentos orales
    20.Sínd. mielodisplásico, leucemia de céls plasmáticas (>2.0 × 109/L céls plasmáticas circulantes por diferencial estándar) o macroglobulinemia de Waldenström o síndr. POEMS (polineuropatía, organomegalia, endocrinopatía, prot. M y cambios cutáneos) o amiloidosis
    21.No poder cumplir con el protocolo (ej. debido al alcoholismo, dependencia de drogas o trastorno psicológico) o el participante tiene alguna condición para la cual, en opinión del investigador, la participación no sería en el mejor interés del participante (ej. comprometer su bienestar) o que podría prevenir, limitar o confundir las evaluaciones especificadas en el protocolo
    22.Cirrosis hepática
    23.Intolerancia a la hidratación debido a un deterioro pulmonar o cardíaco preexistente

    Para más información sobre los criterios de exclusión, véase la página 35 a 38 del protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    The rate of very good partial response (VGPR) or better as defined by the IMWG criteria.
    La tasa de respuesta parcial muy buena (RPMB) o mejor según lo definido por los criterios del IMWG.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Randomization to death, disease progression ( DP) , or lack of VGPR after 16 cycles of treatment (approximately 1 year and 3 months)
    La probabilidad de muerte, progresión de la enfermedad (PE) o falta de RPMB después de 16 ciclos de tratamiento (aproximadamente 1 año y 3 meses).
    E.5.2Secondary end point(s)
    1. Overall response rate (ORR) [rate of partial response (PR), very good partial response (VGPR), complete response (CR), stringent complete response (sCR)]
    2. Rate of CR/sCR
    3. Progression free survival (PFS)
    4. Overall survival (OS)
    5. Minimal residual disease (MRD) negativity rate
    6. Time to next treatment
    7. Serum daratumumab concentrations
    8. Prevalence and incidence of anti-daratumumab antibodies and anti-rHuPH20 antibodies
    1. Tasa de respuesta global (TRG)[tasa de respuesta parcial (RP), respuesta parcial muy buena (RPMB), respuesta completa (RC), respuesta completa estricta (RCS)].
    2. Tasa de RC/RCS
    3. Supervivencia Libre de Progresión (SLP)
    4. Supervivencia general (SG)
    5. Tasa de negatividad de enfermedad mínima residual
    6. Tiempo hasta el próximo tratamiento
    7. Concentraciones de daratumumab en suero
    8. Prevalencia e incidencia de anticuerpos antiparatumab y anticuerpos anti-rHuPH20
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.Randomization (R) to death, DP or lack of VGPR/PR/CR/sCR after 16 cycles (C) of treatm.(about 1 yr and 3 mths)
    2.R to death, DP or lack of CR/sCR after 16 C of treatment (about 1 yr and 3 months)
    3.From R to PFS after about 18.7 mths
    4.From R to end of study(defined as no later than 2 yrs after the last participant has received their initial dose of study intervention or when the sponsor decides to stop the study)
    5.Bone marrow aspirates will be collected at time of suspected CR/sCR and for participants achieve CR,have not progressed, and remain on the study,additional bone marrow aspirate will be obtained at 12,18 and 24 mth post C1Day1
    6.From R to next Myeloma treatm.(about 16 C)
    7.Arm A: C1, C3; Arm B: C1,C3,C7 and Post-treatm. Wk8
    8.Arm A: C1; Arm B: C1,C7 and Post-treatm. Wk8
    -Prob(p)de muerte,DP o falta de RPMB/RP/RC/RCS tras 16 ciclos(C)de tto(aprox 1 año y 3 m)
    -P a la muerte,DP o falta de RC/RCS tras 16 C de tto(aprox de 1 año 3 m)
    -De P a PFS tras de aprox 18.7mths
    -De P a fin de estudio(definido como no más tarde de 2 años después de que el último paciente haya recibido su dosis inicial de intervención del estudio o cuando el patrocinador decida interrumpir el estudio)
    -Se tomarán aspirados de médula ósea en el momento de la sospecha de RC/RCS y para los pacientes que logren RC,no hayan progresado y permanezcan en el estudio,se obtendrán aspirados adicionales de médula ósea a los 12,18,24m después de C1Day1
    -desde P al siguiente tto del mieloma(alrededor de 16 C)
    -BrazoA:C1,C3;BrazoB:C1,C3,C7 y Post-tto.Wk8
    -BrazoA:C1;Brazo B:C1,C7 y Post-tto.Wk8
    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 and Biomarker analyses
    Análisis de Inmunogenicidad y Biomarcadores
    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. 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 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.8.2.4Number 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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA55
    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
    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
    The end of study is no later than 2 years after the last participant has received their initial dose of study intervention or when the sponsor decides to stop the study.
    El final del estudio es a más tardar 2 años después de que el último participante haya recibido su dosis inicial de intervención del estudio o cuando el patrocinador decida interrumpir el estudio.
    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 months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    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: 23
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 207
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 155
    F.4.2.2In the whole clinical trial 230
    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 sponsor will ensure that participants benefiting from treatment with daratumumab subcutaneous will be able to continue receiving treatment after the end of the study. Subsequent therapy is left to the investigator's discretion.
    El esponsor se asegurará de que los pacientes que se beneficien del tratamiento con daratumumab subcutáneo puedan seguir recibiendo tratamiento después del final del estudio. La terapia posterior se deja a la discreción del investigador.
    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 Decision2019-05-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-24
    P. End of Trial
    P.End of Trial StatusOngoing
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