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    Summary
    EudraCT Number:2017-004203-41
    Sponsor's Protocol Code Number:54767414MMY2040
    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:2018-03-14
    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 number2017-004203-41
    A.3Full title of the trial
    A Multicenter Phase 2 Study to Evaluate Subcutaneous Daratumumab in Combination with Standard Multiple Myeloma Treatment Regimens
    Estudio de fase 2 multicéntrico para evaluar daratumumab subcutáneo en
    combinación con los regímenes de tratamiento habituales para el mieloma
    múltiple
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to evaluate the safety, effectiveness and pharmacokinetics of Daratumumab given through the subcutaneous route in combination with standard bone marrow cancer treatment regimens
    Se trata de un estudio abierto, internacional y multicéntrico para
    demostrar que daratumumab administrado mediante inyección subcutánea
    (SC) en combinación con los regímenes terapéuticos habituales es seguro y
    eficaz en sujetos con mieloma múltiple (MM) de nuevo diagnóstico o en
    sujetos con enfermedad recidivante o resistente.
    A.4.1Sponsor's protocol code number54767414MMY2040
    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.1.3.4CountryBelgium
    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.5.3.4CountryNetherlands
    B.5.4Telephone number+31715242166
    B.5.5Fax number+31715242110
    B.5.6E-mailClinicalTrialsEU@its.jnj.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/3/13/1153
    D.3 Description of the IMP
    D.3.1Product nameDaratumumab co-formulated with recombinant human hyaluronidase (rHuPH20)
    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
    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 number120
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRecombinant human hyaluronidase PH20 (Vorhyaluronidase Alfa)
    D.3.9.1CAS number 757971-58-7
    D.3.9.2Current sponsor coderHuPH20 (Gen1, HZ201, HUA) or (Gen2, HZ202, HUB) PH20
    D.3.9.3Other descriptive namePEGYLATED RECOMBINANT HUMAN HYALURONIDASE PH20
    D.3.9.4EV Substance CodeSUB180813
    D.3.10 Strength
    D.3.10.1Concentration unit U/ml unit(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2000
    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 No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple Myeloma
    Mieloma múltiple
    E.1.1.1Medical condition in easily understood language
    Bone marrow cancer
    Cáncer de médula osea
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the clinical benefit of subcutaneous (SC) daratumumab administered in combination with standard multiple myeloma (MM) regimens in subjects with MM as measured by overall response rate (ORR) or very good partial response (VGPR) or better rate.
    Evaluar el beneficio clínico de daratumumab SC administrado en combinación con los regímenes habituales para el MM en sujetos con MM, lo que se determinará mediante la tasa de respuesta global (TRG) o la tasa de respuesta parcial muy buena (RPMB) o mejor.
    E.2.2Secondary objectives of the trial
    - To evaluate safety and pharmacokinetics (PK) of SC administration of daratumumab in combination with standard MM regimens
    - To evaluate additional clinical benefit of SC daratumumab administered in combination with standard MM regimens in subjects with MM
    - To characterize the immunogenicity of daratumumab and rHuPH20 following SC administration
    - To evaluate minimal residual disease (MRD) negativity rate in the D-VMP (daratumumab SC in combination with bortezomib, melphalan, and prednisone), and D-Rd (daratumumab SC in combination with lenalidomide and dexamethasone) cohorts
    - Evaluar la seguridad y la farmacocinética de la administración SC de daratumumab en combinación con los regímenes habituales para el MM.
    - Evaluar el beneficio clínico adicional de daratumumab SC administrado en combinación con los regímenes habituales para el MM en sujetos con MM.
    - Caracterizar la inmunogenicidad de daratumumab y de rHuPH20 tras la administración SC
    - Evaluar la tasa de negatividad de enfermedad residual mínima en las cohortes D-VMP (daratumumab en combinación con bortezomib,melfalán y prednisona) y D-Rd (daratumumab en combinación con
    lenalidomida y dexametasona).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each potential subject must satisfy all the following criteria to be enrolled in the study:
    1. ≥18 years of age (or the legal age of consent if it is higher than 18 years of age in the jurisdiction in which the study is taking place)
    2. Multiple myeloma diagnosed according to the International Myeloma Working Group (IMWG) diagnostic criteria
    3. Measurable, secretory disease as defined by any of the following:
    • Serum M-protein level ≥1.0 gram per decilitre (g/dL); or
    • Urine M-protein level ≥200 mg/24 hours; or
    • Light chain MM, for subjects without measurable disease in the serum or urine: serum Ig freel light chain (FLC) ≥10 milligrams per decilitre (mg/dL) and abnormal FLC ratio
    4. Meets one of the sets of the following criteria:
    a. For inclusion into the D-VRd cohort for newly diagnosed disease:
    - Newly diagnosed MM by IMWG criteria and eligible/planned for high-dose therapy and autologous stem cell transplant (ASCT)
    b. For inclusion into the D-VMP cohort:
    - Newly diagnosed and previously untreated MM by IMWG criteria and not considered a candidate for high-dose chemotherapy with ASCT due to:
    • Being age ≥65 years, or
    • In subjects <65 years: presence of important comorbid condition(s) will make stem cell transplant intolerable for the subject. Sponsor review of these comorbid conditions and approval is required before the first dose of study treatment
    c. For inclusion into the D-Rd cohort for relapsed or refractory disease:
    - Relapsed disease is defined as progression of disease after an initial response to previous treatment, more than 60 days after cessation of treatment
    - Refractory disease is defined as <25% reduction in M-protein or confirmed progressive disease (PD) by IMWG criteria during previous treatment or ≤60 days after cessation of treatment
    - Subject must have received at least 1 prior line of therapy for MM
    - 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.
    - Subjects must have progressed from or be refractory to their last line of treatment
    - Subject must have achieved a response (partial response [PR] or better based on investigator’s determination of response by the IMWG criteria) to at least 1 prior regimen in past
    5. Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0, 1, or 2
    6. Pretreatment clinical laboratory values during the Screening Phase (all cohorts):
    a) hemoglobin ≥7.5 g/dL (≥4.65 mmol/L) (without prior red blood cell [RBC] transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted);
    b) absolute neutrophil count ≥1.0 × 10^9/L (prior growth factor support is permitted);
    c) platelet count ≥50 × 10^9/L;
    d) aspartate aminotransferase ≤2.5 × upper limit of normal (ULN);
    e) alanine aminotransferase ≤2.5 × ULN;
    f) total bilirubin ≤2.0 × ULN; except in subjects with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤2.0 × ULN is required);
    g) estimated creatinine clearance ≥40 mL/min (D-VMP cohort) or ≥30 mL/min (for D-VRd and D-Rd cohorts)
    h) corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L)
    7. D-VRd and D-Rd cohorts: A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at screening, the first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing.
    D-VMP cohort: A woman of childbearing potential must have a negative serum or urine pregnancy test at screening within 14 days prior to dosing and as clinically indicated thereafter during the Treatment Phase
    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. Contraception must begin 4 weeks prior to dosing.
    Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 3 months after discontinuing study treatment (even after a successful vasectomy)
    9. During the study, and for 3 months after receiving the last dose of daratumumab, a woman must agree not to donate eggs (ova, oocytes) and men must agree not to donate sperm for the purposes of assisted reproduction
    10. Each subject (or their legally acceptable representative) must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
    Para participar en el estudio;
    1.Edad mínima de 18 años
    2.Mieloma múltiple diagnosticado según los criterios de diagnóstico del IMWG
    3.Enfermedad secretora mensurable, definida por cualquiera de los siguientes:
    •Concentración sérica de proteína M1,0 g/dl; o
    •Concentración urinaria de proteína M200 mg/24 horas; o
    •MM de cadenas ligeras, en los sujetos sin enfermedad mensurable en el suero o la orina: cadenas ligeras libres (CLL) de Ig en suero 10 mg/dl y cociente de CLL anormal.
    4.Cumple uno de los siguientes grupos de criterios:
    a.Para la inclusión en la cohorte D-VRd en caso de enfermedad recién diagnosticada: MM recién diagnosticado según los criterios del IMWG y elegible/previsto para tratamiento en dosis altas y trasplante autólogo de células madre (TACM).
    b.Para la inclusión en la cohorte D-VMP:MM recién diagnosticado y no tratado previamente según los criterios del IMWG, que no se considera candidato a quimioterapia en dosis altas con TACM debido a:
    •Edad 65 años, o en el caso de los sujetos menores de 65 años: la presencia de enfermedades concomitantes importantes hará que el trasplante de células madre sea intolerable para el sujeto. Es necesario que el promotor revise y apruebe estas enfermedades concomitantes antes de la administración de la primera dosis del tratamiento del estudio.
    c.Para la inclusión en la cohorte D-Rd en caso de enfermedad recidivante o resistente:
    La enfermedad recidivante se define como la progresión de la enfermedad después de una respuesta inicial al tratamiento previo, más de 60 días después de la suspensión del tratamiento la enfermedad
    resistente se define por una disminución <25 % de la proteína M o por la presencia de progresión de la enfermedad (PE) confirmada según los criterios del IMWG durante el tratamiento previo o 60 días después de la suspensión del tratamiento.
    El sujeto deberá haber recibido al menos una línea previa de tratamiento para el MM.
    Cada línea de tratamiento puede constar de uno o más fármacos y puede incluir una fase de inducción, un trasplante de células madre hematopoyéticas y un tratamiento de mantenimiento. La radioterapia,
    los bisfosfonatos o un único ciclo corto de corticosteroides no se consideran líneas de tratamiento previas. Los sujetos deberán haber presentado progresión o ser resistentes a su última línea de tratamiento.
    El sujeto deberá haber obtenido una respuesta como mínimo a un tratamiento previo.
    5.Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0, 1 o 2
    6.Valores analíticos previos al tratamiento durante la fase de selección:
    a)Hemoglobina 7,5 g/dl (mmol/l).
    b)Recuento absoluto de neutrófilos 1,0 × 109/l.
    c)Recuento de plaquetas 50 x 109/l.
    d)Aspartato aminotransferasa 2,5 veces el límite superior de la normalidad (LSN).
    e)Alanina aminotransferasa 2,5 veces el LSN.
    f)Bilirrubina total 2,0 veces el LSN; excepto en sujetos con bilirrubinemia congénita.
    g)Aclaramiento de creatinina estimado ml/min (cohorte D-VMP) o 30 ml/min (en las cohortes D-VRd y D-Rd);
    h)Calcemia corregida 14 mg/dl (3,5 mmol/l) o calcio ionizado libre 6,5 mg/dl ( 1,6 mmol/l)
    7.Cohortes D-VRd y D-Rd: Las mujeres en edad fértil deberán obtener un resultado negativo en dos pruebas de embarazo en suero u orina en la selección, la primera realizada entre 10 y 14 días antes de la
    administración y la segunda, en las 24 horas previas a la administración.
    Cohorte D-VMP: Las mujeres en edad fértil deberán obtener un resultado negativo en una prueba de embarazo en suero u orina en la selección, realizada 14 días antes de la administración, y posteriormente cada vez que esté indicado clínicamente durante la fase de tratamiento.
    8.Las mujeres en edad fértil deben comprometerse a abstenerse
    continuamente de mantener relaciones heterosexuales o a utilizar simultáneamente dos métodos anticonceptivos fiables. Esto incluye un método anticonceptivo muy eficaz y un método anticonceptivo eficaz adicional. La anticoncepción deberá iniciarse 4 semanas antes de la administración del tratamiento. La anticoncepción fiable está indicada incluso cuando existan antecedentes de infertilidad, a menos que se deban a una histerectomía.
    Los varones con capacidad reproductiva que mantengan relaciones sexuales con mujeres fértiles deberán utilizar siempre un preservativo de látex o sintético durante el estudio y durante 3 meses después de suspender el tratamiento del estudio.
    9.Durante el estudio y durante 3 meses después de recibir la última dosis de daratumumab, las mujeres deberán comprometerse a no donar óvulos y los varones a no donar semen con fines de reproducción
    asistida.
    10.Todos los sujetos deberán firmar un documento de consentimiento informado (DCI) que indique que entienden la finalidad del estudio y los procedimientos necesarios y que están dispuestos a participar en él. Los sujetos deberán ser capaces de respetar las prohibiciones y limitaciones especificadas en este protocolo y estar dispuestos a cumplirlas.
    E.4Principal exclusion criteria
    Any potential subject who meets any of the following criteria will be excluded from participating in the study:
    1. Prior or concurrent exposure to any of the following:
    • Daratumumab or other anti-CD38 therapies
    • Approved or investigational treatments for MM (including but not limited to conventional chemotherapies, immunomodulatory drugs [IMiDs], or proteasome inhibitors [PIs]) within 2 weeks of Cycle 1 Day 1
    • Maximum of 40 mg dexamethasone (or equivalent) daily for a maximum of 4 days up to 21 days prior to the 1st dose
    • Investigational drug (including investigational vaccines) or an invasive investigational medical device within 4 weeks or 5 half-lives (whichever is longer) before Cycle 1 Day 1, or is currently enrolled in another investigational study
    • Refractory to lenalidomide, (ie, subjects who had progression of disease while receiving lenalidomide therapy or within 60 days of ending lenalidomide therapy) or who are intolerant to lenalidomide (ie, discontinued due to any drug-related adverse event) while on lenalidomide treatment are not eligible for the lenalidomide-containing cohorts
    • ASCT within 12 weeks before the date of administration of study treatment, or allogeneic stem cell transplant (regardless of timing) for the D-Rd cohort
    • Received a cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within the 2-week period before the administration of study treatment
    2. History of malignancy (other than multiple myeloma) if all treatment of that malignancy was completed at least 2 years before registration and the patient has no evidence of disease (exceptions are squamous and basal cell carcinomas of the skin and 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)
    3. Exhibits clinical signs of meningeal involvement of MM
    4. Either of the following:
    • Chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) is <50% of predicted normal. Note that FEV1 testing also is required for subjects suspected of having chronic obstructive pulmonary disease (COPD) and subjects must be excluded if FEV1 is <50% of predicted normal
    • Moderate or severe persistent asthma, or a history of asthma within the last 2 years, or currently has uncontrolled asthma of any classification (Subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study)
    5. Any of the following:
    • Seropositive for human immunodeficiency virus;
    • Hepatitis B (hepatitis B surface antigen [HBsAg] positive, or antibodies to hepatitis B surface or core antigens [antiHBs or antiHBc] with hepatitis B virus [HBV]-DNA quantitation positive). Subjects who are positive for antiHBs or antiHBc must have a negative polymerase chain reaction (PCR) for HBV-DNA quantitation result at screening. Those who are PCR positive will be excluded
    6. Seropositive for hepatitis C (except in the setting of a sustained virologic response, defined as aviremia at least 12 weeks after completion of antiviral therapy)
    7. 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
    8. Clinically significant cardiac disease, including:
    • Myocardial infarction within 6 months before Cycle 1 Day 1, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV);
    • Uncontrolled cardiac arrhythmia (National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE, Version 4.03] Grade 2 or higher) or clinically significant electrocardiogram (ECG) abnormalities; or screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTc) >470 msec
    9. Allergies, hypersensitivity, or intolerance to any of the study drugs, hylauronidase, monoclonal antibodies, human proteins, or their excipients (refer to daratumumab Investigator’s Brochure [IB] and rHuPH20 IB), or known sensitivity to mammalian-derived products
    10. Plasma cell leukemia, Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or amyloidosis
    11. Unable to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments
    1.Exposición previa o concomitante a cualquiera de los siguientes:
    •Daratumumab u otros tratamientos anti-CD38.
    •Tratamientos para el MM aprobados o en investigación en las 2 semanas previas al día 1 del ciclo 1.
    •Máximo de 40 mg de dexametasona a diario durante un máximo de 4 días hasta 21 días antes de la primera dosis.
    •Fármaco en investigación o un producto sanitario en investigación invasivo en las 4 semanas o el período equivalente a 5 semividas antes del día 1 del ciclo 1, o participación actualmente en otro estudio de investigación.
    •No podrán ser incluidos en las cohortes que contengan lenalidomida los sujetos con resistencia a lenalidomida o intolerancia a lenalidomida durante el tratamiento con lenalidomida.
    •TACM en las 12 semanas previas a la fecha de administración del tratamiento del estudio o alotrasplante de células madre en la cohorte DRd.
    •Dosis acumulada de corticosteroides equivalente a 140 mg de prednisona en el período de 2 semanas previo a la administración del tratamiento del estudio.
    2.Antecedentes de neoplasias malignas si la totalidad del tratamiento de dicha neoplasia se completó como mínimo 2 años antes del registro y el sujeto no tiene indicios de enfermedad
    3.Presenta signos clínicos de afectación meníngea del MM.
    4.Cualquiera de los siguientes:
    •Enfermedad pulmonar obstructiva crónica con un volumen espiratorio máximo en el primer segundo (FEV1) <50 % del valor normal teórico. Obsérvese que también es necesario realizar pruebas del FEV1 en los sujetos con sospecha de enfermedad pulmonar obstructiva crónica (EPOC), que quedarán excluidos si el FEV1 es < 50% del valor normal teórico.
    •Asma persistente moderada o grave, o antecedentes de asma en los 2 años anteriores, o asma no controlada de cualquier tipo en la actualidad.
    5.Cualquiera de los siguientes:
    •Seropositividad del virus de la inmunodeficiencia humana.
    •Hepatitis B (antígeno de superficie del virus de la hepatitis B [HBsAg] positivo, o anticuerpos contra los antígenos de superficie o central del virus de la hepatitis B [antiHBs o antiHBc] con cuantificación del ADN del virus de la hepatitis B [VHB] positiva). Los sujetos positivos para antiHBs o antiHBc deberán tener un resultado negativo en la reacción en cadena de la polimerasa (PCR) para cuantificación del ADN del VHB en la selección. Se excluirá a los sujetos con resultados positivos en la PCR.
    6.Seropositividad del virus de la hepatitis C
    7.Trastorno o enfermedad médica o psiquiátrica concurrente que probablemente interfiera en los procedimientos o resultados del estudio o que, en opinión del investigador, supondría un riesgo para la
    participación en este estudio.
    8.Cardiopatía de importancia clínica, como:
    •Infarto de miocardio en los seis meses previos al día 1 del ciclo 1 o enfermedad/proceso inestable o no controlado relacionado con o que afecta a la función cardíaca.
    •Arritmia cardíaca no controlada o anomalías electrocardiográficas (ECG) clínicamente significativas; o ECG de 12 derivaciones en la selección que muestre un intervalo QT basal corregido con la fórmula de
    Fridericia (QTc) >470 ms.
    9.Alergias, hipersensibilidad o intolerancia a alguno de los fármacos del estudio, a la hialuronidasa, a los anticuerpos monoclonales, a las proteínas humanas o a sus excipientes o sensibilidad conocida a los
    productos derivados de mamíferos.
    10.Leucemia de células plasmáticas, macroglobulinemia de Waldenström o síndrome POEMS o amiloidosis.
    11.Incapacidad de cumplir el protocolo del estudio o el sujeto presenta alguna circunstancia por la que, en opinión del investigador, no sería conveniente su participación o podría impedir, limitar o generar
    confusión en las evaluaciones especificadas en el protocolo.
    12.Mujeres embarazadas, en período de lactancia o que tengan intención de quedarse embarazadas durante su participación en este estudio o en los 3 meses siguientes a la última dosis del fármaco del estudio.
    13.Varones que tengan previsto engendrar un hijo durante su participación en este estudio o en los 3 meses siguientes a la última dosis del fármaco del estudio.
    14.Cirugía mayor en las 2 semanas previas a la administración del tratamiento del estudio, o recuperación incompleta de la intervención quirúrgica, o programación de una intervención quirúrgica durante el período en el que se espera que el sujeto participe en el estudio o en las
    2 semanas siguientes a la administración de la última dosis del fármaco del estudio. La cifoplastia o la vertebroplastia no se consideran intervenciones de cirugía mayor. Nota: Podrán participar los sujetos que
    tengan intervenciones quirúrgicas programadas que se lleven a cabo con anestesia local. En caso de duda acerca de si una intervención se considera o no de cirugía mayor, el investigador deberá consultar con el representante del promotor correspondiente y resolver cualquier problema antes de incluir al paciente en el estudio.
    15.Plasmaféresis en los 28 días anteriores al día 1 del ciclo 1
    E.5 End points
    E.5.1Primary end point(s)
    1. Overall Response Rate (ORR), defined as the proportion of subjects with a partial response or better as defined by the International Myeloma Working Group (IMWG) response criteria (for D-VMP and D-Rd cohorts)
    2. Very Good Partial Response (VGPR) or better rate, defined as the proportion of subjects with a VGPR or better rate as defined by the IMWG response criteria (for D-VRd cohort)
    •TRG, definida como la proporción de sujetos que presentan una espuesta parcial o mejor según la definición de los criterios de respuesta del International Myeloma Working Group (IMWG) (cohortes
    D-VMP y D-Rd).
    •Tasa de RPMB o mejor, definida como la proporción de sujetos con una RPMB o una respuesta mejor, conforme a los criterios de respuesta del IMWG (cohorte D-VRd).
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. At the end of each treatment cycle in D-VMP and D-Rd cohorts
    2. At the end of each treatment cycle in D-VRd cohort
    1. Al final de cada ciclo de tratamiento en las cohortes D-VMP y D-Rd.
    2. Al final de cada ciclo de tratamiento en la cohorte D-VRd.
    E.5.2Secondary end point(s)
    1. Serum concentrations of daratumumab
    2. Rate of Infusion-related Reaction (IRRs)
    3. VGPR or better rate as defined by the IMWG response criteria (for D-VMP and D-Rd cohort), and ORR as defined by the IMWG response criteria (for D-VRd cohort)
    4. Complete Response (CR) or better rate, as defined by the IMWG response criteria
    5. Duration of response (DOR), defined as the time from the date of initial documented response (PR or better for D-VMP and D-Rd cohorts, or VGPR or better for D-VRd cohort) to the date of first documented evidence of progressive disease or death due to progressive disease (PD)
    6. Incidence of anti-drug antibodies against daratumumab or rHuPH20
    7. Minimal residual disease (MRD) negativity rate in the D-VMP and D-Rd cohorts
    1.Concentraciones séricas de daratumumab.
    2.Tasa de RRI.
    3.Tasa de RPMB o mejor según lo definido por los criterios de respuesta del IMWG (cohortes D-VMP y D-Rd) y TRG según lo definido por los criterios de respuesta del IMWG (cohorte D-VRd)
    4.Tasa de RC o mejor, definida conforme a los criterios de respuesta del IMWG.
    5.Duración de la respuesta (DR), definida como el tiempo transcurrido desde la fecha de la respuesta documentada inicial (RP o mejor en las cohortes D-VMP y D-Rd, o RPMB o mejor en la cohorte D-VRd) hasta la fecha del primer indicio documentado de progresión de la enfermedad o de la muerte por PE.
    6.Incidencia de anticuerpos contra daratumumab o rHuPH20.
    7.Tasa de negatividad de enfermedad residual mínima (ERM) en las cohortes D-VMP y D-Rd
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.Predose on Day(D)1 of Cycle(C)1,C3,C4,postdose on D4 ofC1,C4(D-VRd cohort);Predose on D1 ofC1,C2,C3,C6,C9,postdose on D4 ofC1,C2(D-VMP cohort);Predose on D1 ofC1,C3,C6,C9,C12,postdose on D4 ofC1,C3(D-Rd cohort) &at post-treatment Week 4&8 for all cohorts
    2.Throughout study at the time of daratumumab administration in all cohorts
    3&4.At screening and when CR is suspected or maintained throughout treatment phase&30-days post-treatment
    5.At the date of first documented evidence of progressive disease (PD) or death due to PD
    6.Predose on D1 ofC1,C4(D-VRd);Predose on D1 ofC1,C3,C6,C9(D-VMP);Predose on D1 ofC1,C3,C6,C9,C12(D-Rd)&at post-treatment Week 4&8 for all cohorts
    7.At screening, at the time of suspected CR,and in patients who maintain CR, at 12,18,24 months(M)&every 12M thereafter
    1.Predosis en dia (D)1 de Ciclo (C)1,C3,C4, postdosis en D4 de C1,C4(DVRd); predosis en D1 de C1,C2,C3,C6,C9, postdosis en D4 de C1,C2(DVMP); Predosis en D1 de C1,C3,C6,C9,C12,postdosis en D4 de C1,C3(DRd) y post-tratamiento semanas 4 y 8 para todas las cohortes.
    2.A lo largo del estudio en la administración de daratumumab.
    3/4. En selección y sospecha RC o se mantiene a lo largo de la fase del tratamiento y 30 dias postratamiento.
    5. En la primera evidencia de enfermedad progresiva o muerte debido a progresión.
    6.Predosis en D1 de C1,C4(D-VRd);Predosis en D1 de C1,C3,C6,C9(DVMP); Predosis en D1 de C1,C3,C6,C9,C12(D-Rd) y post-tratamiento de semanas 4 y 8.
    7. Selección y sospecha de RC, en pacientes que mantienen RC y a los 12, 18, 24 meses y cada 12 meses a partir de ahí
    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
    Inmunogenicidad y analisis de 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.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 trial3
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA27
    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
    Brazil
    Czech Republic
    France
    Germany
    Israel
    Japan
    Spain
    United Kingdom
    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 study is considered completed approximately 18 months after the last subject is enrolled or when the sponsor decides to stop the study.
    El estudio se considerar completo aproximadamente 18 meses despues de la inclusion del ultimo paciente o cuando el promotor decida parar el estudio
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months4
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state11
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 92
    F.4.2.2In the whole clinical trial 180
    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)
    Patients who have completed participation in the trial will be eligible to receive further treatment off protocol as per local standard of care
    Los pacientes que hayan completado la participación en el ensayo serán elegibles para recibir tratamiento adicional fuera del protocolo según el estándar de cuidado local.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-05-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-26
    P. End of Trial
    P.End of Trial StatusOngoing
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