Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   40650   clinical trials with a EudraCT protocol, of which   6634   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2019-002161-36
    Sponsor's Protocol Code Number:OP-108
    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:2020-07-20
    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 number2019-002161-36
    A.3Full title of the trial
    A Randomized, Controlled, Open-Label Phase 3 Study of Melflufen in combination with Daratumumab Compared with Daratumumab in Patients with Relapsed or Relapsed-Refractory Multiple Myeloma
    Ensayo en fase III, aleatorizado, comparativo y abierto, en el que se compara Melflufen en combinación con Daratumumab con Daratumumab en monoterapia en pacientes con Mieloma múltiple en recidiva o recidivante y resistente al tratamiento
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study comparing treatment with Melflufen in combination with Daratumumab and daratumumab treatment only in patients with Relapsed or Relapsed-Refractory Multiple Myeloma
    Ensayo en el que se compara el tratamiento con Melflufen en combinación con Daratumumab con Daratumumab solo en pacientes con Mieloma múltiple en recidiva o recidivante y resistente al tratamiento
    A.3.2Name or abbreviated title of the trial where available
    LIGHTHOUSE
    A.4.1Sponsor's protocol code numberOP-108
    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 SponsorOncopeptides AB
    B.1.3.4CountrySweden
    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 supportOncopeptides AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOncopeptides AB
    B.5.2Functional name of contact pointClinical Trials Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressVästra Trädgårdsgatan 15
    B.5.3.2Town/ cityStockholm
    B.5.3.3Post codeSE-111 53
    B.5.3.4CountrySweden
    B.5.6E-mailtrials@oncopeptides.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 numberEMA/OD/293/14
    D.3 Description of the IMP
    D.3.1Product nameMelflufen
    D.3.4Pharmaceutical form Powder 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 INNmelphalan flufenamide hydrochloride
    D.3.9.1CAS number 380449-54-7
    D.3.9.4EV Substance CodeSUB22033
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Dexamethason 4 mg, JENAPHARM
    D.2.1.1.2Name of the Marketing Authorisation holdermibe GmbH Arzneimittel
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDexamethasone
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDEXAMETHASONE
    D.3.9.1CAS number 50-02-2
    D.3.9.4EV Substance CodeSUB07017MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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 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 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.3.11 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 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
    Patients with relapsed or relapsed-refractory multiple myeloma.
    Pacientes con mieloma múltiple en recidiva o recidivante y resistente al tratamiento.
    E.1.1.1Medical condition in easily understood language
    Patients with Multiple Myeloma.
    Pacientes con mieloma multiple.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level HLT
    E.1.2Classification code 10028229
    E.1.2Term Multiple myelomas
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To show superiority of progression free-survival (PFS) in patients treated with melflufen and dexamethasone in combination with daratumumab compared to daratumumab alone.
    Demostrar la superioridad desde el punto de vista de la supervivencia libre de progresión (SLP) en pacientes que reciben melflufen y dexametasona en combinación con daratumumab, en comparación con la administración de daratumumab en monoterapia.
    E.2.2Secondary objectives of the trial
    - to assess the safety and tolerability of melflufen and dexamethasone in combination with daratumumab compared to daratumumab alone
    - to evaluate and compare efficacy in patients treated with melflufen and dexamethasone in combination with daratumumab compared to daratumumab alone:
    • Overall response rate (ORR)
    • Duration of response (DOR)
    • Best response during the study
    • Clinical benefit rate (CBR)
    • Duration of Clinical Benefit (DOCB)
    • Time to response (TTR)
    • Time to progression (TTP)
    • Time to next treatment (TTNT)
    • Overall survival (OS)
    - to assess and compare functional status and wellbeing based on patient reported outcome (PRO) assessments for patients treated with melflufen and dexamethasone in combination with daratumumab compared to daratumumab alone.
    - evaluar la seguridad y la tolerabilidad de melflufen y dexametasona en combinación con daratumumab, en comparación con daratumumab en monoterapia.
    - evaluar y comparar la eficacia en pacientes tratados con melflufen en combinación con dexametasona y daratumumab, o con daratumumab:
    • Tasa global de respuesta (TGR)
    • Duración de la respuesta (DdR)
    • Mejor respuesta durante el estudio
    • Tasa de beneficio clínico (TBC)
    • Duración del beneficio clínico (DBC)
    • Tiempo transcurrido hasta la respuesta (THR)
    • Tiempo transcurrido hasta la progresión (THP)
    • Tiempo transcurrido hasta el tratamiento siguiente (THTS)
    • Supervivencia global (SG)
    - evaluar y comparar el estado funcional y el bienestar de acuerdo con los resultados percibidos por el paciente (RPP) en los pacientes tratados con melflufen y dexametasona en combinación con daratumumab, en comparación con daratumumab en monoterapia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female, age 18 years or older;
    2. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol;
    3. A prior diagnosis of multiple myeloma with documented disease progression in need of treatment at time of screening;
    4. Double refractory to an IMiD and a PI (regardless of the number of prior lines of therapy), or have received at least 3 prior lines of therapy including an IMiD and a PI (the definition of refractory includes intolerance to an IMiD/PI after at least two 28-day cycles of therapy);
    5. Measurable disease defined as any of the following:
    • Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP)
    • ≥ 200 mg/24hr of monoclonal protein in the 24-hour urine collection by electrophoresis (UPEP)
    • Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain (FLC) ratio
    6. Life expectancy of ≥ 6 months;
    7. ECOG performance status ≤ 2. (Patients with lower performance status based solely on bone pain secondary to multiple myeloma may be eligible following consultation and approval of the Medical Monitor);
    8. Ability to understand the purpose and risks of the study, ability to participate in all the procedures required by the protocol and provide signed and dated informed consent;
    9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (Q-TcF) interval of ≤ 470 msec;
    10. Adequate organ function with the following laboratory results during screening (within 21 days) and immediately before study treatment administration on Cycle 1 Day 1:
    • Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (Growth factors cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of study treatment)
    37
    • Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (without transfusions during the 10 days prior to initiation of therapy)
    • Hemoglobin ≥ 8.0 g/dL (RBC transfusions are permitted)
    • Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), except patients diagnosed with Gilbert’s syndrome that have been reviewed and approved by the Medical Monitor
    • AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN
    • Renal function: Estimated creatinine clearance by Cockcroft- Gault formula of ≥ 45 mL/min
    11. Must have or be willing to have an acceptable central catheter. (Port A cath, peripherally inserted central catheter (PICC) line, or central venous catheter);
    12. a) Male patients: Male patient that agrees to use contraception during the treatment period and for at least 3 months after the last dose of study treatment and refrain from donating sperm during this period.
    b) Female patients: A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
    i. Not a woman of childbearing potential (WOCBP)
    or
    ii. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 3 months after the last dose of study treatment
    1. Pacientes de ambos sexos, de ≥ 18 años de edad;
    2. Ser capaz de otorgar (firmar) el documento de consentimiento informado, lo que incluye cumplir los requisitos y las limitaciones que se recogen en el documento de consentimiento informado (CI) y en este protocolo;
    3. Diagnóstico previo de mieloma múltiple con progresión documentada de la enfermedad que precise tratamiento en el momento de la selección;
    4. Paciente doble refractario a un fármaco inmunomodulador (IMiD) y a un inhibidor del proteasoma (PI) (independientemente del número de líneas previas de tratamiento), o haber recibido al menos 3 líneas previas de tratamiento, incluido un IMiD y un PI (el término refractario incluye intolerancia a un IMiD/PI transcurridos al menos 2 ciclos de 28 días de tratamiento);
    5. Enfermedad medible, definida por cualquiera de los criterios siguientes:
    • Concentración sérica de proteínas monoclonales ≥ 0,5 g/dl, de acuerdo con los resultados de una electroforesis de proteínas séricas (SPEP).
    • ≥ 200 mg/24 h de proteínas monoclonales en una muestra de orina de 24 horas, de acuerdo con los resultados de una electroforesis (UPEP).
    • Concentración de cadenas ligeras libres en suero (SFLC) ≥ 10 mg/dl Y un ratio anómalo entre las cadenas ligeras libres (CLL) κ y λ.
    6. Esperanza de vida ≥ 6 meses;
    7. Categoría funcional ECOG ≤ 2 (los pacientes con una categoría funcional más baja debido únicamente a la presencia de dolor óseo asociado con el mieloma múltiple podrán incluirse tras consultarlo con el monitor médico si este lo aprueba);
    8. Capacidad para comprender el objetivo y los riesgos del estudio; capacidad para participar en todos los procedimientos requeridos por el protocolo y para proporcionar el documento informado firmado y fechado;
    9. Valor ≤ 470 milisegundos en el intervalo QT de un electrocardiograma (ECG) de 12 derivaciones calculado de acuerdo con la fórmula de Fridericia (QTcF);
    10. Función orgánica aceptable, con los siguientes resultados analíticos durante la selección (en el transcurso de los 21 días) e inmediatamente antes de la administración del tratamiento del estudio el día 1 del ciclo 1:
    • Recuento absoluto de neutrófilos (ANC) ≥ 1000 células/mm3 (1,0 x 109/l) (no pueden administrarse factores de crecimiento en el transcurso de los 10 días [14 días en el caso de pegfilgrastim] anteriores al inicio del tratamiento del estudio)
    • Número de plaquetas ≥ 75 000 células/mm3 (75 x 109/l) (sin administración de transfusiones en el transcurso de los 10 días anteriores al inicio del tratamiento)
    • Concentración de hemoglobina ≥ 8,0 g/dl (se permite la administración de eritrocitos [RBC])
    • Concentración de bilirrubina total ≤ 1,5 veces el límite superior de la normalidad (LSN), salvo para los pacientes con síndrome de Gilbert, cuyo caso haya sido revisado y aprobado por el monitor médico.
    • Concentración de aspartato transaminasa/aspartato aminotransferasa/glutámico ([AST], transaminasa glutámica oxalacética sérica [SGOT]) y concentración de alanina transaminasa/alanina aminotransferasa ([ALT], transaminasa glutámico pirúvica sérica [SGPT]) ≤ 3,0 veces el LSN
    • Función renal: aclaramiento de creatinina estimado ≥ 45 ml/min de acuerdo con la fórmula de Cockcroft-Gault.
    11. Debe tener o estar dispuesto a que se le ponga un catéter central aceptable (un dispositivo "port A cath", un catéter central insertado periféricamente [PICC] o un catéter venoso central);
    12. a) Pacientes varones: deben estar de acuerdo en utilizar métodos anticonceptivos de conformidad con el protocolo, durante el período de tratamiento y al menos durante los 3 meses posteriores a la última dosis del tratamiento del estudio. Asimismo, no podrán donar esperma durante este período.
    b) Pacientes mujeres: podrán participar si no están embarazadas, no están en período de lactancia y cumplen al menos una de las condiciones siguientes:
    I. Que no puedan quedarse embarazadas o
    ii. Si pueden quedarse embarazadas, que acepten utilizar las medidas anticonceptivas durante el período de tratamiento y al menos durante los 3 meses posteriores a la última dosis del tratamiento del estudio.
    E.4Principal exclusion criteria
    1. Primary refractory disease (i.e. never responded with at least MR to any prior therapy);
    2. If treated with daratumumab or another anti-CD38 antibody: Refractory to treatment or failure to achieve at least PR as best response;
    3. Prior treatment with CD38 CAR-T cell therapy or CD38/CD3 bispecific antibodies;
    4. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) less than 50% of predicted normal;
    5. Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification;
    6. Evidence of mucosal and/or internal bleeding or platelet transfusion refractory (platelet count fails to increase by > 10,000 cells/mm3 after a transfusion of an appropriate dose of platelets);
    7. Any medical conditions that, in the Investigator’s opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study. Examples of such conditions are: a significant history of cardiovascular disease (e.g., heart failure class III or IV according to New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, significant cardiac conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months);
    8. Known active infection that is uncontrolled or has required intravenous systemic therapy within 14 days of randomization. Patients that has required oral anti-infective treatment within 14 days of randomization should be discussed with the Medical Monitor;
    9. Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance;
    10. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation;
    11. Human immunodeficiency virus or active hepatitis C viral infection, either known or if detected during screening;
    12. Hepatitis B: both active (defined as HBsAg+) or non-active hepatitis B (defined as HBsAg-, Anti-HBs+, Anti-HBc+):
    • Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-).
    13. Concurrent known or suspected amyloidosis or plasma cell leukemia;
    14. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes);
    15. Known CNS or meningeal involvement of myeloma:
    16. Any of the following treatments, within the specified timeframe:
    • Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy.
    • The use of live vaccines within 30 days before initiation of therapy.
    • IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy.
    • Other investigational therapies and mAb within 4 weeks of initiation of therapy.
    • Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to initiation of therapy;
    17. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (alopecia any grade and/or neuropathy Grade 1 without pain are permitted);
    18. Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation of therapy;
    19. Prior allogeneic stem cell transplantation with active graft-versus-host-disease;
    20. Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy);
    21. Known intolerance to the required dose and schedule of steroid therapy, as determined by the investigator;
    22. Known hypersensitivity to any of the agents in this study including hyalonuridase
    23. Prior treatment with melflufen
    1. Enfermedad con resistencia primaria (esto es, que nunca haya presentado al menos una RM a ningún tratamiento anterior);
    2. En caso de haber recibido Daratumumab u otro anticuerpo anti-CD38: resistencia al tratamiento o incapacidad de alcanzar al menos una mejor respuesta de RP;
    3. Haber recibido tratamiento con linfocitos T con CAR frente al CD38 o anticuerpos biespecíficos frente a CD38/CD3;
    4. Presencia de EPOC, con un FEV1 inferior al 50 % del volumen normal previsto;
    5. Asma moderado o grave y persistente en el transcurso de los 2 últimos años, o presentar en la actualidad asma sin controlar de cualquier grado (clasificación);
    6. Signos de hemorragia interna y/o de la mucosa o resistencia a las transfusiones de plaquetas (la cifra de plaquetas no aumenta en > 10 000 células/mm3 tras una transfusión con una dosis de plaquetas suficiente);
    7. Presencia de cualquier enfermedad que, en opinión del investigador, supondría un riesgo excesivo para el paciente o influiría negativamente en su participación en este estudio. Algunos ejemplos son: antecedentes importantes de enfermedad cardiovascular (insuficiencia cardíaca de clase III o IV de acuerdo con los criterios de la NYHA, angioplastia o endoprótesis vascular cardíaca, infarto de miocardio, angina de pecho inestable, alteraciones importantes en el sistema de conducción cardíaca, hipertensión sin controlar, acontecimiento tromboembólico de grado ≥ 3 en los últimos 6 meses);
    8. Presencia de infección activa sin controlar o que haya precisado la administración de tratamiento sistémico intravenoso en el transcurso de los 14 días anteriores a la aleatorización. Los casos de los pacientes que hayan precisado tratamiento antinfeccioso por vía oral en el transcurso de los 14 días anteriores a la aleatorización se comentarán con el monitor médico;
    9. Presencia de otra neoplasia maligna diagnosticada o que haya precisado tratamiento en el transcurso de los 3 últimos años, salvo los casos de carcinoma basocelular tratado adecuadamente, carcinoma escamoso de la piel, cáncer in situ del cuello uterino o de mama, o cáncer de próstata de bajo o muy bajo riesgo en seguimiento activo;
    10. Enfermedades psiquiátricas graves, alcoholismo activo o drogadicción que puedan dificultar o interferir en el cumplimiento o en la evaluación de seguimiento;
    11. Infección por el VIH o infección activa por el virus de la hepatitis C, tanto ya conocida como si se detecta durante la selección;
    12. Hepatitis B: tanto activa (HBsAg+) como inactiva (HBsAg-, Anti-HBs+, Anti-HBc+):
    •Se permite que los pacientes que hayan recibido vacuna contra la hepatitis B participen en el estudio.
    13. Presencia o sospecha de amiloidosis o leucemia de células plasmáticas;
    14. Presentar síndrome de POEMS (discrasia de células plasmáticas con polineuropatía, organomegalia, endocrinopatía, proteínas monoclonales y cambios cutáneos);
    15. Afectación meníngea o del SNC por el mieloma;
    16. Haber recibido alguno de los tratamientos siguientes en los períodos especificados:
    •Tratamientos citotóxicos previos para el mieloma múltiple (incluidos fármacos en investigación) en el transcurso de las 3 semanas anteriores al tratamiento (o de las 6 semanas anteriores, en el caso de las nitrosoureas).
    •Vacunas vivas en el transcurso de los 30 días anteriores al inicio del tratamiento.
    •Uso de IMiDs, PIs y/o corticosteroides en el transcurso de las 2 semanas anteriores al inicio del tratamiento. Otros tratamientos y anticuerpos monoclonales (mAb) en fase de investigación en el transcurso de las 4 semanas anteriores al inicio del tratamiento.
    •Se permite la administración de prednisona oral en una dosis de hasta 10 mg como máximo 1 v/d o su equivalente para tratar los síntomas de las enfermedades concomitantes, pero la dosis debe haberse mantenido estable al menos durante los 7 días anteriores al inicio del tratamiento;
    17. Presencia de efectos secundarios residuales de un tratamiento previo de grado > 1 antes del inicio del tratamiento (se permite la presencia de alopecia de cualquier grado y/o de neuropatía de grado 1 sin la presencia de dolor);
    18. Haber recibido un trasplante de células madres (tanto autotrasplante como alotrasplante) en el transcurso de los 6 meses anteriores al inicio del tratamiento;
    19. Trasplante alogénico previo de células madre con enfermedad activa de injerto contra huésped;
    20. Haberse sometido a una intervención de cirugía mayor o haber recibido radioterapia en el transcurso de las 4 semanas anteriores al inicio del tratamiento (no se incluye la administración de una tanda limitada de radioterapia para el tratamiento del dolor óseo en el transcurso de los 7 días anteriores al inicio del tratamiento);
    21. Presentar intolerancia a la dosis y la pauta posológica requeridas de esteroides, según el criterio del investigador;
    22. Presentar hipersensibilidad a cualquiera de los fármacos del estudio, incluida la hialonuridasa;
    23. Tratamiento previo con melflufen.
    E.5 End points
    E.5.1Primary end point(s)
    PFS (time from the date of randomization to the date of first documentation of confirmed progressive disease (PD) or death due to any cause).
    SLP (tiempo desde la fecha de la aleatorización hasta la fecha en la que se documente por primera vez la progresión confirmada de la enfermedad [PE] o la fecha de fallecimiento por cualquier causa)
    E.5.1.1Timepoint(s) of evaluation of this end point
    During the course of the study.
    Durante el studio.
    E.5.2Secondary end point(s)
    - frequency and Grade of treatment emergent adverse events (TEAE)
    - ORR (proportion of patients who achieve a best confirmed response of stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR))
    - DOR (time from the first evidence of confirmed assessment of sCR, CR, VGPR or PR to first confirmed disease progression, or death due to any cause. DOR is defined only for patients with a confirmed PR or better)
    - Best Response (proportion of patients with sCR, CR, VGPR, PR, Minimal Response (MR), Stable Disease (SD), PD or non-evaluable)
    - CBR (the proportion of patients who achieve a best confirmed response of sCR, CR, VGPR, PR or MR)
    - DOCB (time from first evidence of confirmed assessment of sCR, CR, VGPR, PR, or MR to first confirmed disease progression, or to death due to any cause.) DOCB is defined only for patients with a confirmed MR or better
    - TTR (time from randomization to the date of the first documented confirmed response in a patient that has responded with ≥PR)
    - TTP (time from the date of randomization to the date of the first documented confirmed PD)
    - TTNT (time from randomization to the date of next anti-myeloma treatment or until death)
    - OS (time from date of randomization to death due to any cause)
    - Value and changes from baseline in each scale of the EORTC QLQ-C30, each dimension of the EQ-5D-3L, and the Visual Analogue Scale (VAS) of the EQ-5D-3L.
    - Frecuencia y grado de los acontecimientos adversos aparecidos durante el tratamiento (AA).
    - TGR (proporción de pacientes que alcancen una mejor respuesta confirmada de respuesta completa estricta [RCe], respuesta completa [RC], respuesta parcial muy buena [RPMB] o respuesta parcial [RP]).
    - DdR (tiempo transcurrido desde la fecha en la que se observen por primera vez indicios de RCe, RC, RPMB o RP confirmadas hasta la fecha en la que se determine por primera vez la progresión confirmada de la enfermedad, o el paciente fallezca por cualquier causa. La DdR se define solo para los pacientes con una RP o una mejor respuesta confirmadas).
    - Mejor respuesta (proporción de pacientes con RCe, RC, RPMB, RP, respuesta mínima [RM], enfermedad estable [EE], PE o respuesta no evaluable).
    - TBC (proporción de pacientes que alcancen una mejor respuesta confirmada de RCe, RC, RPMB, RP o RM).
    - DBC (tiempo transcurrido desde la fecha en la que se observen por primera vez indicios de RCe, RC, RPMB, RP o RM hasta la fecha en la que se determine por primera vez la progresión confirmada de la enfermedad, o el paciente fallezca por cualquier causa). La DBC se define solo para los pacientes con una RM o una mejor respuesta confirmadas.
    - THR (tiempo transcurrido desde la fecha de la aleatorización hasta la fecha en la que se documente por primera vez la respuesta confirmada en un paciente que anteriormente haya presentado una respuesta ≥RP).
    - THP (tiempo desde la fecha de la aleatorización hasta la fecha en la que se documente por primera vez la progresión confirmada de la enfermedad).
    - THTS (tiempo transcurrido desde la fecha de la aleatorización hasta el siguiente tratamiento contra el mieloma o hasta la muerte).
    - SG (tiempo transcurrido desde la fecha de la aleatorización hasta la fecha de la muerte por cualquier causa).
    - Valores y cambios respecto al período inicial en cada escala del cuestionario EORTC QLQ-C30, cada dimensión del cuestionario EQ-5D-3L y en la escala visual analógica (EVA) del cuestionario EQ-5D-3L.
    E.5.2.1Timepoint(s) of evaluation of this end point
    During the course of the study.
    Durante el studio.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA47
    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
    Bulgaria
    Czech Republic
    Finland
    Georgia
    Germany
    Greece
    Hungary
    Norway
    Poland
    Russian Federation
    Serbia
    Slovakia
    Spain
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LPLV
    última visita del último paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months2
    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: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 96
    F.4.2.2In the whole clinical trial 170
    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)
    Standard of Care.
    Estándar de cuidado.
    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 Decision2020-07-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-17
    P. End of Trial
    P.End of Trial StatusOngoing
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2021 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA