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    Summary
    EudraCT Number:2019-003047-30
    Sponsor's Protocol Code Number:209664
    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:2019-11-06
    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 number2019-003047-30
    A.3Full title of the trial
    A Phase 3, Randomized, Open-Label Study of Belantamab Mafodotin Administered in Combination with Bortezomib, Lenalidomide and Dexamethasone Versus Bortezomib, Lenalidomide and Dexamethasone Alone in Participants with Newly Diagnosed Multiple Myeloma who are Ineligible for Autologous Stem Cell Transplantation
    Estudio de fase 3, aleatorizado y abierto con Belantamab Mafodotin administrado en combinación con Bortezomib, Lenalidomida y Dexametasona frente a Bortezomib, Lenalidomida y Dexametasona, en pacientes con mieloma múltiple recién diagnosticado que no son elegibles para trasplante autólogo de células madre.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial of belantamab mafodotin plus standard of care treatments compared with standard of care treatments alone for patients with newly diagnosed multiple myeloma not eligible for transplant
    Estudios con belantamab mafodotin en combinación con los tratamientos estándar frente a los tratamientos estándar, en pacientes con mieloma múltiple recién diagnosticado que no son elegibles para trasplante
    A.3.2Name or abbreviated title of the trial where available
    Phase 3 Study of Belantamab Mafodotin Plus VRd vs. VRd in Transplant Ineligible Newly Diagnosed MM
    A.4.1Sponsor's protocol code number209664
    A.5.4Other Identifiers
    Name:DREAMMNumber:9
    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 SponsorGlaxoSmithKline, S.A.
    B.1.3.4CountrySpain
    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 supportGlaxoSmithKline, S.A.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline
    B.5.2Functional name of contact pointCentro de Información
    B.5.3 Address:
    B.5.3.1Street AddressC/Severo Ochoa, 2 (P.T.M.)
    B.5.3.2Town/ cityTres Cantos (Madrid)
    B.5.3.3Post code28760
    B.5.3.4CountrySpain
    B.5.4Telephone number+34 902202700
    B.5.5Fax number+34 918070479
    B.5.6E-mailes-ci@gsk.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/3/17/1925
    D.3 Description of the IMP
    D.3.1Product namebelantamab mafodotin
    D.3.2Product code GSK2857916
    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 INNbelantamab mafodotin
    D.3.9.2Current sponsor codeGSK2857916
    D.3.9.4EV Substance CodeSUB130430
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) 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 Yes
    D.3.11.13.1Other medicinal product typeBelantamab mafodotin is a humanized afucosylated, maleimidocaproyl monomethyl auristatin phenylalanine (mcMMAF) conjugated IgG1 antibody
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namebortezomib
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBORTEZOMIB
    D.3.9.1CAS number 179324-69-7
    D.3.9.4EV Substance CodeSUB20020
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLenalidomide
    D.3.2Product code Lenalidomide
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.2Product code Dexamethasone
    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 N/A
    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 number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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
    Multiple Myeloma
    mieloma múltiple
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    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
    Part 1
    Determine safety and tolerability of belantamab mafodotin in combination with VRd to establish a recommended dose for participants with transplant ineligible (TI) newly diagnosed multiple myeloma (NDMM)

    Part 2
    To compare the efficacy of belantamab mafodotin in combination with VRd with that of VRd alone in participants with TI NDMM
    Parte 1
    Determinar la seguridad y la tolerabilidad de belantamab mafodotin en combinación con VRd para establecer una dosis recomendada para los participantes con MMRD no elegibles para trasplante.

    Parte 2
    Comparar la eficacia de belantamab mafodotin en combinación con VRd con la de VRd en monoterapia en participantes con MMRD no elegibles para trasplante.
    E.2.2Secondary objectives of the trial
    Part 1
    -Effect of combining belantamab mafodotin with VRd in relation to lenalidomide & bortezomib relative dose intensity (RDI)
    -To evaluate the pharmacokinetics profile of belantamab mafodotin, when administered in combination with VRd
    -To assess ADAs against belantamab mafodotin

    Part 2
    -To assess the efficacy of belantamab mafodotin in combination with VRd with that of VRd alone in participants with TI NDMM
    -To evaluate the safety and tolerability of belantamab mafodotin when administered in combination with VRd
    -To further characterize the exposure to belantamab mafodotin when administered in combination with VRd
    -To assess ADAs against belantamab mafodotin
    -To evaluate and compare changes in HRQOL
    -To evaluate the safety and tolerability of belantamab mafodotin based on self-reported symptomatic adverse effects when administered in combination with VRd
    -To evaluate self-reported ocular symptomatic adverse effects of belantamab mafodotin in combination with VRd
    Parte 1
    -Efecto de la combinación de belantamab mafodotin con VRd en relación con la intensidad de dosis relativa (IDR) de lenalidomida y bortezomib.
    -Evaluar el perfil farmacocinético de belantamab mafodotin cuando se administra en combinación con VRd.
    -Evaluar la aparición de anticuerpos contra el fármaco (ACF) dirigidos contra belantamab mafodotin.

    Parte 2
    Evaluar la eficacia de belantamab mafodotin en combinación con VRd frente a la de VRd en monoterapia en participantes con MMRD no elegibles para trasplante.
    Evaluar la seguridad y la tolerabilidad de belantamab mafodotin cuando se administra en combinación con VRd.
    Definir con mayor precisión la exposición a belantamab mafodotin cuando se administra en combinación con VRd.
    Evaluar la aparición de ACF dirigidos contra belantamab mafodotin.
    Evaluar y comparar las variaciones de la calidad de vida relacionada con la salud (CVRS).
    (Consultar el Protocolo para una lista de todos los Objetivos Secundarios de la Parte 2)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Age
    1. Participant must be over 18 years of age.

    Type of Participant and Disease Characteristics
    2. Diagnosis of multiple myeloma with a requirement for treatment as documented per International Myeloma Working Group (IMWG) criteria.
    Must have at least ONE aspect of measurable disease, defined as one of the following:
    a. Urine M-protein excretion ≥200 mg/24 hrs (≥0.2g/24 hrs), or
    b. Serum M-protein concentration ≥0.5 g/dL (≥5.0 g/L), or
    c. Serum free light chain (FLC) assay: involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum free light chain ratio (<0.26 or >1.65).
    3. Not a candidate for high-dose chemotherapy with ASCT due to presence of frailty and/or significant comorbid condition(s), such as cardiac, pulmonary or other major organ dysfunction that are likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation, as judged by the investigator.
    4. ECOG status of 0-2
    5. Adequate organ system functions as defined by the laboratory assessments listed in the protocol.

    Sex
    6. Male and/or female
    a. Female Participants:
    A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
    - Is not a woman of childbearing potential (WOCBP)
    OR
    -WOCBP participants must use a contraceptive method that is highly effective as detailed in the protocol.
    b. Male Participants:
    Male participants are eligible to participate if they agree to the following
    - Refrain from donating sperm
    PLUS either:
    - Be abstinent from heterosexual intercourse
    OR
    - Must agree to use contraception/barrier as detailed in the protocol.

    Informed Consent
    7. Capable of giving signed informed consent.
    Edad
    1.El participante deberá ser mayor de 18 años.

    Tipo de participante y características de la enfermedad
    2. Diagnóstico de mieloma múltiple con necesidad de tratamiento documentado según los criterios del Grupo de trabajo internacional sobre el mieloma (IMWG).
    Presencia de al menos UN aspecto de enfermedad medible, definido como uno de los siguientes:
    a. Excreción urinaria de proteína M ≥200 mg/24 h (≥0,2 g/24 h).
    b. Concentración sérica de proteína M ≥0,5 g/dl (≥5,0 g/l).
    c. Análisis de cadenas ligeras libres (CLL) en suero: concentración de CLL afectadas ≥10 mg/dl (≥100 mg/l) y cociente anormal de cadenas ligeras libres en suero (<0,26 o >1,65).
    3. No son candidatos a quimioterapia en dosis altas con TACM porque presentan un estado delicado o enfermedades concomitantes importantes, como disfunción cardíaca, pulmonar o de otros órganos importantes, que probablemente repercutan negativamente en la tolerabilidad de la quimioterapia en dosis altas con trasplante de células madre, según el criterio del investigador.
    4. Estado funcional del ECOG de 0-2.
    5. Función orgánica adecuada, definida por las evaluaciones analíticas que se presentan en el Protocolo.

    Sexo
    6. Varones y mujeres
    a. Mujeres participantes:
    Las mujeres podrán participar si no están embarazadas ni en periodo de lactancia y si se cumple al menos una de las condiciones siguientes:
    -No es una mujer en edad fértil (MEF)
    O
    -Las MEF deberán utilizar un método anticonceptivo muy eficaz (con un índice de fallos < 1 % anual) durante otros 7 meses.
    b.Varones participantes:
    Los varones podrán participar si se comprometen a lo siguiente:
    -Abstenerse de donar semen.
    MÁS:
    -Abstinencia de relaciones heterosexuales.
    O
    -Compromiso de utilizar métodos anticonceptivos/de barrera tal como se detalla en el Protocolo.

    Consentimiento informado
    7. Capacidad de otorgar el consentimiento informado firmado.
    E.4Principal exclusion criteria
    Type of Participant and Disease Characteristics
    1. Smoldering multiple myeloma (SMM).
    2. Prior systemic therapy for multiple myeloma, or SMM. An emergency course of steroids (defined as no greater than 40 mg of dexamethasone, or equivalent per day for a maximum of 4 days (that is, a total of 160 mg) is permitted.
    3. Patient is eligible for high dose chemotherapy with ASCT.

    Medical Conditions
    4. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI-CTCAE Version 5.
    5. Major surgery within 4 weeks prior to the first dose of study drug.
    6. Presence of active renal condition (infection, requirement for dialysis or any other significant condition that could affect participant’s safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil criteria given in the protocol.
    7. Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures.
    8. Evidence of active mucosal or internal bleeding uncontrolled by local therapy and not explained by reversible coagulopathy.
    9. Current active liver or biliary disease (except for Gilbert’s syndrome or asymptomatic gallstones, or otherwise stable chronic liver disease as per the Investigator’s assessment).
    10. Participants with previous or concurrent malignancies other than multiple myeloma are excluded. Exceptions are surgically treated cervical carcinoma in situ, or any other malignancy that has been considered medically stable for at least 2 years. The participant must not be receiving active therapy, other than hormonal therapy for this disease.
    Note: Participants with curatively treated non-melanoma skin cancer are allowed without a 2-year restriction.
    11. Evidence of cardiovascular risk
    12. Active infection requiring treatment.
    13. Known HIV infection.
    14. Presence of hepatitis B surface antigen (HbsAg), or hepatitis B core antibody (HbcAb), at Screening or within 3 months prior to first dose of study treatment.
    15. Positive hepatitis C antibody test result.
    Note: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
    16. Current corneal epithelial disease except for mild punctate keratopathy (Appendix 12 of the protocol).
    Note: Participants with mild punctate keratopathy are allowed.
    17. Intolerance or contraindications to anti-viral prophylaxis.
    18. Unable to tolerate antithrombotic prophylaxis.
    19. AL amyloidosis (light chain amyloidosis), active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) or active plasma cell leukemia at the time of screening.
    20. Exhibiting clinical signs of or has a known history of meningeal or central nervous system involvement by multiple myeloma.

    Prior/Concomitant Therapy
    21. Use of an investigational drug within 14 days or five half-lives (whichever is longer) preceding the first dose of study drug.
    Tipo de participante y características de la enfermedad
    1. Mieloma múltiple latente (MML).
    2. Tratamiento sistémico previo para el mieloma múltiple o el MML. Se permite un ciclo de urgencia de esteroides (es decir, dosis no superiores a 40 mg de dexametasona o equivalente al día durante un máximo de 4 días [es decir, un total de 160 mg]).
    3. El paciente es apto para recibir quimioterapia en dosis altas con un TACM.

    Enfermedades
    4. Neuropatía periférica o dolor neuropático de grado 2 o superior, según lo definido por los criterios CTCAE del NCI, versión 5.
    5. Intervención de cirugía mayor en las 4 semanas previas a la primera dosis del fármaco del estudio.
    6. Presencia de una enfermedad renal activa (infección, necesidad de diálisis o cualquier otro trastorno importante que pueda afectar a la seguridad del participante). Podrán participar pacientes con proteinuria aislada debida al MM, siempre que cumplan los criterios indicados en la Tabla 1.
    7. Presencia de cualquier trastorno médico, psiquiátrico o de otro tipo grave o inestable (incluidas anomalías analíticas) que pueda interferir en la seguridad del participante, la obtención del consentimiento informado o el cumplimiento de los procedimientos del estudio.
    8. Signos de hemorragia activa de mucosas o interna no controlada con tratamiento local y no explicada por una coagulopatía reversible.
    9. Enfermedad hepática o biliar activa presente (excepto síndrome de Gilbert o litiasis biliar asintomática o una hepatopatía crónica por lo demás estable según la evaluación del investigador).
    10. Se excluirá a los participantes con neoplasias malignas previas o simultáneas distintas del mieloma múltiple. Son excepciones el carcinoma in situ de cuello uterino tratado quirúrgicamente o cualquier otra neoplasia maligna que se haya considerado médicamente estable durante al menos 2 años. El participante no podrá estar recibiendo tratamiento activo, aparte del tratamiento hormonal para esta enfermedad.
    Nota: se permite la participación de pacientes con cáncer de piel distinto del melanoma tratado con intención curativa sin la restricción de 2 años.
    11. Signos de riesgo cardiovascular.
    12. Infección activa con necesidad de tratamiento.
    13. Infección conocida por el VIH.
    14. Presencia de antígeno de superficie del virus de la hepatitis B (HBsAg) o de anticuerpos contra el antígeno central del virus de la hepatitis B (anti-HBc) en el momento de selección o en los tres meses previos a la primera dosis del tratamiento del estudio.
    Nota: la presencia de anticuerpos contra el antígeno de superficie del virus de la hepatitis B que indiquen una vacunación previa no será motivo de exclusión.
    15. Resultado positivo en el análisis de anticuerpos contra el virus de la hepatitis C.
    Nota: podrán participar pacientes con anticuerpos contra el virus de la hepatitis C debido a enfermedad resuelta previa solo si se obtiene una prueba de confirmación negativa basada en la determinación del ARN del virus de la hepatitis C.
    16. Presencia de epiteliopatía corneal, excepto queratopatía punteada leve (Apéndice 12).
    Nota: podrán participar pacientes con queratopatía punteada leve.
    17. Intolerancia o contraindicaciones de la profilaxis antiviral.
    18. Intolerancia a la profilaxis antitrombótica.
    19. Amiloidosis AL (amiloidosis de cadenas ligeras), síndrome de POEMS (polineuropatía, organomegalia, endocrinopatía, trastorno proliferativo de células plasmáticas monoclonales, alteraciones cutáneas) activo o leucemia de células plasmáticas activa en el momento de la selección.
    20. Presencia de signos clínicos o antecedentes conocidos de afectación meníngea o del sistema nervioso central por el mieloma múltiple.

    Tratamiento previo/concomitante
    21. Uso de un fármaco en investigación en los 14 días o el período correspondiente a cinco semividas (lo que suponga más tiempo) anteriores a la primera dosis del fármaco del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1
    - Number (%) of participants with dose limiting toxicities (DLTs)
    - Number (%) of participants with adverse events (AEs)

    Part 2
    - Minimal Residual Disease (MRD) negativity rate, defined as the percentage of participants who are MRD negative by next-generation sequencing (NGS) with sensitivity of 10-5
    - PFS, defined as the time from the date of randomization until the earliest date of documented disease progression or death due to any cause
    Parte 1
    - Número (%) de participantes con toxicidad limitante de la dosis (TLD).
    - Número (%) de participantes con acontecimientos adversos (AA).

    Parte 2
    - Tasa de negatividad de ERM, definida como el porcentaje de participantes con negatividad de ERM mediante secuenciación de nueva generación (SNG) con un nivel de 10-5.
    - SSP, definida como el tiempo transcurrido entre la fecha de aleatorización y la fecha más temprana de progresión de la enfermedad documentada o muerte por cualquier causa.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1
    The review of DLTs and AEs will be continuous to inform dose escalation, and then after all patients recruited in Part 1 have completed four cycles of treatment.

    Part 2
    - MRD endpoint: (Part 2) final analysis (i.e. when all participants have
    been followed for up to 12 months from first dose)
    - PFS endpoint: (Part 2) 1st interim analysis for futility (approximately
    25 months from First Subject First Visit [FSFV]), 2nd interim analysis for efficacy (approximately 42 months from FSFV) and final analysis (approximately 51 months from FSFV).
    Parte 1
    La revisión de las DLT y los AA será continua para informar el aumento de la dosis, y después de que todos los pacientes reclutados en la Parte 1 hayan completado cuatro ciclos de tratamiento.

    Parte 2
    - Variable de enfermedad mínima residual: (Parte 2) análisis final (es decir, cuando se haya hecho un seguimiento de hasta 12 meses desde la primera dosis de todos los pacientes)
    - Variable de progresión libre de enfermedad: (Parte 2) 1er análisis intermedio de futilidad (aproximadamente 25 meses desde la primera visita del primer paciente), 2do análisis intermedio de eficacia (aproximadamente 42 meses desde la primera visita del primer paciente) y análisis final (aproximadamente 51 meses desde la primera visita del primer paciente).
    E.5.2Secondary end point(s)
    Part 1:
    - Lenalidomide RDI after 4 cycles of treatment with belantamab mafodotin in combination with VRd
    - Bortezomib RDI after 4 cycles of treatment with belantamab mafodotin in combination with VRd
    - Cumulative administered dose of belantamab mafodotin after 4 cycles of treatment in combination with VRd
    - Belantamab mafodotin, total mAb, and cys-mcMMAF PK parameters, as data permit
    - Incidence and titers of ADAs against belantamab mafodotin

    Part 2:
    - ORR, defined as the percentage of participants with a confirmed PR or better (i.e., PR, VGPR, CR, sCR)
    - CRR, defined as the percentage of participants with a confirmed CR or better (i.e., CR, sCR)
    - Rate of VGPR or better, defined as the percentage of participants with a confirmed VGPR or better (i.e. VGPR, CR, sCR)
    - DoR, defined as the time from first documented evidence of PR or better until PD or death due to PD among participants who achieve confirmed PR or
    better
    - TTP, defined as the time from the date of randomization until the earliest date of documented PD or death due to PD
    - OS, defined as the time from the date of randomization until the date of death due to any cause
    - Sustained MRD negativity defined as the percentage of patients with MRD negativity confirmed 1 year apart
    - Incidence of adverse events (AEs)
    - Ocular findings on ophthalmic exam
    -Plasma concentrations of belantamab mafodotin, total mAb, and cys-mcMMAF
    -ncidence and titers of ADAs against belantamab mafodotin
    -Change from baseline in HRQOL as measured by EORTC QLQ-C30 and EORTC QLQ-MY20 symptoms (pain) domain
    - Changes from baseline in symptoms and related impacts as measured by PRO-CTCAE
    - Changes from baseline in symptoms and related impacts as measured by OSDI
    Parte 1:
    - IDR de lenalidomida después de 4 ciclos de tratamiento con belantamab mafodotin en combinación con VRd.
    - IDR de bortezomib después de 4 ciclos de tratamiento con belantamab mafodotin en combinación con VRd.
    - Dosis acumulada de belantamab mafodotin después de 4 ciclos de tratamiento en combinación con VRd.
    - Parámetros farmacocinéticos (FC) de belantamab mafodotin, AcM totales y cys-imMMAF, cuando lo permitan los datos.
    - Incidencia y títulos de ACF dirigidos contra belantamab mafodotin.

    Parte 2:
    - TRG, definida como el porcentaje de participantes con una RP o una mejor respuesta confirmada (es decir, RP, RPMB, RC, RCr).
    - Tasa de respuesta completa (TRC), definida como el porcentaje de participantes con una RC o una mejor respuesta confirmada (es decir, RC, RCr).
    - Tasa de RPMB o mejor respuesta, definida como el porcentaje de participantes con una RPMB o una mejor respuesta confirmada (es decir, RPMB, RC, RCr).
    - DR, definida como el tiempo transcurrido entre el primer signo documentado de RP o una respuesta mejor hasta la PE o la muerte por PE en los participantes que logren una RP o una respuesta mejor confirmada.
    - THP, definido como el tiempo transcurrido entre la fecha de aleatorización y la fecha más temprana de PE documentada o muerte por PE.
    - SG, definida como el tiempo transcurrido entre la fecha de aleatorización y la fecha de la muerte por cualquier causa.
    - Negatividad mantenida de ERM, definida como el porcentaje de pacientes con negatividad de ERM confirmada con 1 año de diferencia.
    - Incidencia de acontecimientos adversos (AA).
    - Hallazgos oculares en la exploración oftalmológica.
    - Concentraciones plasmáticas de belantamab mafodotin, AcM totales y cys-imMMAF.
    - Incidencia y títulos de ACF dirigidos contra belantamab mafodotin.
    - Variación de la CVRS con respecto al momento basal, determinada mediante el dominio de síntomas (dolor) de los cuestionarios QLQ-C30 y QLQ-MY20 de la EORTC.
    - Variaciones con respecto al momento basal de los síntomas y sus repercusiones, determinados mediante PRO-CTCAE.
    - Variaciones con respecto al momento basal de los síntomas y sus repercusiones, determinados mediante OSDI.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part 1:
    - Lenalidomide and bortezomib RDI endpoints: after all patients recruited in Part 1 have completed 4 cycles of treatment.
    - PK and ADAs endpoints: final analysis
    Part 2:
    -Efficacy endpoints: Part 2 1st interim analysis (IA) for futility (approximately 25 months from FSFV), 2nd IA for efficacy (approximately 42 months from FSFV) & final analysis (approximately 51 months from FSFV)
    -Safety and tolerability endpoints (AEs and ocular findings): safety IAs (every 6 months), Part 2 1st IA for futility, 2nd IA for efficacy and finalanalysis
    - Belantamaf mafodotin exposure endpoint, ADAs endpoint, HRQOL endpoint, safety and tolerability endpoint (self-reported symptomatic adverse effects), self-reported ocular symptomatic adverse effects endpoint: final analysis
    Parte 1: Variable de:
    - la intensidad de dosis relativa de lenalidomida y bortezomib: después de que todos los pacientes reclutados en la Parte 1 hayan completado 4 ciclos de tratamiento.
    - PK y anticuerpos contra el fármaco: análisis final
    Parte 2: Variables de:
    - eficacia: primer análisis intermedio de la parte 2 para la futilidad, segundo análisis intermedio para la eficacia y análisis final.
    - seguridad y tolerabilidad: análisis intermedio de seguridad (cada 6 meses), primer análisis intermedio de la parte 2 para la futilidad, segundo análisis intermedio para la eficacia y análisis final
    - exposición a belantamab mafodotin; anticuerpos contra el fármaco; calidad de vida relacionada con salud y seguridad y tolerabilidad (AA sintomáticos comunicados por los pacientes)
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Design in 2 parts: Part 1 (dose selection) and Part 2 (randomized Phase 3 part)
    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 trial7
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA96
    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
    Argentina
    Australia
    Belgium
    Brazil
    Canada
    China
    Denmark
    France
    Germany
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    Norway
    Poland
    Romania
    Russian Federation
    Spain
    Sweden
    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
    When the last participant in Part 2 (Randomised Phase 3 part) of the study completes the last overall survival (OS) follow-up visit (expected to occur at completion of the 5-year OS follow-up period from disease progression)
    Cuando el último paciente de la Parte 2 (parte de la Fase 3 aleatorizada) del estudio completa la última visita de seguimiento de supervivencia global (se espera que ocurra al finalizar el período de seguimiento de supervivencia global de 5 años desde la progresión de la enfermedad)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years12
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years12
    E.8.9.2In all countries concerned by the trial months4
    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: 79
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 719
    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 state54
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 413
    F.4.2.2In the whole clinical trial 798
    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)
    There is no planned provision of study treatment following the end of the study.
    The Investigator is responsible for ensuring that consideration has been given to the poststudy care of the participant’s medical condition.
    No está previsto suministrar tratamiento del estudio después del final del estudio. El investigador es responsable de garantizar que se haya considerado la asistencia médica del paciente tras el estudio.
    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 Decision2020-03-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-28
    P. End of Trial
    P.End of Trial StatusOngoing
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