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    Summary
    EudraCT Number:2016-002044-16
    Sponsor's Protocol Code Number:20150292
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-09-26
    Trial results View 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 number2016-002044-16
    A.3Full title of the trial
    A Phase 2/3 Multi-center Study of Evaluate the Safety and Efficacy of Blinatumomab in Subjects with Relapsed/Refractory Aggressive B-Cell Non Hodgkin Lymphoma
    Estudio multicéntrico de fase 2/3 para evaluar la seguridad y la eficacia de blinatumomab en sujetos con linfoma no Hodgkin de células B agresivo en recaída/refractario
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical phase 2/3 study to investigate the safety and efficacy of Blinatumomab in subjects with Non Hodgkin Lymphoma that did not respond to previous therapy or that relapsed after initially successful previous therapy
    Ensayo clínico de fase 2/3 para investigar la seguridad y la eficacia de Blinatumomab en pacientes con linfoma no Hodgkin que no respondieron a tratamientos previos o que recayeron tras un tratamiento previo satisfactorio.
    A.4.1Sponsor's protocol code number20150292
    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 SponsorAmgen Inc.
    B.1.3.4CountryUnited States
    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 supportAmgen Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen (EUROPE) GmbH
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressDammstrasse 23, P.O. Box 1557
    B.5.3.2Town/ cityZug
    B.5.3.3Post codeCH-6301
    B.5.3.4CountrySwitzerland
    B.5.6E-mailMedinfoInternational@amgen.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 Yes
    D.2.1.1.1Trade name Blincyto
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V.
    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 nameBlinatumomab
    D.3.2Product code AMG 103, MT103
    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 INNBlinatumomab
    D.3.9.1CAS number 853426-35-4
    D.3.9.2Current sponsor codeAMG 103
    D.3.9.4EV Substance CodeSUB35403
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number38.5
    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) Yes
    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
    Subjects with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma (B-NHL)
    Pacientes con linfoma no Hodgkin de células B (LNH-B) agresivo en recaída o refractario
    E.1.1.1Medical condition in easily understood language
    Subjects with Non-Hodgkin Lymphoma which did not completely respond to treatment or has relapsed after first responding to therapy
    Pacientes con linfoma no Hodgkin que no hayan respondido
    completamente al tratamiento o que hayan recaído tras responder primero al
    tratamiento.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10020067
    E.1.2Term High grade B-cell lymphoma Burkitt-like lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10036710
    E.1.2Term Primary mediastinal large B-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10063908
    E.1.2Term Non-Hodgkin's lymphoma unspecified histology aggressive
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10012818
    E.1.2Term Diffuse large B-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 2:
    • estimate the complete metabolic response (CMR) rate following blinatumomab monotherapy administered in the second salvage (S2) treatment of transplant-eligible subjects with relapsed or refractory (R/R) aggressive B-NHL who have not achieved CMR1 following 2 cycles of standard platinum-based first salvage (S1) chemotherapy
    Phase 3:
    • compare the CMR rates following blinatumomab to those following investigator’s choice (IC) S2 chemotherapy
    Fase 2:
    • Estimar la tasa de RMC después de monoterapia con blinatumomab administrada en el S2 de los sujetos aptos para un trasplante con LNH-B agresivo en recaída o refractario (R/R) que
    no hayan alcanzado una RMC después de 2 ciclos de la primera S1 estándar basada en platino.
    Fase 3:
    • Comparar las tasas de RMC después del tratamiento con blinatumomab con las de la
    quimioterapia S2 de elección del investigador.
    E.2.2Secondary objectives of the trial
    Phase 2:
    • To evaluate the efficacy parameters following blinatumomab treatment, of:
    - Response duration
    - The rate of successful hematopoietic stem cell mobilization
    • To evaluate the safety of blinatumomab in the S2 setting
    Phase 3:
    • To compare the efficacy of blinatumomab to investigator’s choice chemotherapy (ICC) in:
    - Overall survival
    - Response duration
    - Capacity to mobilize HSCs
    - Ability to proceed to hematopoietic stem cell transplant (both autologous and allogeneic) rates among responding subjects (CMR) or those in sustained partial metabolic response (PMR)
    - Objective response rate (ORR; CMR + PMR)
    • To compare the safety profile of blinatumomab to that of ICC
    • To compare the quality of life reported by subjects treated with blinatumomab or ICC
    Phases 2 and 3
    • To characterize the pharmacokinetic parameters of blinatumomab administered to subjects with R/R aggressive B-NHL
    • Progression-free survival
    Fase 2: Evaluar parámetros de eficacia después del
    tratamiento con blinatumomab:
    - La duración de la respuesta
    - La tasa de movilización de CPH satisfactoria
    Evaluar la seguridad de blinatumomab en el contexto de la S2
    Fase 3: Comparar la eficacia de blinatumomab con la quimioterapia de
    elección del investigador (QEI) con respecto a:
    - La SG
    - La duración de la respuesta
    - La capacidad de movilizar las CPH
    - La capacidad de determinar las tasas de TCPH (tanto autólogo como
    alogénico) entre los sujetos con respuesta (RMC) o los sujetos con RMP
    continuada
    - La tasa de respuesta objetiva (TRO; RMC + RMP)
    Comparar el perfil de seguridad de blinatumomab con el de la QEI
    Comparar la calidad de vida notificada por los sujetos tratados con
    blinatumomab o la quimioterapia de elección del investigador
    Fases 2 y 3: Describir los parámetros PK de blinatumomab cuando se
    administra a sujetos con LNH-B agresivo R/R
    supervivencia libre de progresión
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject has provided informed consent prior to initiation of any study-specific activities/procedures OR subject’s legally acceptable representative has provided informed consent prior to any study-specific activities/procedures being initiated when the subject has any kind of condition that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent.
    2. Age ≥ 18 at the time of informed consent
    3. Biopsy proven aggressive B-NHL, including DLBCL NOS, follicular lymphoma Grade 3B, Primary Mediastinal B-Cell Lymphoma, T-cell rich B-cell lymphoma, or DLBCL that represents transformation of indolent NHL, (including follicular, marginal zone, and lymphoplasmacytoid lymphoma) excluding chronic lymphocytic leukemia or Hodgkin Lymphoma. Subjects with prior indolent lymphoma must have received therapy after a diagnosis of transformation that is appropriate for aggressive histology as described in 4. The following histologies are not eligible:
    • Lymphoblastic lymphoma
    • Burkitt lymphoma
    Any histologies not specifically mentioned must be discussed with the medical monitor.
    4. Refractory (no prior CMR) or relapsed (prior CMR) following front line treatment of standard multiagent chemotherapy containing an anthracycline AND an approved anti-CD20 agent. Examples of appropriate therapy include but are not limited to R-CHOP (14 or 21), R-CHOEP, and DA-R-EOCH. For refractory disease, PET positivity should be demonstrated no less than 6 weeks after radiotherapy
    5. Biopsy evidence of relapsed disease. For subjects with de novo aggressive B-cell lymphoma and primary refractory disease (ie never achieving CMR), biopsy of persistent disease is preferred but persistent PET positivity (ie Deauville ≥ 4) is acceptable at a minimum. For all subjects that have received radiotherapy for DLBCL, PET should be performed no less than 42 days (6 weeks) after the last dose of radiotherapy. For subjects with transformed disease that has been characterized as refractory, rebiopsy (core or excisional biopsy) with demonstration of persistent aggressive B-NHL is required
    6. Received 2 cycles of standard of care platinum-based chemotherapy in the S1 setting and had a response of PMD, NMR, PMR as centrally assessed by PET-CT scan or received at least 1 cycle of S1 chemotherapy and had evidence of PD as centrally assessed
    7. Radiographically measurable disease with a clearly demarcated nodal lesion at least 1.5 cm in its largest dimension or a target extranodal lesion at least 1.0 cm in its largest dimension
    8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
    9. Potentially eligible for HDT and autologous HSCT per institutional standards
    10. Laboratory parameters (completed within 14 days prior to enrollment and after the last cycle of S1 chemotherapy):
    Hematology:
    • Absolute neutrophil count (ANC) ≥ 1.0 x 1000000000/L
    • Platelets ≥ 75 x 1000000000/L
    Chemistry:
    • Creatinine clearance ≥ 50 mL/min (calculated)
    •Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 3X upper limit of normal (ULN)
    •Total bilirubin (TBL) < 2x ULN (unless Gilbert's disease or if liver involvement with lymphoma)
    1. El sujeto ha proporcionado el consentimiento informado antes del inicio de cualquier actividad/procedimiento específico del estudio O su representante legal autorizado ha proporcionado el consentimiento informado antes del inicio de cualquier actividad/procedimiento específico del estudio cuando el sujeto sufre cualquier tipo de enfermedad que, según la opinión del investigador, puede comprometer su capacidad para proporcionar el consentimiento informado por escrito.
    2. Edad ≥ 18 años en el momento del consentimiento informado.
    3. LNH-B agresivo demostrado por biopsia, que incluye DLBCL NEOM, linfoma folicular de grado 3B, linfoma mediastínico de células B primario, linfoma de células B rico en células T o DLBCL que represente la transformación del LNH indolente (incluyendo los linfomas folicular, de zona marginal o linfoplasmocitoide), excepto leucemia linfocítica crónica o linfoma de Hodgkin. Los sujetos con linfoma indolente previo deben haber recibido, después del diagnóstico de transformación, tratamiento apropiado para una histología agresiva según se describe en el punto 4. No son elegibles las siguientes histologías:
    • Linfoma linfoblástico.
    • Linfoma de Burkitt.
    Las histologías no mencionadas específicamente deben ser comentadas con el monitor médico.
    4. Enfermedad refractaria (sin RMC previa) o en recaída (RMC previa) después del tratamiento de primera línea con quimioterapia estándar con varios agentes que contenga una antraciclina Y un agente anti-CD20 aprobado. Los ejemplos de tratamiento adecuado incluyen, entre otros, R-CHOP (14 o 21), RCHOEP y DA-R-EOCH. Para la enfermedad refractaria, la positividad en la PET debe demostrarse a partir de las 6 semanas después de la radioterapia.
    5. Evidencia de enfermedad en recaída mediante biopsia. En el caso de los sujetos con linfoma de células B agresivo de novo y enfermedad refractaria primaria (es decir, que no alcanzaron nunca la RMC), se prefiere una biopsia de la enfermedad persistente, aunque se acepta una positividad persistente en la PET (es decir, Deauville ≥ 4) como mínimo. En todos los sujetos que hayan recibido radioterapia para DLBCL, la PET debe realizarse a partir de los 42 días (6 semanas) después de la última dosis de radioterapia. En los sujetos con enfermedad transformada que ha sido caracterizada como refractaria, se requiere una nueva biopsia (biopsia con aguja gruesa o por escisión) con demostración de LNH-B agresivo persistente. 6. Haber recibido 2 ciclos de tratamiento estándar con quimioterapia basada en platino en el entorno S1 y presentar una respuesta de EMP, RNM o RMP evaluada centralmente mediante exploración PET-TC o haber recibido al menos 1 ciclo de quimioterapia S1 y presentar evidencia de EP evaluada centralmente.
    7. Enfermedad medible radiográficamente con una lesión ganglionar claramente delimitada de al menos 1,5 cm en su dimensión más larga o una lesión extraganglionar diana de al menos 1 cm en su dimensión más larga.
    8. Estado funcional ECOG (Eastern Cooperative Oncology Group) ≤ 2.
    9. Potencialmente aptos para tratamiento a dosis altas y TCPH autólogo según los estándares institucionales.
    10. Parámetros analíticos (completados en los 14 días previos a la inclusión y después del primer ciclo de quimioterapia S1):
    Hematología:
    • Recuento absoluto de neutrófilos (RAN) ≥ 1,0 x 109/L.
    • Plaquetas ≥ 75 x 109/L.
    Bioquímica:
    • Aclaramiento de creatinina ≥ 50 mL/min (calculado).
    • Aspartato aminotransferasa (AST)/alanina aminotransferasa (ALT) < 3 x el límite superior de la normalidad (LSN).
    • Bilirrubina total (BiT) < 2x LSN (excepto en caso de enfermedad de Gilbert o afectación hepática con linfoma).
    E.4Principal exclusion criteria
    1. CMR following S1 chemotherapy
    2. Treatment within 30 days prior to randomization with another investigational device or drug study (ies). Other investigational procedures while participating in this study are excluded
    3. Prior anti-CD19-directed therapies
    4. Prior HDT with autologous HSCT
    5. Prior allogeneic HSCT
    6. Presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis
    7. Evidence of CNS involvement by NHL
    8. Known infection with human immunodeficiency virus or chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (anti-hepatitis C virus positive)
    9. History of malignancy other than B-NHL within the past 3 years with the exception of:
    • Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    • Adequately treated cervical carcinoma in situ without evidence of disease
    • Adequately treated breast ductal carcinoma in situ without evidence of disease
    • Prostatic intraepithelial neoplasia without evidence of prostate cancer
    • Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ
    10. Subject has known sensitivity to immunoglobulins or any of the products or components to be administered during dosing.
    11. Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge.
    12. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
    13. Female subjects who are pregnant or breastfeeding or planning to become pregnant or breastfeed while receiving blinatumomab and for an additional 48 hours after the last dose of blinatumomab. (Females of child bearing potential should only be included after a confirmed menstrual period and a negative highly sensitive urine or serum pregnancy test.)
    14. Female subjects of childbearing potential unwilling to use an effective method of contraception while receiving blinatumomab and for an additional 48 hours after the last dose of blinatumomab.
    Note: The pregnancy, breastfeeding and contraceptive requirements are specific for blinatumomab. The investigator is responsible for providing the subject (male and female) with pregnancy and breastfeeding (female only) avoidance requirements for other medications given during the study.
    1. RMC después de quimioterapia S1.
    2. Tratamiento en los 30 días previos a la aleatorización en otro estudio con fármacos o dispositivos en investigación. Están excluidos otros procedimientos experimentales durante la participación en este estudio.
    3. Tratamientos previos dirigidos anti-CD19.
    4. Tratamiento a dosis altas y TCPH autólogo previo.
    5. TCPH alogénico previo.
    6. Presencia de una patología del sistema nervioso central (SNC) clínicamente relevante como epilepsia, paresia, afasia, infarto cerebral, lesiones cerebrales graves, demencia, enfermedad de Parkinson, enfermedad del cerebelo, síndrome orgánico cerebral o psicosis.
    7. Evidencia de afectación del SNC por el LNH.
    8. Infección conocida por el virus de la inmunodeficiencia humana o infección crónica por el virus de la hepatitis B (positivo para antígeno de superficie de la hepatitis B) o por el virus de la hepatitis C (anti-VHC positivo).
    9. Antecedentes de tumores malignos distintos al LNH-B en los últimos 3 años, con la excepción de:
    • Tumor maligno tratado con intención curativa y sin enfermedad activa conocida durante ≥ 3 años antes de la inclusión y que el médico tratante considere de bajo riesgo de recurrencia.
    • Cáncer de piel no melanomatoso o lentigo maligno tratados adecuadamente sin evidencia de enfermedad.
    • Carcinoma cervicouterino in situ tratado adecuadamente sin evidencia de enfermedad.
    • Carcinoma ductal de mama in situ tratado adecuadamente sin evidencia de enfermedad.
    • Neoplasia intraepitelial prostática sin evidencia de cáncer de próstata.
    • Carcinoma urotelial papilar no invasivo o carcinoma in situ tratados adecuadamente.
    10. El sujeto presenta una sensibilidad conocida a las inmunoglobulinas o a alguno de los productos o componentes que se administrarán durante la dosificación.
    11. Según informan el sujeto y el investigador, es posible que el sujeto no esté disponible para completar todas las visitas o procedimientos del estudio requeridos por el protocolo y/o cumplir todos los procedimientos requeridos por el estudio.
    12. Antecedentes o evidencia de cualquier otro trastorno, condición o enfermedad clínicamente significativos (excepto los indicados anteriormente) que, en opinión del investigador o del médico de Amgen, si se le consulta, pudieran suponer un riesgo para la seguridad del sujeto o interferir en la evaluación, los procedimientos o la realización del estudio. 13. Mujeres embarazadas o que den el pecho o que planeen quedarse embarazadas o dar el pecho mientras reciben blinatumomab y durante 48 horas adicionales después de la última dosis de blinatumomab. (Las mujeres en edad fértil solo deben incluirse después de un período menstrual confirmado y un resultado negativo en una prueba de embarazo en suero u orina altamente sensible.)
    14. Mujeres en edad fértil y que no quieran utilizar un método anticonceptivo eficaz mientras reciben blinatumomab y durante 48 horas adicionales después de la última dosis de blinatumomab.
    Nota: los requisitos sobre embarazo, lactancia y anticonceptivos son específicos para blinatumomab. El investigador es responsable de informar al sujeto (hombres y mujeres) de los requisitos para evitar el embarazo y la lactancia (solo mujeres) para otros medicamentos administrados durante el estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Phases 2 and 3:
    • CMR as determined by central radiographic assessment of positron emission tomography-computed tomography (PET-CT) scans using the Lugano Classification
    Fases 2 y 3:
     La RMC determinada por la evaluación radiográfica central mediante exploraciones por tomografía por emisión de positrones-tomografía computarizada (PET-TC) utilizando la clasificación de Lugano.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From first subject randomised: 8, 13, 18, 23 months
    Desde el primer paciente aleatorizado: 8, 13, 18, 23 meses
    E.5.2Secondary end point(s)
    Key Secondary Endpoint:
    Phase 3:
    • OS
    Other Secondary Endpoints:
    Phase 2:
    • ORR
    • PFS
    • Duration of response (DOR)
    • Successful mobilization rate
    • HSCT (both autologous and allogeneic) rates among subjects with post-blinatumomab complete response (CMR) + partial response (PMR)
    • 100-day non-relapse mortality (NRM) after autologous HSCT
    • Blinatumomab concentration steady state, clearance, and half life
    • Incidence and severity of adverse events
    Phase 3:
    • Objective response rate (ORR; CMR+PMR)
    • PFS
    • DOR
    • Successful mobilization rate following protocol assigned therapy
    • HSCT (both autologous and allogeneic) rates among responding subjects (CMR or PMR)
    • 100-day NRM after autologous HSCT rate
    • Patient-reported clinical outcome assessments quality of life (QOLCOA) using the EQ-5D and FACT-Lymphoma tools
    • Blinatumomab steady state concentration and clearance
    • Safety:
    - Overall incidence and severity of treatment-emergent adverse events
    Exploratory Endpoints (Phase 2 and 3):
    • Pharmacodynamics, including descriptive analysis of quantitative and qualitative features of lymphocyte populations and serum or plasma concentrations of cytokines
    • Response rates and duration according to COO designation and c-myc and bcl-2 rearrangement as determined from pretreatment specimens
    • Quantitative analysis of CT-DNA as determined by NGS quantitation of clonotypic IgH sequences from plasma collected at various timepoints before, during, and after treatment
    Variable secundaria principal:
    Fase 3:
     La SG.
    Otras variables secundarias:
    Fase 2:
     La TRO.
     La SLP.
     La duración de la respuesta (DR).
     La tasa de movilización satisfactoria.
     Las tasas de TCPH (tanto autólogo como alogénico) entre los sujetos con respuesta completa después del tratamiento con blinatumomab (RMC) + respuesta parcial (RMP).
     La mortalidad sin recaída (RNM) a los 100 días tras el TCPH autólogo.
     La concentración en estado de equilibrio, el aclaramiento y la semivida de blinatumomab.
     La incidencia y la gravedad de los acontecimientos adversos.
    Fase 3:
     La tasa de respuesta objetiva (TRO; RMC + RMP).
     La SLP.
     La DR.
     La tasa de movilización satisfactoria después del tratamiento asignado por el protocolo.
     Las tasas de TCPH (tanto autólogo como alogénico) entre los sujetos con respuesta (RMC o RMP).
     La RNM a los 100 días tras el TCPH autólogo.
     Las evaluaciones de los resultados clínicos notificados por los pacientes de la calidad de vida (QOLCOA) mediante las herramientas EQ-5D y FACT-Lymphoma.
     La concentración en estado de equilibrio y el aclaramiento de blinatumomab.
     Seguridad:
    - Incidencia global y gravedad de los acontecimientos adversos que aparecen durante el tratamiento.
    Variables exploratorias (fases 2 y 3):
     La farmacodinámica, incluido el análisis descriptivo de las características cuantitativas y cualitativas de las poblaciones de linfocitos y las concentraciones séricas o plasmáticas de citocinas.
     Las tasas de respuesta y la duración según la designación de la CDO y las reordenaciones de c-Myc y Bcl-2 determinadas a partir de muestras previas al tratamiento.
     El análisis cuantitativo del ADN-TC determinado por la cuantificación de la NGS de las secuencias de IgH clonotípicas a partir del plasma recogido en distintos momentos antes, durante y después del tratamiento.
    E.5.2.1Timepoint(s) of evaluation of this end point
    From first subject randomised: 18, 26 months
    Desde el primer paciente aleatorizado: 18, 26 meses
    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 Yes
    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) Yes
    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 No
    E.8.1.2Open No
    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 Yes
    E.8.1.7.1Other trial design description
    Un estudio fase 2/3 abierto con aleatorización en fase 3 solamente,con la elección del investiga
    A phase 2/3 open label study with randomisation in phase 3 only, against investigators choice
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    En fase 3, elección del investigador de la lista del protocolo
    In phase 3, Investigator’s Choice from a list in the protocol
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA119
    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
    Australia
    European Union
    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
    Study completion will occur once 236 death events for phase 3 subjects have occurred or 12 months after the last subject in phase 3 is randomized if 236th death in phase 3 subjects is not observed
    El análisis final se llevará a cabo cuando se notifique la 236a muerte de un paciente
    en la fase 3, o cuando hayan transcurrido 12 meses
    desde la aleatorización del último sujeto, si la 236ª muerte no se ha observado en la fase 3.
    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 months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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: 166
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 166
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 195
    F.4.2.2In the whole clinical trial 332
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    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 Decision2016-12-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-03-12
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