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    Summary
    EudraCT Number:2018-000929-32
    Sponsor's Protocol Code Number:JCAR017-BCM-003
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-05-21
    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 number2018-000929-32
    A.3Full title of the trial
    A global randomized multicenter Phase 3 trial to compare the efficacy and safety of JCAR017 to standard of care in adult subjects with high-risk, transplant-eligible relapsed or refractory aggressive B-cell non-Hodgkin lymphomas (TRANSFORM)
    Estudio internacional de fase III, multicéntrico, y aleatorizado, para comparar la eficacia y seguridad de JCAR017 frente al tratamiento de referencia de pacientes adultos de alto riesgo, con linfoma no Hodgkin de células B agresivo en recaída o refractario y elegibles a trasplante (TRANSFORM).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase 3 study to assess the efficacy and safety of JCAR017, a CAR-T cell therapy, in adults with aggressive B-Cell non-Hodgkin lymphoma
    Estudio de fase III para evaluar la eficacia y seguridad de JCAR017, un tratamiento de células T con CAR, en adultos con linfoma no Hodgkin de células B agresivo
    A.4.1Sponsor's protocol code numberJCAR017-BCM-003
    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 SponsorCelgene Corporation
    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 supportCelgene Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelgene Corporation
    B.5.2Functional name of contact pointClinicalTrialDisclosure
    B.5.3 Address:
    B.5.3.1Street Address9225 Indian Creek Parkway, Suite 900
    B.5.3.2Town/ cityOverland Park, Kansas
    B.5.3.3Post code66210
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1888260 1599
    B.5.5Fax number+1913266 0394
    B.5.6E-mailClinicalTrialDisclosure@celgene.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/3/17/1890
    D.3 Description of the IMP
    D.3.1Product nameJCAR017
    D.3.2Product code JCAR017
    D.3.4Pharmaceutical form Suspension for injection
    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 INNAutologous CD4+ and CD8+ T cells expressing a CD19-specific chimeric antigen receptor (CAR)
    D.3.9.2Current sponsor codeJCAR017
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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 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.2.5The 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 nameCARMUSTINE
    D.3.4Pharmaceutical form Injection
    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 INNCARMUSTINE
    D.3.9.1CAS number 154-93-8
    D.3.9.3Other descriptive nameBCNU
    D.3.9.4EV Substance CodeSUB06132MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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 Yes
    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.2.5The 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 nameETOPOSIDE
    D.3.4Pharmaceutical form Injection
    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 INNETOPOSIDE
    D.3.9.1CAS number 33419-42-0
    D.3.9.3Other descriptive nameETOPOSIDE
    D.3.9.4EV Substance CodeSUB07337MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Yes
    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.2.5The 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 nameCytarabine
    D.3.4Pharmaceutical form Injection
    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 INNCYTARABINE
    D.3.9.1CAS number 147-94-4
    D.3.9.3Other descriptive nameCYTARABINE, Ara-C, cytosine arabinoside
    D.3.9.4EV Substance CodeSUB06880MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Yes
    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: 5
    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.2.5The 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 nameMELPHALAN
    D.3.4Pharmaceutical form Injection
    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
    D.3.9.1CAS number 148-82-3
    D.3.9.4EV Substance CodeSUB08728MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    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 Yes
    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
    Transplant-eligible relapsed or refractory (R/R) aggressive B-cell Non Hodgkin Lymphoma (B-NHL)
    Linfoma no Hodgkin (LNH ) de células B agresivo en recaída o refractario (R/R) y elegibles a trasplante
    E.1.1.1Medical condition in easily understood language
    A cancer of B-cells, a type of white blood cell responsible for producing Antibodies
    Cáncer de células B, un tipo de leucocitos responsables de la producción de anticuerpos
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10029593
    E.1.2Term Non-Hodgkin's lymphoma NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLGT
    E.1.2Classification code 10025320
    E.1.2Term Lymphomas non-Hodgkin's B-cell
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to compare the efficacy in subjects treated with JCAR017 versus subjects treated according to standard of care (SOC) defined as event-free survival (EFS).
    El objetivo principal es comparar la eficacia del tratamiento de pacientes con JCAR017 con el tratamiento de referencia (TR), definida como la supervivencia sin acontecimientos (SSA).
    E.2.2Secondary objectives of the trial
    The key secondary objectives are to compare the efficacy in subjects treated with JCAR017 versus subjects treated according to SOC defined as complete response rate (CRR), progression-free survival (PFS) and overall survival (OS).

    - To compare other parameters of efficacy, defined as duration of response (DOR), overall response rate (ORR), PFS on next line of treatment (PFS-2)

    - To compare efficacy rates (EFS, PFS, OS) at 6, 12 and 24 months after randomization

    - To compare the safety defined as type and frequency of adverse events (AEs), serious adverse events (SAEs), and laboratory abnormalities

    - To compare the safety and efficacy in clinical, histological and molecular subgroups

    - To compare health-related quality of life (HRQoL)

    - To compare hospital resource utilization (HRU)

    - To describe the rate of completion of high dose chemotherapy (HDCT) and hematopoietic stem cell transplant (HSCT)

    - To assess the response 3 months after-HSCT
    Objetivos secundarios clave:
    Comparar parámetros adicionales de eficacia en pacientes tratados con JCAR017 con pacientes tratados con arreglo al TR, específicamente tasa de respuesta completa (TRC), supervivencia sin progresión (SSP) y supervivencia global (SG).Comp. otros parámetros de eficacia, específicamente duración de la respuesta (DdR), tasa de respuesta global (TRG) y SSP tras la admón de nueva línea de tratamiento (SSP-2).Comp. tasas de eficacia (SSA, SSP, SG) a los 6, 12 y 24 meses de la aleatorización.Comp. seguridad, definida como tipo y frecuencia de acontecimientos adversos (AA), acontecimientos adversos graves (AAG) y anomalías analíticas.Comp seguridad y eficacia en subgrupos clínicos, histológicos y moleculares. Comp calidad de vida relacionada con la salud (CVRS).Comp uso de recursos hospitalarios (URH).Describir tasa de finalización de quimioterapia de dosis altas (QTDA) y trasplante de progenitores hematopoyéticos (TPH).Evaluar respuesta a los 3 meses del TPH.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject is ≥ 18 years and ≤ 75 years of age at the time of signing the informed consent form (ICF).

    2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.

    3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.

    4. ECOG performance status ≤ 2.

    5. Histologically proven diffuse large B-cell lymphoma (DLBCL) NOS (de novo or transformed FL), high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma [DHL/THL]) or follicular lymphoma grade 3B. Enough tumor material must be available for confirmation by central pathology. If archival sample is before most recent relapse or no or insufficient archival sample is available, a new tumor biopsy is mandated to confirm diagnosis.
    Note: Subjects with secondary CNS involvement are eligible.

    6. Refractory (SD, PD, PR or CR with relapse before 3 months) or relapsed (CR with relapse on or after 3 months) within 12 months from CD20 antibody and anthracycline containing first line therapy.

    7. [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) positive lesion at screening.

    8. Adequate organ function, defined as:
    - Adequate bone marrow function as assessed by the Investigator
    - Serum creatinine < 1.5 x age-adjusted upper limit of normal (ULN) or creatinine clearance > 30 mL/min (estimated glomerular filtration rate [eGFR] by Cockcroft Gault see Appendix D for calculation)
    - Alanine aminotransferase (ALT) ≤ 5 x ULN and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert's syndrome or lymphomatous infiltration of the liver)
    - Adequate pulmonary function, defined as ≤ Grade 1 dyspnea according to Common Terminology Criteria for Adverse Events (CTCAE) and oxygen saturation (SaO2) ≥ 92% on room air
    - Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) performed within 4 weeks of randomization

    9. Adequate vascular access for leukapheresis

    10. Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals while receiving as well as within 12 months after the JCAR017 infusion and until CAR T cells are no longer present by quantitative polymerase chain reaction (qPCR) on 2 consecutive tests, whichever occurs last.

    11. Females of childbearing potential (FCBP) must:
    - Have a negative pregnancy test as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence* from heterosexual contact.
    - Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception without interruption. Contraception methods must include 1 highly effective and 1 additional effective (barrier) method of contraception from screening until at least 12 months after the JCAR017 infusion and until CAR T cells are no longer present by qPCR on 2 consecutive tests, whichever is later (Arm B) and until 12 months after the last chemotherapy (Arm A),
    - Agree to abstain from breastfeeding during study participation and for at least 3 months after the last dose of JCAR017 or until CAR T cells are no longer present by qPCR on 2 consecutive tests, whichever is later.
    Note: Highly effective methods are defined as those that result in a low failure rate (ie, less than 1% per year) when used consistently and correctly. The following are examples of highly effective and additional effective methods of contraception:
    Intrauterine device (IUD)
    Hormonal (birth control pill, injections, implants)
    Tubal ligation
    Partner's vasectomy
    Male condom (additional effective method)
    Diaphragm (additional effective method)
    Cervical cap (additional effective method)

    12. Male subjects must:
    - Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for 12 months after the JCAR017 infusion even if he has undergone a successful vasectomy and until CAR T cells are no longer present by qPCR on 2 consecutive tests, whichever occurs last (Arm B) and for 12 months after the last chemotherapy (Arm A).
    * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. In contrast, periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    1≥18 años y ≤75 años a la firma del formulario de consentimiento informado (FCI). 2Comprender un FCI y firmarlo de forma voluntaria antes de ninguna eval/procedimiento del estudio. 3Dispuesto a cumplir el calendario de visitas y otros req. del prot. y tener capacidad para ello 4ECOG ≤ 2. 5Confir. histológica de linfoma difuso de células B grandes (LDCBG) sin especificar (de nueva aparición o LF transformado)linfoma de células B de alto grado con reordenamiento de MYC y BCL2 y/o BCL6 con histología de LDCBG (linfoma doble hit y triple hit [LDH/LTH]) o linfoma folicular de grado 3B. Disponer de mat. tumoral suficiente para q el lab de análisis clínicos central pueda realizar la confirmación. Si la muestra de archivo es anterior a la reciente recaída, es insuf. o no está disponible, es obligatorio realizar una nueva biopsia tumoral para confirmar el diagnóstico.Nota: los suj con afectación secundaria del SNC son aptos.6Ser refractario (EE, PE, RP o RC con recaída antes de los 3 meses) o recidivante (RC con recaída a los 3 meses o más) en los 12 meses siguientes a la adm. de un tto de primera línea con anticuerpos anti-CD20 y antraciclina.7Lesión detectable mediante tomografía por emisión de positrones (PET) con [18F] -fluorodeoxiglucosa (FDG) en el momento de la selección.8Función orgánica satisfactoria, definida: F.medular satisf. conforme a evaluación del investigador.Creatinina sérica < 1,5 veces el límite superior de la normalidad (LSN) ajustado por edad o aclaramiento de creatinina >30 ml/min (filtración glomerular estimada [FGe] mediante la fórmula de Cockcroft Gault; véase anexo D para realizar cálculo).Alanina-aminotransferasa (ALT) ≤ 5 veces el LSN y bilirrubina total <2,0 mg/dl (o <3,0 mg/dl en el caso de los sujetos con síndrome de Gilbert o infiltración linfomatosa hepática).F.pulmonar satisfactoria, disnea de grado ≤1 con arreglo a criterios terminológicos comunes para a. adversos (CTCAE) y sat. de oxígeno (SaO2) ≥92 % respirando aire ambiental.Función cardiaca satisf:fracción eyección ventrículo izdo (FEVI) ≥40 % evaluada mediante ecocardio o ventriculografía isotópica (MUGA) realizada en las 4 semanas previas a la aleat.9Acceso vascular adecuado para leucaféresis.10Acceder a no donar sangre, órganos, esperma o semen y ovocitos para uso en otras personas mientras reciben la infusión de JCAR017,durante 12 meses siguientes, hasta que no se detecten células T con CAR en dos pruebas consec. reacción en cadena de polimerasa cuantitativa (qPCR),lo q ocurra más tarde.11Mujeres en edad fértil (MEF); resultado negativo en prueba de embarazo verificado por el investigador antes de empezar a recibir el tto. del estudio. Aceptar pruebas de embarazo continuas durante el estudio y una vez finalizado el tto del estudio, incluso si practica una abstinencia real* de rel. sex. heterosexuales;compromiso a abstinencia real*de rel. sex. heterosexuales (revisarse mensualmente y anotarse en documentos fuente) o aceptar utilizar y ser capaz de seguir mét. ac eficaces sin interrupción. Entre los mét. ac debe haber 1 método altamente eficaz y 1 método eficaz ad. (de barrera), q deberán utilizarse desde el momento de la selección hasta q hayan transcurrido, como mínimo, 12 meses desde la infusión de JCAR017 y hasta q no se detecten células T con CAR en 2 pruebas consecutivas de qPCR, lo q ocurra más tarde (grupo B) y hasta q hayan transcurrido 12 meses desde la última quimio (grupo A);aceptar abstenerse de dar el pecho mientras participa en el estudio y durante un mínimo de 3 meses tras la última dosis de JCAR017 o hasta q no se detecten células T con CAR en 2 pruebas consecutivas de qPCR, lo q ocurra más tarde. Nota: Met altamente eficaces se definen como aquellos con los que se obtiene un bajo índice de fallo (es decir, menos de un 1 % al año) cdo se utilizan de forma correcta y sistemática. Ejs de métodos ac altamente eficaces y métodos eficaces ad:dispositivo intrauterino (DIU),métodos hormonales (píldora anticonceptiva, inyecciones, implantes),ligadura trompas,vasectomía de pareja,preservativo masculino (método eficaz ad),diafragma (método eficaz ad),capuchón cervical (método eficaz adicional).12Participantes varones:Abstinencia real* (debe revisarse mensualmente) o aceptar utilizar preservativo durante las relaciones sexuales con mujeres embarazadas o en edad fértil mientras participan en el estudio, durante las interrupciones de la dosis y durante los 12 meses siguientes a la infusión de JCAR017, incluso si se ha sometido a una vasectomía satisfactoria, y hasta que no se detecten células T con CAR en dos pruebas consecutivas de qPCR, lo que ocurra más tarde (grupo B) y hasta que hayan transcurrido 12 meses desde la última quimioterapia (grupo A).La abstinencia real es aceptable cuando es coherente con el estilo de vida preferido y habitual del sujeto. En cambio, la abstinencia periódica, (p. ej., métodos de Ogino, ovulación, sintotérmico o posovulación) y el coito interrumpido no se consideran métodos ac aceptables.
    E.4Principal exclusion criteria
    1. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.

    2. Subject has any condition including the presence of laboratory abnormalities, which would place the subject at unacceptable risk if participating in the study.

    3. Subject has any condition that confounds the ability to interpret data from the study.

    4. Subjects not eligible for hematopoietic stem cell transplantation (HSCT).

    5. Subjects planned to undergo allogeneic stem cell transplantation.

    6. Subjects with T cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV (Epstein-Barr virus) positive DLBCL of the elderly and Burkitt lymphoma, transformed indolent NHL except transformed FL.

    7. Subjects with prior history of malignancies, other than aggressive R/R NHL, unless the subject has been free of the disease for ≥ 2 years with the exception of the following noninvasive malignancies:
    - Basal cell carcinoma of the skin
    - Squamous cell carcinoma of the skin
    - Carcinoma in situ of the cervix
    - Carcinoma in situ of the breast
    - Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative.
    - Other completely resected stage 1 solid tumor with low risk for recurrence

    8. Treatment with any prior gene therapy product

    9. Subjects who have received previous CD19-targeted therapy.

    10. History of or active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.

    11. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment.

    12. Active autoimmune disease requiring immunosuppressive therapy.

    13. History of any one of the following cardiovascular conditions within the past 6 months prior to signing the ICF: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease.

    14. History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.

    15. Pregnant or nursing (lactating) women.

    16. Use of the following:
    - Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to unstimulated leukapheresis. Physiologic replacement, topical, and inhaled steroids are permitted.
    - Cytotoxic chemotherapeutic agents that are not considered lymphotoxic (see below) must be stopped ≥ 7 days prior to unstimulated leukapheresis.
    - Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide, ifosfamide, bendamustine) prior to unstimulated leukapheresis.
    - Experimental agents within 4 weeks prior to signing the ICF unless no response or progressive disease (PD) is documented on the experimental therapy and at least 3 half-lives have elapsed prior to unstimulated leukapheresis.
    - Immunosuppressive therapies within 4 weeks prior to unstimulated leukapheresis (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-tumor necrosis factor [TNF], anti-IL-6, or anti-IL-6R).
    - Radiation within 4 weeks prior to signing the ICF. Subjects must have progressive disease in irradiated lesions or have additional non-irradiated, PET-positive lesions to be eligible. Radiation to a single lesion, if additional non-irradiated, measurable PETpositive lesions are present, is allowed up to 2 weeks prior to unstimulated leukapheresis.
    1. Sujetos que padezcan una enfermedad, anomalía analítica o enfermedad psiquiátrica relevante que impediría su participación en el estudio2. Sujetos que padezcan una enfermedad, incluidas las anomalías analíticas, que podría suponer un riesgo inaceptable para ellos en caso de participar en el estudio3. Sujetos que padezcan una enfermedad que induzca a confusión en la capacidad para interpretar los datos del estudio4. Sujetos que no sean aptos para un trasplante de células madre hematopoyéticas (TCMH)5. Sujetos que tengan previsto someterse a un alotrasplante de progenitores hematopoyéticos6. Sujetos con linfoma de células B grandes rico en células T/histiocitos (LCBGRTH), linfoma primario cutáneo de células B grandes, linfoma primario mediastínico de células B (LPMCB), LDCBG del anciano positivo para el VEB (virus de Epstein-Barr) y linfoma de Burkitt, LNH transformado de crecimiento lento, salvo el LF transformado.7. Sujetos con antecedentes de otra neoplasia maligna que no sea el LNH R/R agresivo,a menos que el sujeto lleve sin enfermedad un plazo ≥2 años, con la excepción de las siguientes neoplasias malignas no invasivas:
    carcinoma basocelular,carcinoma epidermoide,carcinoma de cuello uterino localizado,carcinoma de mama localizado,hallazgo histológico incidental de cáncer de próstata (T1a o T1b en el sistema de estadificación clínica TNM [tumor, ganglios y metástasis] o cáncer de próstata curable,otro tumor sólido de estadio 1 completamente resecado con bajo riesgo de recidiva8. Sujetos que hayan recibido tratamiento previo con cualquier producto de genoterapia.9. Sujetos que hayan recibido previamente tratamiento dirigido al CD19.10. Sujetos con antecedentes o presencia de hepatitis B, hepatitis C o infección por el virus de la inmunodeficiencia humana (VIH).11. Sujetos con infecciones sistémicas fúngicas, bacterianas, víricas o de otro
    tipo no controladas (incluida la tuberculosis), a pesar de haberse administrado un tratamiento antibiótico adecuado u otro tratamiento12. Sujetos con enfermedad autoinmune activa que requiera tratamiento inmunosupresor13. Sujetos con antecedentes de cualquiera de las enfermedades cardiovasculares siguientes en los 6 meses anteriores a la firma del FCI: insuficiencia cardiaca de clase III o IV, según la definición de la New York Heart Association (NYHA), angioplastia cardiaca o colocación de endoprótesis vascular, infarto de miocardio, angina inestable u otra cardiopatía clínicamente importante14. Sujetos con antecedentes o presencia de enfermedad del sistema nervioso central (SNC) de importancia clínica, como por ejemplo: epilepsia, convulsiones, paresia, afasia, ictus, lesiones cerebrales importantes, demencia, enfermedad de Parkinson, enfermedad cerebelosa, síndrome cerebral orgánico o psicosis15. Mujeres embarazadas o en periodo de lactancia.16. Sujetos que utilizan lo siguiente:
    - Corticoides en dosis terapéuticas (definidas como >20 mg/día
    de prednisona o un equivalente) en los 7 días previos a la
    leucaféresis no estimulada. Los corticoides para reposición fisiológica, tópicos e inhalados están
    permitidos.
    - Los quimioterápicos citotóxicos que no se consideren
    linfotóxicos (véase más adelante) deben interrumpirse ≥7 días antes de la leucaféresis no estimulada.
    - Quimioterápicos linfotóxicos (p. ej., ciclofosfamida, ifosfamida , bendamustina) antes de la leucaféresis no estimulada.
    - Fármacos experimentales en las 4 semanas previas a la firma del FCI, a menos que
    se documente ausencia de respuesta o progresión de la enfermedad con el tratamiento experimental y hayan transcurrido al menos 3 semividas antes de la leucaféresis no estimulada.
    - Tratamientos inmunosupresores administrados en las 4 semanas previas a la leucaféresis no estimulada (p. ej., inhibidores de la calcineurina, metotrexato u otros quimioterápicos, micofenolato, rapamicina, talidomida, anticuerpos inmunosupresores, como el anticuerpo contra el factor de necrosis tumoral [TNF], anti-IL-6 o anti-IL-6R).
    - Radiación en las 4 semanas previas a la firma del FCI. Para ser aptos, los sujetos deben presentar progresión de la enfermedad en las lesiones irradiadas o tener lesiones adicionales no irradiadas positivas en el PET. La irradiación de una única lesión, si existen lesiones adicionales no irradiadas mensurables positivas en el PET, se permitirá hasta 2 semanas antes de la leucaféresis sin estimulación.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy:

    Event-free survival (EFS):
    Time from randomization to death from any cause, progressive disease (PD), as assessed by the independent review committee (IRC) or start of new antineoplastic therapy, whichever occurs first.
    Criterio de valoración principal de la eficacia:
    Supervivencia sin acontecimientos (SSA)
    Tiempo transcurrido desde la aleatorización hasta la muerte por cualquier causa, la progresión de la enfermedad (PE) evaluada por el comité de revisión independiente (CRI) o el comienzo de un nuevo tratamiento antineoplásico, lo que ocurra en primer lugar.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 3 years post-randomization
    Hasta 3 años después de la aleatorización
    E.5.2Secondary end point(s)
    Key Secondary Efficacy:

    1. Complete response rate (CRR):
    Percentage of subjects achieving a complete response (CR) according to the Lugano Classification (Cheson, 2014) assessed by the IRC.

    2. Progression-free survival (PFS):
    Time from randomization to PD, SD at 1st response assessment as per protocol schedule, as per IRC review or death from any cause, whichever occurs first.

    3. Overall survival (OS):
    Time from randomization to time of death due to any cause.

    Secondary Efficacy:

    1. Overall response rate (ORR):
    Percentage of subjects achieving an objective response of partial response (PR) or better according to the Lugano Classification (Cheson, 2014) as assessed by IRC review.

    2. Duration of response (DOR):
    Time from first response to disease progression, start of new antineoplastic therapy or death from any cause.

    3. PFS-2:
    Time from randomization to second objective disease progression or death from any cause, whichever is first.

    4. EFS rate

    5. PFS rate

    6. OS rate

    See protocol for additional study endpoints
    Criterios de valoración secundarios clave de la eficacia:
    1. Tasa de respuesta completa (TRC):
    Porcentaje de sujetos en los que se obtiene una respuesta completa (RC) de acuerdo con la clasificación de Lugano (Cheson, 2014), evaluada por el CRI.

    2. Supervivencia sin progresión (SSP):
    Tiempo transcurrido desde la aleatorización hasta la PE o la EE en la primera evaluación de la respuesta, de conformidad con el calendario del protocolo y la evaluación del CRI, lo que ocurra en primer lugar.

    3. Supervivencia global (SG):
    Tiempo transcurrido desde la aleatorización hasta el momento de la muerte por cualquier causa.

    Criterios de valoración secundarios de la eficacia:
    1. Tasa de respuesta global (TRG):
    Porcentaje de sujetos en los que se obtiene una respuesta parcial (RP) objetiva o una respuesta mejor de acuerdo con la clasificación de Lugano (Cheson, 2014), evaluada por el CRI.

    2. Duración de la respuesta (DR):
    Tiempo transcurrido desde la primera respuesta hasta la progresión de la enfermedad, el comienzo de un nuevo tratamiento antineoplásico o la muerte por cualquier causa.

    3. SSP-2:
    Tiempo transcurrido desde la aleatorización hasta la segunda progresión objetiva de la enfermedad o la muerte por cualquier causa, lo que ocurra en primer lugar.

    4. Tasa de SSA

    5. Tasa de SSP

    6. Tasa de SG

    Consulte el protocolo para ver otros criterios de valoración empleados en el estudio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Key Secondary Efficacy:
    1 and 2 - Up to 3 years post-randomization
    3 - Up to last subject last visit

    Secondary Efficacy:
    1, 2, 3 - Up to 3 years post-randomization
    4, 5, 6 - At 6, 12 and 24 months post-randomization
    Criterios de valoración secundarios clave de la eficacia:
    1 y 2: hasta tres años después de la aleatorización
    3: hasta la última visita del último sujeto

    Criterios de valoración secundarios de la eficacia:
    1, 2, 3: hasta tres años después de la aleatorización
    4, 5, 6: a los 6, 12 y 24 meses de la aleatorización
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Inmunoquimioterapia seguida de QTDA y TCMH.
    Immunochemotherapy followed by HDCT and HSCT
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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
    Belgium
    Canada
    France
    Germany
    Italy
    Japan
    Netherlands
    Spain
    Sweden
    Switzerland
    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
    The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date when the last subject enters the LTFU study, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol, whichever is the later date.
    El final del estudio se define, bien como la fecha de la última visita del último sujeto para finalizar el seguimiento postratamiento, bien como la fecha de incorporación del último sujeto al estudio de seguimiento a largo plazo, o bien como la fecha de recepción del último punto de datos del último sujeto necesario para el análisis principal, secundario y/o exploratorio conforme a lo especificado en el protocolo, lo que ocurra más tarde.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    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: 91
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 91
    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 150
    F.4.2.2In the whole clinical trial 182
    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)
    Because this protocol involves gene transfer, long-term follow-up for lentiviral vector safety, disease status, and survival will continue after EOS under a separate LTFU protocol thereafter for up to 15 years after the JCAR017 infusion. All subjects who either complete the follow-up period specified in the protocol or who prematurely withdraw after JCAR017 infusion will be asked to enroll in the LTFU protocol at the EOS visit or at the time of withdrawal, respectively.
    Este prot. implica transf d genes x lo q el sto a largo plazo para determinar seguridad del vector lentivirus, estado de enfermedad y supervivencia continuará tras fin estudio,conforme con prot d sto a largo pl diferente, hasta 15 años tras infusión de JCAR017. Los suj q finalicen el periodo d sto especificado en prot o q se retiren prematuram después d la infu d JCAR017 se les pedirá q se incorporen al prot de sto a largo plazo en la visita d fin de estudio o en la retirada,lo q corresponda.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-08-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-28
    P. End of Trial
    P.End of Trial StatusOngoing
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