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    EudraCT Number:2017-000106-38
    Sponsor's Protocol Code Number:JCAR017-BCM-001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2018-03-14
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-000106-38
    A.3Full title of the trial
    A Phase 2, Single-arm, Multi-cohort, Multi-center Trial to Determine the Efficacy and Safety of JCAR017 in Adult Subjects with Aggressive B-Cell Non-Hodgkin Lymphoma
    Ensayo de fase II, multicéntrico, de cohortes múltiples y de un solo brazo para evaluar la eficacia y seguridad de JCAR017 en sujetos adultos con linfoma no Hodgkin de células B agresivo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the efficacy and safety of JCAR017, a CAR-T cell therapy, in adults with aggressive B-Cell Non-Hodgkin Lymphoma
    Estudio para evaluar la eficacia y seguridad de JCAR017, un tratamiento a base de células T con CAR, en pacientes adultos con linfoma no Hodgkin de células B agresivo
    A.4.1Sponsor's protocol code numberJCAR017-BCM-001
    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
    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. cell therapy medicinal product No
    D. therapy medical product Yes
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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.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
    Aggressive B-cell Non Hodgkin Lymphoma (B-NHL)
    Linfoma no Hodgkin de células B agresivo
    E.1.1.1Medical condition in easily understood language
    A cancer of B-cells, a type of white blood cell responsible for producing Antibodies
    Un cáncer de las células B, un tipo de leucocito responsable de producir 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 determine the efficacy, defined as overall response rate (ORR), of JCAR017 in subjects with aggressive B-cell non-Hodgkin lymphoma.
    El objetivo principal del estudio es determinar la eficacia, definida como la tasa de respuesta global (TRG), de JCAR017 en sujetos con linfoma no Hodgkin de células B agresivo
    E.2.2Secondary objectives of the trial
    - To evaluate the safety and feasibility of administering JCAR017
    - To evaluate ORR of JCAR017 in underlying chronic lymphocytic leukemia (CLL) in subjects with Richter’s transformation (Cohort 6)
    - To evaluate other measures of efficacy of JCAR017 ( e.g., complete response rate [CRR], event-free survival [EFS], progression-free survival [PFS], overall survival [OS], duration of response [DOR])
    - Characterize the cellular pharmacokinetic (PK) profile of JCAR017, including the quantity and persistence of the chimeric antigen receptor (CAR) T cells in the peripheral blood
    - Describe changes in health-related quality of life using the European Organisation for Research and Treatment of Cancer – Quality of Life C30 questionnaire (EORTC QLQ-C30), the European Quality of Life-5 Dimensions health state classifier to 5 Levels (EQ-5D-5L) and Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) "Additional concerns" scale
    -Evaluar la seguridad y viabilidad de la administración de JCAR017. -Evaluar la TRG del JCAR017 en la leucemia linfocítica crónica (LLC) subyacente en sujetos con síndrome de Richter (cohorte 6). -Evaluar otras medidas de la eficacia de JCAR017 (p. ej., la tasa de remisión completa [TRC], la tasa de supervivencia sin acontecimientos [SSA], la supervivencia sin progresión [SSP], la supervivencia global [SG] o la duración de la remisión [DdR]). -Caracterizar el perfil farmacocinético (FC) celular de JCAR017, incluyendo la cantidad y persistencia de las células T con receptor de antígeno quimérico (CAR, por sus siglas en inglés) en la sangre periférica. -Describir los cambios provocados en la calidad de vida relacionada con la salud empleando el cuestionario C30 de la Organización europea para la investigación y el tratamiento del cáncer (European Organisation for Research and Treatment of Cancer - Ver versión en inglés.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject is ≥ 18 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. Investigator considers the subject is appropriate for adoptive T cell therapy.

    5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

    6. Subjects with one of the following:
    • Cohort 1: Subjects with DLBCL NOS (de novo or tFL), high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) and FL3B per WHO 2016 classification (Swerdlow, 2016), after ≥ 2 lines of therapy, including an anthracycline and rituximab (or other CD20-targeted agent)*.
    • Cohort 2: Transplant not eligible subjects with DLBCL NOS (de novo or tFL), high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) and FL3B per WHO 2016 classification (Swerdlow, 2016), who failed first line therapy including an anthracycline and rituximab (or other CD-20-targeted agent).
    - Transplant not eligible subjects will include those who are deemed ineligible for high-dose chemotherapy and HSCT due to age, performance status or comorbidity. At the very least, subjects have to meet one of the following criteria:
    age ≥ 70 years, ECOG performance status ≥ 2, impaired pulmonary function (DLCO ≤ 60%), impaired cardiac function (LVEF < 50%), impaired renal function (CrCl < 60 mL/min/1.73m2) or impaired hepatic function (AST/ALT > 2x ULN, bilirubin > 2 mg/dL or cirrhosis Child-Pugh B or C).
    - Subjects must fulfil all other in- and exclusion criteria
    • Cohort 3: (Japan only): Subjects meeting eligibility criteria for either Cohort 1 or 2.
    • Cohort 4: Subjects with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) who failed first line therapy*. Subjects may be screened at time of initial diagnosis and leukapheresis may be performed prior to initiation of first line therapy.
    • Cohort 5: Subjects with PCNSL after ≥ 1 line of therapy, including high-dose methotrexate.
    • Cohort 6: Subjects with Richter’s transformation after ≥ 1 line of therapy for Richter’s transformation.

    Note: Subjects with secondary DLBCL CNS involvement are eligible (not applicable for Cohort 5).

    7. Histological confirmation of diagnosis at last relapse. Enough tumor material must be available for central confirmation of diagnosis, otherwise a new tumor biopsy is mandated. NOTE: if subsequent therapies are given after last relapse with SD/PD as best response, the tissue from that last relapse will be considered adequate to participate in the trial.

    8. For subjects with NHL and Richter’s transformed CLL: Subject must have positron emission tomography (PET)-positive disease as per Lugano Classification (Cheson, 2014).

    9. For subjects with PCNSL: Subjects must have disease that is objectively measurable by International Workshop to Standardize Baseline Evaluation and Response Criteria in Primary Central Nervous System (CNS) Lymphoma (Abrey, 2005), cerebrospinal fluid (CSF) cytology (in case of leptomeningeal only disease), or vitreal aspiration cytology and/or retinal photographs (in case of ocular lymphoma if clinically indicated).

    10. Adequate organ function, defined as:
    • Adequate bone marrow function to receive LD chemotherapy 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 Cockroft-Gault).
    • 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 Toxicity Criteria for Adverse Events (CTCAE) and
    SaO2 ≥ 92% on room air.
    • Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram or multigated acquisition (MUGA) scan performed within 4 weeks prior to leukapheresis.

    11. Adequate vascular access for leukapheresis procedure.

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

    Please refer to protocol section 4.2 for inclusion criteria 13 and 14
    1. Sujetos ≥ 18 años en el momento de firmar el documento de consentimiento informado (DCI).
    2. El sujeto debe comprender y firmar voluntariamente el DCI antes de realizarse cualquier evaluación/procedimiento relacionado con el estudio.
    3. El sujeto está de acuerdo en cumplir el calendario de visitas del estudio y otros requisitos del protocolo y es capaz de hacerlo.
    4. El investigador considera que el sujeto es adecuado para recibir la transferencia adoptiva de células T.
    5. Estado funcional ECOG (Eastern Cooperative Oncology Group) de 0, 1 o 2.
    6. Sujetos con una de las características siguientes:
    • Cohorte 1: Sujetos con linfoma LBDCG sin especificar (de novo o linfoma folicular transformado), linfoma de células B de alto grado con reordenamientos de MYC y BCL2 y/o BCL6 con histología de LBDCG (LHD/LHT) y LF3B según la clasificación de la OMS de 2016 (Swerdlow, 2016), después de haber recibido ≥ 2 líneas de tratamiento con una antraciclina y rituximab (u otro fármaco dirigido al CD20)*.
    • Cohorte 2: Sujetos no elegibles para un trasplante con linfoma LBDCG sin especificar (de novo o linfoma folicular transformado), linfoma de células B de alto grado con reordenamientos de MYC y BCL2 y/o BCL6 con histología de LBDCG (LHD/LHT) y LF3B según la clasificación de la OMS de 2016 (Swerdlow, 2016), en los que haya fracasado el tratamiento de primera línea con una antraciclina y rituximab (u otro fármaco dirigido al CD-20).
    - Los sujetos no elegibles para un trasplante serán aquellos considerados no elegibles para recibir quimioterapia en altas dosis y TPH debido a su edad, estado funcional o enfermedades concomitantes. Como mínimo indispensable, los sujetos deberán cumplir con uno de los criterios siguientes:
    edad ≥ 70 años, estado funcional ECOG ≥ 2, afectación de la función pulmonar (DLCO ≤ 60 %), afectación de la función cardíaca (FEVI < 50 %), afectación de la función renal (AclCr < 60 ml/min/1,73m2) o afectación de la función hepática (AST/ALT > 2 veces el LSN, bilirrubina > 2 mg/dl o cirrosis de clase B o C en la escala de Child-Pugh).
    - Los sujetos deberán cumplir todos los criterios de inclusión restantes y ninguno de los criterios de exclusión
    • Cohorte 3: (solamente para Japón): Sujetos que cumplan los criterios de elegibilidad para la cohorte 1 o 2.
    • Cohorte 4: Sujetos con linfoma de células B de alto grado con reordenamientos de MYC y BCL2 y/o BCL6 con histología de LBDCG (LHD/LHT) en los que haya fracasado el tratamiento de primera línea*. Los sujetos podrán someterse a los procedimientos de selección en el momento de efectuar el diagnóstico inicial y la leucaféresis podrá realizarse antes de iniciar el tratamiento de primera línea.
    • Cohorte 5: Sujetos con LCP (linfoma cerebral primario), después de haber recibido ≥ 1 línea de tratamiento que incluya metotrexato en dosis altas.
    • Cohorte 6: Sujetos con transformación de Richter, después de haber recibido ≥ 1 línea de tratamiento para la transformación de Richter.
    Nota: Los sujetos con LBDCG con afectación cerebral secundaria serán elegibles (no aplicable a la cohorte 5).
    7. Confirmación histológica del diagnóstico en la última recidiva. Deberá disponerse de material tumoral suficiente para realizar una confirmación centralizada del diagnóstico; en caso contrario, será obligatorio efectuar una nueva biopsia del tumor. NOTA: si se administran tratamientos con posterioridad a la última recidiva con los que se obtenga EE/PE como mejor respuesta, el tejido de la última recidiva se considerará adecuado para participar en el ensayo clínico.
    8. En el caso de los sujetos con LNH y LLC con transformación de Richter: El sujeto debe obtener un resultado positivo en una tomografía por emisión de positrones (PET), de acuerdo con la clasificación de Lugano (Cheson, 2014).
    9. Para los sujetos con LCP: Los sujetos deben presentar una enfermedad mensurable de forma objetiva según el International Workshop to Standardize Baseline Evaluation and Response Criteria in Primary Central Nervous System (CNS) Lymphoma (Abrey, 2005), citología del líquido cefalorraquídeo (LCR) (solo en caso de afectación leptomeníngea) o citología de aspirado de humor vítreo y/o fotografías de la retina (en caso de linfoma ocular, si está clínicamente indicado).
    Ver criterios 10, 11, 12, 13 y 14 en la sección 4.2 del protocolo.
    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 with T cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV positive DLBCL of the elderly and Burkitt lymphoma.

    5. History of another primary malignancy that has not been in remission for at least 2 years prior to enrollment. The following are exempt from the 2-year limit if curatively treated:
    • Non-melanoma skin cancer
    • Localized prostate cancer
    • Cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP smear

    6. Treatment with any prior gene therapy product.

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

    8. Previous history of or active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.

    9. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment at the time of leukapheresis or JCAR017 infusion.

    10. Presence of acute or chronic graft-versus-host disease (GVHD).

    11. Active autoimmune disease requiring immunosuppressive therapy.

    12.History of any one of the following cardiovascular conditions within the past 6 months:
    • Heart failure class III or IV as defined by the New York Heart Association (NYHA)
    • Cardiac angioplasty or stenting
    • Myocardial infarction
    • Unstable angina
    • Other clinically significant cardiac disease

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

    14. Pregnant or nursing women.

    15. Treatment with alemtuzumab within 6 months of leukapheresis, or treatment with fludarabine or cladribine within 3 months of leukapheresis

    16. Use of the following (see Section 8.2 for full details):
    • Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis or
    72 hours prior to JCAR017 infusion. Physiologic replacement, topical, and inhaled steroids are permitted.
    • Low-dose chemotherapy (eg, vincristine, rituximab, cyclophosphamide ≤ 300 mg/m2) given after leukapheresis to maintain disease control must be stopped ≥ 7 days prior to LD chemotherapy.
    • Cytotoxic chemotherapeutic agents that are not considered lymphotoxic (see below) within 1 week prior to leukapheresis. Oral anticancer agents, including lenalidomide and ibrutinib,are allowed if at least 3 half-lives have elapsed prior to leukapheresis.
    • Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide, ifosfamide, bendamustine) within 2 weeks prior to leukapheresis.
    • Experimental agents within 4 weeks prior to leukapheresis unless no response or progressive disease (PD) is documented on the experimental therapy and at least 3 half-lives have elapsed prior to leukapheresis.
    • Immunosuppressive therapies within 4 weeks prior to leukapheresis and JCAR017 infusion (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).
    • Donor lymphocyte infusions (DLI) within 6 weeks prior to JCAR017 infusion.
    • Radiation within 6 weeks prior to leukapheresis. 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 PET-positive lesions are present, is allowed up to 2 weeks prior to leukapheresis.
    • Allogenic HSCT within 90 days prior to leukapheresis.

    17. Prior hematopoietic stem cell transplant (only applicable to Cohort 2).
    1. El sujeto presenta cualquier enfermedad, anormalidad de laboratorio o enfermedad psiquiátrica relevante que impediría su participación en el estudio.
    2. El sujeto presenta cualquier enfermedad, incluidas las anormalidades de laboratorio, que podría suponer un riesgo inaceptable para el sujeto en caso de participar en el estudio.
    3. El sujeto presenta cualquier enfermedad que induzca a confusión en la capacidad para interpretar los datos del estudio.
    4. 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 (LPMB), LBDCG positivo para el VEB o linfoma de Burkitt.
    5. Antecedentes de otra neoplasia maligna primaria que no haya permanecido en remisión durante al menos los 2 años anteriores a la inclusión en el estudio. El límite de 2 años no es aplicable a las siguientes neoplasias, siempre que hayan sido objeto de un tratamiento curativo:
    • Cáncer de piel no melanocítico
    • Cáncer de próstata localizado
    • Carcinoma in situ de cérvix observado en una biopsia o lesión intraepitelial escamosa observada en una citología
    6. Tratamiento previo con cualquier producto de terapia génica.
    7. Sujetos que hayan recibido previamente terapia dirigida al CD19.
    8. Antecedentes de hepatitis B activa, hepatitis C o infección por el virus de la inmunodeficiencia humana (VIH).
    9. Sujetos con infecciones sistémicas fúngicas, bacterianas, víricas o de otro tipo no controladas (incluida la tuberculosis), a pesar de haberse administrado un tratamiento con los antibióticos adecuados u otro tratamiento en el momento de realizar la leucaféresis o la infusión de JCAR017.
    10. Presencia de enfermedad de injerto contra huésped (EICH) crónica.
    11. Enfermedades autoinmunes activas que requieran tratamiento inmunosupresor.
    Antecedentes de cualquiera de las enfermedades cardiovasculares siguientes en los 6 meses anteriores:
    • Insuficiencia cardíaca de clase III o IV, según la definición de la New York Heart Association (NYHA)
    • Angioplastia cardíaca o colocación de stent
    • Infarto de miocardio
    • Angina inestable
    • Otras cardiopatías clínicamente importantes
    13. Antecedentes o presencia de enfermedad del SNC clínicamente relevante, como por ejemplo: epilepsia, convulsiones, paresia, afasia, acontecimiento cerebral vascular, lesiones cerebrales importantes, demencia, enfermedad de Parkinson, enfermedad cerebelosa, síndrome cerebral orgánico o psicosis.
    14. Mujeres embarazadas o en período de lactancia.
    15. Tratamiento con alemtuzumab en los 6 meses previos a la leucaféresis o tratamiento con fludarabina o cladribina en los 3 meses previos a la leucaféresis
    16. Uso de los siguientes tratamientos (véase la sección 8.2 para obtener más detalles):
    • Corticoides en dosis terapéuticas (definidas como > 20 mg/día de prednisona o un equivalente) en los 7 días previos a la leucaféresis o
    72 horas antes de la infusión de JCAR017. La reposición fisiológica y los corticoides tópicos e inhalados están permitidos.
    • La quimioterapia en dosis bajas (p. ej., vincristina, rituximab o ciclofosfamida ≤ 300 mg/m2) administrada después de la leucaféresis para mantener el control de la enfermedad deberá suspenderse ≥ 7 días antes de la quimioterapia en dosis bajas.
    • Quimioterápicos citotóxicos que no se consideren linfotóxicos (véase más abajo) en la semana previa a la leucaféresis. Los antineoplásicos orales, incluidos la lenalidomida y el ibrutinib, están permitidos si han transcurrido como mínimo 3 semividas antes de la leucaféresis.
    • Agentes quimioterápicos linfotóxicos (p. ej., ciclofosfamida, ifosfamida, bendamustina) en las 2 semanas previas a la leucaféresis.
    • Fármacos experimentales en las 4 semanas previas a la leucaféresis, a menos que se haya documentado la ausencia de respuesta o la progresión de la enfermedad (PE) durante la terapia experimental y hayan transcurrido como mínimo 3 semividas antes de la leucaféresis.
    • Terapias inmunosupresoras administradas en las 4 semanas previas a la leucaféresis y la infusión de JCAR017 (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).
    • Infusiones de linfocitos de donante (ILD) en las 6 semanas previas a la infusión de JCAR017.
    • Radioterapia en las 6 semanas previas a la leucaféresis. Para ser elegibles, 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.
    • TPH alogénico en los 90 días previos a la leucaféresis.
    17. Trasplante de progenitores hematopoyéticos previo (solo aplicable a la cohorte 2).
    E.5 End points
    E.5.1Primary end point(s)
    - Non-Hodgkin lymphoma (NHL; including secondary central nervous system [CNS] involvement): Overall Response Rate (ORR)
    Cohorts 1, 2, 3, 4 and 6
    - Relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL): ORR
    Cohort 5
    - Linfoma no Hodgkin (LNH, incluida la afectación secundaria del sistema nervioso central [SNC]): Tasa de respuesta global (TRG)
    Cohortes 1, 2, 3, 4 y 6
    - Linfoma cerebral primario (LCP) recurrente/refractario (r/r): TRG
    Cohorte 5
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 2 years after JCAR017 infusion
    Hasta 2 años después de la infusión de JCAR017
    E.5.2Secondary end point(s)
    - Safety
    - Underlying chronic lymphocytic leukemia (CLL) in subjects with Richter´s transformation: ORR Cohort 6
    - Complete response rate (CRR)
    - Event-free survival (EFS)
    - Progression-free survival (PFS)
    - Overall survival (OS)
    - Duration of response (DOR)
    - PK
    - Patient-Reported Outcomes
    - Seguridad
    - Leucemia linfocítica crónica (LLC) subyacente en sujetos con transformación de Richter: TRG, cohorte 6
    - Tasa de respuesta completa (TRC)
    - Supervivencia sin acontecimientos (SSA)
    - Supervivencia sin progresión (SSP)
    - Supervivencia global (SG)
    - Duración de la respuesta (DdR)
    - FC
    - Resultados comunicados por el paciente
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to 2 years after JCAR017 infusion
    Hasta 2 años después de la infusión de JCAR017
    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. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    United Kingdom
    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 completing the post-treatment follow-up of this study 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 ensayo se define bien como la fecha de la última visita del último sujeto que complete el seguimiento postratamiento de este estudio, bien como la fecha en la que el último sujeto entre en el estudio de seguimiento a largo plazo, o bien como la fecha de recepción de la última entrada de datos del último sujeto necesaria para llevar a cabo el análisis principal, secundario y/o exploratorio, tal como se especifica en el protocolo, la que sea posterior.
    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 months5
    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 months5
    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: 62
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 62
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 114
    F.4.2.2In the whole clinical trial 124
    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 on this protocol until 24 months after last infusion of JCAR017, regardless of disease status, and rolled over to a separate LTFU protocol thereafter for up to 15 years after JCAR017 infusion.
    Dado que este protocolo implica la transferencia génica, el seguimiento a largo plazo de la seguridad del vector lentivírico, el estado de la enfermedad y la supervivencia continuará hasta que hayan transcurrido 24 meses desde la última infusión de JCAR017, independientemente del estado de la enfermedad, y posteriormente se prolongará dentro de un protocolo independiente de seguimiento a largo plazo durante un máximo de 15 años tras la infusión de JCAR017.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-05-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-16
    P. End of Trial
    P.End of Trial StatusRestarted
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