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    Summary
    EudraCT Number:2016-001706-42
    Sponsor's Protocol Code Number:JCAR015-ALL-001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-08-22
    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 number2016-001706-42
    A.3Full title of the trial
    A Phase 2, Open-Label, Multiple Cohort, Single-Arm, Multi-Center Trial To Determine The Safety, Feasibility, And Efficacy Of JCAR015 In Adult Subjects With B-Cell Acute Lymphoblastic Leukemia
    Ensayo clínico multicéntrico de fase II, abierto, de cohortes múltiples y un solo brazo, para determinar la seguridad, viabilidad y eficacia del JCAR015 en sujetos adultos con leucemia linfoblástica aguda de células B
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the safety, feasibility and clinical activity of JCAR015, a CAR-T cell therapy, in adults with B-cell acute lymphoblastic leukemia
    Un estudio que evalúa la seguridad, viabilidad y actividad clinica de JCAR015, una terapia celular de CAR-T, en adultos con leucemia linfoblástica aguda de células B
    A.4.1Sponsor's protocol code numberJCAR015-ALL-001
    A.5.4Other Identifiers
    Name:Results StatementNumber:No subjects were recruited, no results available
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameJCAR015
    D.3.2Product code JCAR015
    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 CD3+ T Cells Expressing CD19 Chimeric Antigen Receptor
    D.3.9.2Current sponsor codeJCAR015
    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) 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 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
    B-cell Acute Lymphoblastic Leukemia (ALL)
    Leucemia linfoblástica aguda (LLA) de linfocitos B
    E.1.1.1Medical condition in easily understood language
    A cancer of B-cells, a type of white blood cell responsible for producing antibodies
    Es un cáncer de los linfocitos B, que son una clase de glóbulos blancos que producen 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 19.0
    E.1.2Level LLT
    E.1.2Classification code 10000845
    E.1.2Term Acute lymphoblastic leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Cohorts 1 – 4:
    To evaluate the efficacy of JCAR015 as measured by overall remission rate (ORR) after the final JCAR015 infusion in subjects with morphologic evidence of disease, based on independent review committee (IRC) assessment

    Cohort 5:
    To evaluate the safety and efficacy of JCAR015 in subjects with Minimal Residual Disease (MRD)
    Cohortes 1 – 4:
    Evaluar la eficacia de JCAR015 medida según la tasa de remisión global (TRG) después de la última infusión de JCAR015 en pacientes con evidencia morfológica de la enfermedad, conforme a la evaluación de un comité de revisión independiente (CRI)
    Cohorte 5:
    Evaluar la seguridad y la eficacia de JCAR015 en pacientes con enfermedad mínima residual (EMR)
    E.2.2Secondary objectives of the trial
    - To determine the safety and feasibility of administering JCAR015 in
    adult B-cell ALL subjects with relapsed/refractory disease.
    - To determine the safety and feasibility of administering JCAR015 in
    adult B-cell ALL subjects with minimal residual disease.
    - To evaluate disease control following administration of JCAR015 in
    adult B-cell ALL subjects with MRD.
    - To evaluate the percentage of subjects who achieve a complete
    remission (CR) or complete remission with incomplete peripheral blood
    count recovery (CRi) with no evidence of MRD in the bone marrow.
    - To characterize the cellular pharmacokinetic (PK) profile of JCAR015,
    including the quantity and persistence in the peripheral blood and bone
    marrow.
    - To evaluate the percentage of subjects who achieve a morphologic
    remission within 6 months after the final JCAR015 infusion and then
    proceed to hematopoietic stem cell transplantation (HSCT).
    • Determinar la seguridad y viabilidad de la administración de JCAR015 a pacientes adultos de LLA con enfermedad recidivante o resistente.
    • Determinar la seguridad y viabilidad de la administración de JCAR015 a pacientes adultos de LLA con enfermedad residual mínima.
    • Determinar la respuesta clínica de JCAR015 en pacientes de LLA tratados con JCAR015.
    • Evaluar el % de pacientes que logran una RC o una RCi sin que haya evidencia de EMR en la médula ósea (por debajo del límite de detección en la secuenciación génica de la inmunoglobulina de cadena pesada (IgH) o en la prueba de la PCRq para detectar BCR-ABL).
    • Caracterizar el perfil farmacocinético (FC) celular de JCAR015, incluida la cantidad y la persistencia en sangre periférica y en médula ósea.
    • Evaluar el porcentaje de pacientes que logran una remisión morfológica dentro de los 6 meses siguientes a la última infusión de JCAR015 y que luego reciben TCMH.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part A
    Inclusion Criteria common to all cohorts:
    1. Age ≥18 years at the time of signing the informed consent form
    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. Diagnosis of B-cell ALL
    5. Evidence of CD19 expression via flow cytometry (peripheral blood or
    bone marrow) or immunohistochemistry (bone marrow biopsy)
    6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
    7. No contraindications to cyclophosphamide. This includes subjects
    with:
    · hypersensitivity to cyclophosphamide, any of its metabolites
    · acute infections
    · bone marrow aplasia or bone marrow depression prior to treatment
    · urinary tract infection
    · acute urothelial toxicity from cytotoxic chemotherapy or radiation
    therapy
    · urinary outflow obstruction
    · obstruction
    8. Adequate organ function, defined as:
    a. Serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) OR
    calculated creatinine clearance (Cockcroft and Gault, see Appendix D) >
    30 mL/min/1.73 m2
    b. Alanine aminotransferase (ALT) ≤ 5 × ULN and direct bilirubin < 2.0
    mg/dL (or < 3.0 mg/dL for subjects with leukemic infiltration of the
    liver)
    c. Adequate pulmonary function, defined as ≤ Grade 1 dyspnea and
    oxygen saturation (SaO2) ≥ 92% on room air
    d. Adequate cardiac function, defined as left ventricular ejection fraction
    (LVEF) ≥ 40% as assessed by echocardiogram (ECHO) or multiple
    uptake gated acquisition (MUGA) performed within 1 month of signing
    the informed consent form
    9. Adequate central or peripheral vascular access for leukapheresis
    procedure. For subjects requiring central venous catheter (CVC)
    placement, a surgical consultation indicating subject eligibility for CVC
    placement is sufficient for enrolment.
    10. Subjects must agree to not donate blood, organs, sperm or semen,
    and egg cells for usage in other individuals without recipient knowledge
    about exposure to a genetically modified organ by the donor and having
    been informed about the potential risks associated with it at any point
    after receiving JCAR015 infusion.
    11. Females of childbearing potential (FCBP) must:
    a. Have two negative pregnancy tests as verified by the Investigator
    (one negative serum beta human chorionic gonadotropin (ß-hCG)
    pregnancy test result within 7 days prior to the first dose of
    cytoreductive chemotherapy, and one negative serum or urine
    pregnancy test at the Part B screening evaluation prior to first JCAR015
    infusion). She must agree to have another pregnancy test 90 days post
    final JCAR015 dose. This applies even if the subject practices true
    abstinence2 from heterosexual contact.
    b. Either commit to true abstinence from heterosexual contact 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 at least 28
    days prior to JCAR015 initial infusion and during the study therapy
    including dose interruptions. Cessation of contraception after this point
    should be discussed with a responsible physician.
    c. Agree to abstain from breastfeeding during study participation and for
    at least 90 days after the last dose of JCAR015.


    d. Agree to use highly effective methods of contraception during the
    entire study period (Part A through 12 months after the final JCAR015
    infusion).
    12. Males who have partners of childbearing potential must agree to use
    an effective barrier contraceptive method during the entire study period
    (Part A through 12 months after the final JCAR015 infusion).
    For additional cohort specific inclusion criteria, please refer to the
    protocol
    Part B
    1. Completion of Part A and successful generation of a JCAR015 cell
    product
    2. Results from bone marrow examination following Part A:
    a. Group 1: Morphological evidence of disease (≥ 5% blasts by
    morphology)
    b. Group 2: Morphologic complete remission (bone marrow with < 5%
    blasts) with or without blood count recovery (CR or CRi) or a
    hypoplastic, aplastic, or "recovery" marrow at Day 42 of Part A
    3. ECOG performance status between 0 and 2
    4. Adequate organ function, defined as:
    a. Serum creatinine ≤ 1.5 × age-adjusted ULN OR calculated creatinine
    clearance
    b. (Cockcroft and Gault) > 30 mL/min/1.73 m2
    c. ALT ≤ 5 × ULN (or ≤ 8 × ULN for subjects with leukemic infiltration of
    the liver) and direct bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects
    with leukemic infiltration of the liver)
    d. Adequate pulmonary function, defined as ≤ Grade 1 dyspnea and SaO2
    ≥ 92% on room air
    5. Females of childbearing potential and males who have partners of
    childbearing potential follow the same inclusion criteria as Part A.
    Parte A: Criterios de inclusión comunes a todas las cohortes: 1. Edad ≥18 años en el momento de la firma del consentimiento informado (FCI). 2. El paciente debe comprender y firmar de forma voluntaria un FCI antes de realizar cualquier evaluación/procedimiento del estudio. 3. El paciente es capaz y tiene la voluntad de cumplir con el calendario de visitas del estudio y otros requisitos del protocolo. 4. Diagnóstico de LLA de linfocitos B. 5. Evidencia de expresión de CD19 mediante citometría de flujo (sangre periférica o médula ósea) o inmunohistoquímica (biopsia de médula ósea). 6. Estado general <= 2 según la “Eastern Cooperative Oncology Group”. 7. No hay contraindicaciones para la ciclofosfamida. Esto incluye sujetos con: · Hipersensibilidad a ciclofosfamida, cualquiera de sus metabolitos ; Infecciones agudas; Aplasia de la médula ósea o depresión de la médula ósea antes del tto; Infección del tracto urinario; Toxicidad aguda urotelial por quimioterapia citotóxica o radioterapia; Obstrucción del flujo urinario; Obstrucción. 8. Función orgánica adecuada, definida como: a. Creatinina sérica ≤1,5 x límite sup. de la normalidad (LSN) ajustado por edad O aclaramiento de creatinina calculado (Cockcroft y Gault)>30 ml/min/1,73m2 b. Alanina aminotransferasa (ALT) ≤5 × LSN y bilirrubina directa <2,0mg/dl (o <3,0mg/dl para pacientes con infiltración leucémica del hígado). c. Función pulmonar adecuada, definida como disnea de grado ≤1 y saturación de oxígeno (SaO2) ≥92% en aire ambiental. d. Función cardíaca adecuada, definida como FEVI ≥40% determinada mediante ecocardiograma o MUGA dentro del mes siguiente a la firma del FCI. 9. Acceso vascular central o periférico adecuado para el procedimiento de leucoaféresis. Para incluir pacientes que necesitan la colocación de un catéter venoso central, es suficiente que haya una consulta quirúrgica que indique la elegibilidad del paciente. 10. Los sujetos deben aceptar no donar sangre, órganos, esperma o semen, y óvulos para su uso en otros individuos sin conocimiento del destinatario acerca de la exposición a un organismo modificado genéticamente por el donante y habiendo sido informado acerca de los riesgos potenciales asociados en cualquier momento después de recibir la infusión JCAR015 11. Mujeres con capacidad de concebir deben: a. Presentar 2 pruebas de embarazo negativas verificadas por el investigador (un resultado negativo en una prueba de embarazo de detección de β-hCG en los 7 días anteriores a la primera dosis de quimioterapia citorreductora y un test de embarazo en sangre u orina negativo en la selección de la parte B antes de la primera infusión de JCAR015). Aceptar someterse a otras pruebas de embarazo 90 días tras la dosis final de JCAR015. También aunque la paciente practique abstinencia total de contacto heterosexual. b. Compromiso bien de abstinencia total de contacto heterosexual o bien aceptar usar, y ser capaz de cumplir con un método anticonceptivo eficaz sin interrupción. Los métodos anticonceptivos deben incluir un método de eficacia elevada y un método adicional eficaz (de barrera) desde al menos 28 días antes de la infusión inicial de JCAR015 y durante todo el tto. del estudio, incluidas las interrupciones de dosis. Tras ese momento, deberá informarse a un médico responsable del cese de la toma de medidas anticonceptivas. c. Aceptar no amamantar durante la participación en el estudio y durante al menos 90 días tras la última dosis de JCAR015. d. Aceptar usar métodos anticonceptivos de eficacia elevada durante todo el estudio (y para la parte A, durante 12 meses tras la última infusión de JCAR015). 12. Los varones que tienen parejas con capacidad de concebir deben: a. Aceptar usar un método anticonceptivo de barrera eficaz durante todo el estudio (y para la parte A, durante 12 meses tras la última infusión de JCAR015). Parte B 1. Completar la parte A y generación con éxito de un producto celular JCAR015. 2. Resultados del examen de la médula ósea tras la parte A: a. Grupo 1: Evidencia morfológica de enfermedad (≥5% de blastos según morfología). b. Grupo 2: Remisión morfológica completa (médula ósea con <5% de blastos) con o sin recuperación del recuento sanguíneo (RC o RCi) o médula hipoplásica, aplásica o "en recuperación" el día 42 de la parte A. 3. Estado general entre 0 y 2 de la ECOG. 4. Función orgánica adecuada, definida como: a. Creatinina sérica ≤1,5 × LSN ajustado por edad O aclaramiento de creatinina calculado. b. (Cockcroft y Gault) >30 ml/min/1,73 m2. c. ALT ≤5 × LSN (o ≤8 × LSN para pacientes con infiltración leucémica del hígado) y bilirrubina directa <2,0 mg/dl (o <3,0 mg/dl para pacientes con infiltración leucémica del hígado) d. Función pulmonar adecuada, definida como disnea de grado ≤1 y SaO2 ≥92 % en aire ambiental. 5. Para las mujeres con capacidad de concebir y los varones que tienen parejas con capacidad de concebir se aplicarán los mismos criterios de inclusión que en la parte A
    E.4Principal exclusion criteria
    Part A
    1. Isolated extramedullary disease relapse
    2. Concomitant genetic syndrome such as Fanconi anemia, Kostmann
    syndrome, Shwachman syndrome, or any other known bone marrow
    failure syndrome
    3. Burkitt's lymphoma/leukemia or chronic myelogenous leukemia (CML)
    lymphoid blast crisis (p210 BCR-ABL+)
    4. Prior malignancy, unless treated with curative intent and with no
    evidence of active disease present for > 5 years before signing the
    informed consent form, with the following exceptions:
    a. Subjects with Stage I breast cancer that has been completely and
    successfully treated, requiring no therapy or only anti-hormonal therapy
    b. Subjects with T1N0M0 or T2N0M0 colorectal cancer who have been
    completely and successfully resected and who are disease-free for > 2
    years prior to screening
    c. Subjects with indolent prostate cancer, defined as clinical stage T1 or
    T2a, Gleason score ≤ 6, and prostate-specific antigen (PSA) < 10 ng/mL,
    requiring no therapy or only anti- hormonal therapy
    d. Subjects with a history of basal cell or squamous cell carcinoma of the
    skin, or carcinoma in situ of the cervix, fully resected, and with no
    evidence of active disease
    5. Treatment with any prior gene therapy product
    6. Active hepatitis B, active hepatitis C, or any human immunodeficiency
    virus (HIV) infection at the time of signing the informed consent form
    7. Systemic fungal, bacterial, viral, or other infection that is not
    controlled (defined as exhibiting ongoing signs/symptoms related to the
    infection and without improvement, despite appropriate antibiotics or
    other treatment) at the time of signing the informed consent form
    8. Presence of Grade II-IV (Glucksberg) or B-D (IBMTR) acute or
    extensive chronic GVHD at the time of signing the informed consent form
    9. Active CNS involvement by malignancy, defined as CNS-3 per NCCN
    guidelines. Subjects with a history of CNS disease that has been
    effectively treated (defined as one documented negative CSF evaluation
    within 1 month prior to signing the informed consent form) will be
    eligible
    10. History of any one of the following cardiovascular conditions within
    the past 6 months of signing the informed consent form: 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
    11. History or presence of clinically relevant CNS pathology such as
    epilepsy, generalized seizure disorder, paresis, aphasia, stroke, severe
    brain injuries, dementia, Parkinson's disease, cerebellar disease, organic
    brain syndrome, or psychosis
    12. Participation in an investigational research study using an
    investigational agent within 30 days of signing the informed consent
    form, with the exception of investigational anti-infective agents (eg,
    antibacterial, antifungal, antiviral)
    13. History of treatment with a murine-derived biological product
    (unless subject has been shown to be negative for human anti-mouse
    antibodies [HAMA] prior to or during screening). Prior use of
    blinatumomab is permitted (provided there is evidence of CD19
    expression per Part A Inclusion Criterion #4). Chimeric biological
    products (eg, rituximab) are not considered murine for the purpose of
    this protocol.
    14. Pregnant or nursing (lactating) women
    15. Use of prohibited medications (see Section 8.3 of the protocol for full
    details)
    16. Treatment with alemtuzumab within 6 months prior to
    leukapheresis, or treatment with clofarabine or cladribine within 3
    months prior to leukapheresis
    17. Uncontrolled medical, psychological, familial, sociological, or
    geographical conditions that do not permit compliance with the protocol,
    as judged by the Investigator; or subject unwillingness or inability to
    follow the procedures required in the protocol
    Part B
    1. Systemic fungal, bacterial, viral, or other infection that is not
    controlled (defined as exhibiting ongoing signs/symptoms related to the
    infection and without improvement, despite appropriate antibiotics or
    other treatment)
    2. Active CNS involvement by malignancy, defined as CNS-3 per NCCN
    guidelines. Subjects with a history of CNS disease that has been
    effectively treated (defined as one documented negative CSF evaluation
    within 1 month prior to signing the informed consent form) will be
    eligible
    3. Presence of clinically relevant CNS pathology such as epilepsy,
    generalized seizure disorder, paresis, aphasia, stroke, severe brain
    injuries, dementia, Parkinson's disease, cerebellar disease, organic brain
    injuries, dementia, Parkinson's disease, cerebellar disease, organic brain
    syndrome, or psychosis
    4. Presence of Grade II-IV (Glucksberg) or B-D (IBMTR) acute or
    extensive chronic GVHD
    5. Use of prohibited medications (see Section 8.3 of the protocol)
    6. Female subjects that have a positive serum or urine pregnancy test, or
    are pregnant
    Parte A : 1. Recidiva aislada de enfermedad extramedular. 2. Síndromes genéticos concomitantes: anemia de Fanconi, s. de Kostmann, s. de Shwachman o cualquier otro síndrome conocido de insuficiencia de la médula ósea.3. Linfoma/leucemia de Burkitt o crisis blástica linfoide (p210 BCR-ABL+) de leucemia mielógena crónica (LMC). 4. Neoplasia maligna previa, a no ser que se tratase con intención de curar y sin evidencia de enfermedad activa durante >5 años antes de la firma del FCI, con las excepción de: a. Pacientes con cáncer de mama en estadio I tratado completamente y con éxito, y que no requiere tto. o solo requiere tto. antihormonal. b. Pacientes con cáncer colorrectal T1N0M0 o T2N0M0 sometidos a una resección completa con éxito y que han estado sin enfermedad durante >2 años antes de la selección c. Pacientes con cáncer de próstata indolente, definido como en fase clínica T1 o T2a, con puntuación de Gleason ≤6, y PSA <10 ng/ml, que no necesitan tto. o solo necesitan tto. antihormonal d. Pacientes con antecedentes de carcinoma de células escamosas o carcinoma basal de la piel o carcinoma in situ del cuello uterino tratados con éxito y sin evidencia de enfermedad activa. 5. Cualquier tto. previo con un producto de terapia génica. 6. Hepatitis B o C activas o infección por cualquier virus de la inmunodeficiencia humana (VIH) en el momento de la firma del FCI. 7. Cualquier infección fúngica, bacteriana, vírica o de otro tipo no controlada (es no controlada si hay signos/síntomas en curso relacionados con la infección y no ha mejorado a pesar de haber recibido tto. adecuado con antibióticos u otros fármacos) en el momento de la firma del FCI. 8. Presencia de EICH aguda o extensiva crónica de grado II-IV (Glucksberg) o de grado B-D” (IBMTR) en el momento de la firma del FCI. 9. Compromiso activo del SNC por neoplasia maligna, definida como SNC-3 por las directrices NCCN. Los sujetos con historial de enfermedad del SNC efectivamente tratada (definida como una evaluación documentada negativa del LCR en el plazo de 1 mes antes de firmar el FCI) será elegible. 10. Historial de una de las siguientes enfermedades cardiovasculares en los 6 meses anteriores a la firma del FCI: Insuficiencia cardíaca de grado III o IV según la NYHA, angioplastia o stent cardíacos, infarto de miocardio, angina inestable u otra enfermedad cardíaca clínicamente significativa. 11. Historial o presencia de patología del SNC clínicamente relevante, como epilepsia, trastorno convulsivo generalizado, paresis, afasia, accidente cerebrovascular, lesión cerebral grave, demencia, enf. de Parkinson, enfermedad cerebelar, síndrome cerebral orgánico o psicosis. 12. Participación en un estudio de investigación con un fármaco en investigación en los 30 días anteriores a la firma del FCI, con la excepción de los fármacos antiinfecciosos en investigación (p. ej., antibacterias, antifúngicos, antivirales). 13. Antecedentes de tto. con un producto biológico de origen murino (a no ser que el paciente haya mostrado ser negativo para anticuerpos humanos antirratón [HAMA] antes de o durante la selección). Está permitido el uso previo de blinatumomab (siempre que haya evidencia de expresión de CD19 conforme al criterio de inclusión n.º 4 de la parte A). Los productos biológicos quiméricos (p. ej., rituximab) no se consideran murinos para los fines de este protocolo. 14. Mujeres embarazadas o lactantes. 15. Uso de medicación prohibida (ir a la sección 8.3 del protocolo para más detalles): 16. Tto. con alemtuzumab en los 6 meses anteriores a la leucoaféresis o tratamiento con clofarabina o cladribina en los 3 meses anteriores a ella. 17. Cualquier motivo médico, psicológico, familiar, sociológico o geográfico no controlado que no permita el cumplimiento con el protocolo, según el criterio del investigador, o falta de voluntad o de capacidad por parte del paciente para seguir los procedimientos exigidos por el protocolo.
    Parte B
    1. Cualquier infección fúngica, bacteriana, vírica o de otro tipo no controlada (es no controlada si hay signos/síntomas relacionados con la infección en curso y no ha mejorado a pesar de haber recibido tto. adecuado con antibióticos u otros fármacos). 2. Compromiso activo del SNC por neoplasia maligna, definida como SNC-3 por las directrices NCCN. Los sujetos con historial de enfermedad del SNC
    efectivamente tratada (definida como evaluación documentada negativa del LCR en el plazo de 1 mes antes de firmar el FCI) será elegible. 3. Presencia de patología clínicamente relevante del SNC: epilepsia, trastorno convulsivo generalizado, paresia, afasia, derrame cerebral, lesión cerebral grave, demencia, enf. de Parkinson, enf. del cerebelo, sindrome orgánico cerebral o psicosis. 4. Presencia de grado II-IV (Glucksberg) o de grado B-D (IBMTR) o EICH crónica aguda o extensiva. 4. Uso de medicación prohibida (ver sección 8. 3 del protocolo). 6. Mujeres con una prueba positiva de embarazo en orina o en suero o están embarazadas.
    E.5 End points
    E.5.1Primary end point(s)
    Cohorts 1 – 4:
    Efficacy: ORR, defined as the proportion of subjects with CR or CRi as
    determined by examination of the bone marrow, peripheral blood, and
    cerebrospinal fluid (CSF), as well as physical examination and evaluation
    of central nervous system (CNS) symptoms.
    Cohort 5:
    - Efficacy: MRD negative rate
    Cohortes 1 – 4:
    Eficacia: TRG, definida como la proporción de pacientes con RC o RCi determinada mediante análisis de la médula ósea, de la sangre periférica y del líquido cefalorraquídeo (LCR), así como mediante exploración física y mediante la evaluación de los síntomas del sistema nervioso central (SNC).
    Cohorte 5:
    - Eficacia: EMR negativa
    E.5.1.1Timepoint(s) of evaluation of this end point
    Cohorts 1 – 4:
    ORR: up to 6 months post final JCAR015 infusion
    Cohort 5:
    MRD negative rate: : 90 days post the final JCAR015 infusion
    Cohortes 1 – 4:
    TRG hasta 6 meses tras la infusión final JCAR015
    Cohorte 5:
    - Ratio EMR negativa: 90 dias tras la infusion final de JCAR015
    E.5.2Secondary end point(s)
    Safety: Type, frequency, and severity of adverse events (AEs) and
    laboratory abnormalities
    Efficacy:
    Efficacy:
    - Time from MRD response until MRD recurrence, morphologic relapse, or
    death
    - Relapse-free survival (RFS), defined as the time from achievement of
    CR or CRi, whichever occurs first, to relapse or death due to any cause
    - Event-free survival (EFS), defined as the time from the date of the first
    JCAR015 infusion to death from any cause, relapse, or treatment failure,
    whichever occurs first
    - Overall survival (OS), defined as the time from the date of the first
    JCAR015 infusion to date of death due to any reason
    - Percentage of subjects who achieve CR or CRi with an MRD-negative
    bone marrow, as assessed by IgH gene sequencing (or BCR-ABL qPCR or
    flow cytometry for Philadelphia chromosome-positive [Ph+] ALL
    subjects)
    - Depth of MRD response at 90 days after the last infusion of JCAR015. subjects)
    Feasibility: Proportion of subjects that have undergone leukapheresis
    who receive infusion of JCAR015
    Biomarker:
    - Cellular PK profile of JCAR015 (eg, Cmax, Tmax, AUC)
    - Maximum expansion of JCAR015 as defined by maximum copies/μg of
    genomic DNA and/or CAR-T cells/μL whole blood
    - Duration of persistence of JCAR015
    Seguridad: Tipo, frecuencia y gravedad de los acontecimientos adversos (AA) y anomalías de laboratorio.
    Eficacia:
    - Duración de la EMR o de la recidiva morfológica, o muerte debida a LLA de linfocitos B.
    - Supervivencia sin recidivas (SSR), definida como el tiempo transcurrido desde que se logra RC o RCi, lo que ocurra primero, hasta la recidiva o la muerte por cualquier motivo.
    - Supervivencia sin acontecimientos (SSA), definida como el tiempo transcurrido entre la fecha de la primera infusión de JCAR015 y la muerte por cualquier causa, la recidiva o el fracaso terapéutico, lo que ocurra primero.
    - Supervivencia global (SG), definida como el tiempo desde la fecha de la primera infusión de JCAR015 hasta el momento de la muerte por cualquier causa.
    - Porcentaje de pacientes que logran RC o RCi con una médula ósea negativa para EMR, evaluado mediante secuenciación génica de IgH (o PCRq para detectar BCR-ABL o citometría de flujo en pacientes con LLA positivos para el cromosoma Filadelfia [ph+]).
    Viabilidad: Proporción de pacientes que se han sometido a leucoaféresis y que reciben infusión de JCAR015.
    Biomarcador:
    - Perfil FC celular de JCAR015 (p. ej., Cmax, Tmax, ABC).
    - Expansión máxima de JCAR015, definida como el máximo de copias/μg de ADN genómico y/o células T CAR/μl de sangre completa.
    - Duración de la persistencia de JCAR015
    E.5.2.1Timepoint(s) of evaluation of this end point
    AE assessment: up to 24 months post the final JCAR015 infusion
    Efficacy: up to 24 months post the final JCAR015 infusion
    Depth of MRD response: 90 days post the final JCAR015 infusion
    Feasibility: From initiation of Part A until subject withdraws,
    discontinues or completes study
    Biomarker: up to 24 months post the final JCAR015 infusion
    Evaluación de acontecimientos adversos (AA) hasta 24 meses tras la infusión final de JCAR015.
    Eficacia: hasta 24 meses tras la infusión final de JCAR015

    Respuesta profunda de ERM: 90 días tras la infusión final de JCAR015
    Viabilidad: desde el inicio de la parte A hasta que el sujeto se retire, discontinúe o complete el estudio
    Biomarcador: hasta 24 meses después de la infusión final de JCAR015
    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) 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 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 concerned6
    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
    Germany
    Italy
    Spain
    Switzerland
    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 to complete the post-treatment follow-up, 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.
    Hay disponible un protocolo de extensión en el que se puede admitir a todos los pacientes que permanecen en el estudio, de modo que continúen teniendo acceso a JCAR015-LLA-001.
    Se realizará un seguimiento de los pacientes durante 15 años como máximo en un protocolo aparte de seguimiento a largo plazo.
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    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: 105
    F.1.3Elderly (>=65 years) No
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 105
    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)
    The Sponsor may consider closing this trial after data supporting key endpoints and objectives of the study have been analyzed. In the case
    where there are subjects who have undergone apheresis, and it is the opinion of the investigator that these subjects would receive benefit from treatment, the Sponsor may choose to initiate an open-label (rollover or extension) study under a separate protocol to allow these subjects continued access to JCAR015 following their participation in this study.
    El promotor puede considerar cerrar este estudio tras el analisis de los datos que apoyan los criterios de valoración principales y los objetivos.Si hay pacientes que hayan sido sometidos a aféresis, y que según criterio medico esos pacientes se pudieran beneficiar del tratamiento, el Promotor podrá optar por iniciar un estudio abierto (rollover o de extensión) bajo un protocolo separado para permitir que estos pacientes continúen accediendo a JCAR015 tras su participación en este estudio.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-11-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-10-07
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-03-01
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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