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    Summary
    EudraCT Number:2017-002116-14
    Sponsor's Protocol Code Number:CCTL019G2201J
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2018-07-13
    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 number2017-002116-14
    A.3Full title of the trial
    A phase II trial of tisagenlecleucel in first-line high-risk (HR) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (B-ALL) who are minimal residual disease (MRD) positive at the end of consolidation (EOC) therapy
    Ensayo fase II de tisagenlecleucel en primera línea en pacientes pediátricos y adultos jóvenes diagnosticados de leucemia linfoblástica aguda B (LLAB)
    de alto riesgo (AR) con enfermedad mínima residual positiva al final del tratamiento de consolidación.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to determine the efficacy and safety of tisagenlecleucel, an investigational therapy, in first-line high-risk children and adolescent patients with B-cell acute lymphoblastic leukemia who are minimal residual disease positive at the end of consolidation therapy
    Estudio clinico para determinar la eficacia y seguridad de tisagenlecleucel en primera línea en pacientes pediátricos y adultos jóvenes diagnosticados de leucemia linfoblástica aguda B (LLAB) de alto riesgo (AR) con enfermedad mínima residual positiva al final del tratamiento de consolidación.
    A.3.2Name or abbreviated title of the trial where available
    Study of efficacy and safety of tisagenlecleucel in HR B-ALL EOC MRD positive patients.
    Estudio de eficacia y seguridad de tisagenlecleucel en pacientes con LLAB de EMR+
    A.4.1Sponsor's protocol code numberCCTL019G2201J
    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 SponsorNovartis Farmacéutica, S.A
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica, S.A.
    B.5.2Functional name of contact pointTrial Monitoring Organization (TMO)
    B.5.3 Address:
    B.5.3.1Street AddressGran Vía de les Corts Catalanes 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number+34933064464
    B.5.5Fax numberNA
    B.5.6E-maileecc.novartis@novartis.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/3/14/1266
    D.3 Description of the IMP
    D.3.1Product nametisagenlecleucel
    D.3.2Product code CTL019
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTISAGENLECLEUCEL
    D.3.9.1CAS number 1823078-37-0
    D.3.9.2Current sponsor codeCTL019
    D.3.9.3Other descriptive nameAUTOLOGOUS T CELLS TRANSDUCED WITH LENTIVIRAL VECTOR CONTAINING A CHIMERIC ANTIGEN RECEPTOR DIRECTED AGAINST CD19
    D.3.9.4EV Substance CodeSUB177825
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number200000 to 250000000
    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 No
    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 RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name RoActemra
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nametocilizumab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtocilizumab
    D.3.9.1CAS number 375823-41-9
    D.3.9.3Other descriptive nameTOCILIZUMAB
    D.3.9.4EV Substance CodeSUB20313
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) 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 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
    Pediatric and young adult patients aged 1 to 25 years with first-line NCI high-risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) who are in CR1 with minimal residual disease (MRD) positive (MRD ≥ 0.01%) at the end of consolidation (EOC) therapy by central laboratory assessment.
    La población diana consiste en pacientes pediátricos y adultos jóvenes con edades de 1 a 25 años diagnosticados de LLA-B de novo de AR según el Instituto Nacional de Cáncer (INC), que presenten RC1 después del tratamiento de primera línea y enfermedad mínima residual ≥ 0.01% al
    final del tratamiento de consolidación con evaluación del laboratorio central.
    E.1.1.1Medical condition in easily understood language
    High-risk B-cell acute lymphoblastic leukemia
    Leucemia linfoblástica aguda B (LLAB) de alto riesgo
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10063625
    E.1.2Term Acute lymphoblastic leukemia recurrent
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10063621
    E.1.2Term Acute lymphoblastic leukaemia recurrent
    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
    To evaluate efficacy of tisagenlecleucel therapy as measured by the 5 years disease-free survival (DFS) rate by investigator assessment.
    Evaluar la eficacia de la terapia con tisagenlecleucel medida con la supervivencia libre de enfermedad (SLE) a los 5 años con evaluación del
    investigador.
    E.2.2Secondary objectives of the trial
    - Proportion of patients who are disease free without allogeneic SCT at 1 year
    - Overall survival (OS)
    - Proportion of patients achieving MRD-negative CR or CRi at month 3 post-tisagenlecleucel infusion
    - Proportion of patients in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion
    - Tisagenlecleucel manufacturing success rate in patients ≥1 year and <3 years
    - Impact of tisagenlecleucel on health-related Quality of Life (QoL) measures
    - Impact of tisagenlecleucel on neurocognitive measures
    - Safety of tisagenlecleucel therapy
    - Prevalence and incidence of immunogenicity to tisagenlecleucel and its impact on efficacy, safety and cellular kinetics
    - Characterize in vivo cellular kinetic profile of tisagenlecleucel transgene and CD3+ CAR-positive viable T cells including second infusion
    - Evaluate the relationship between B-cell and transgene persistence
    - Evaluate dose-exposure-response relationship
    Evaluar:
    -Proporción de pacientes libres de enfermedad sin TCM alogénico en 1 año.
    - Supervivencia global (SG)
    - Proporción de pacientes con RC o remisión completa con recuperación incompleta del recuento sanguíneo (RCi) con enfermedad mínima residual - a los 3 meses de la infusión de tisagenlecleucel
    - % de pacientes con RC o RCi con aplasia de células B persistente a lo largo del tiempo, después de la infusión de tisagenlecleucel.
    - Tasas de éxito de fabricación de tisagenlecleucel en pacientes de ≥1 año y < 3 años.
    - Impacto de tisagenlecleucel en las medidas de calidad de vida relacionada con la salud (QoL).
    - Impacto de tisagenlecleucel en la mediciones neurocognitivas.
    - Seguridad de la terapia con tisagenlecleucel.
    - Prevalencia e incidencia de inmunogenicidad a tisagenlecleucel e impacto en eficacia, seguridad y cinética celular.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for inclusion in this study have to meet all of the following criteria:
    1. CD19 expressing B-cell Acute Lymphoblastic Leukemia
    2. De novo NCI HR B-ALL who received 1st line treatment and are at MRD ≥ 0.01% at EOC. EOC bone marrow MRD will be collected prior to screening and will be assessed by multi-parameter flow cytometry using central laboratory analysis.
    3. Age 1 to 25 years at the time of screening
    4. Lansky (age <16 years) or Karnofsky (age ≥16 years) performance status ≥60% at screening
    5. Adequate organ function during the screening period
    • Renal function based on age/gender as described in the protocol
    • ALT ≤5 times ULN for age
    • AST ≤5 times ULN for age
    • Total bilirubin <2 mg/dL (for Gilbert’s Syndrome patients total bilirubin <4 mg/dL)
    • Adequate pulmonary function defined as
    - no or mild dyspnea (≤ Grade 1)
    - oxygen saturation of > 90% on room air
    • Adequate cardiac function defined as LVSF ≥ 28% confirmed by echocardiogram or LVEF ≥ 45% confirmed by echocardiogram or MUGA within 6 weeks of screening
    6. Prior induction and consolidation chemotherapy allowed, as decribed in the protocol
    7. Signed written informed consent and assent forms, if applicable, must be obtained prior to any study procedures
    8. Must meet the institutional criteria to undergo leukapheresis
    9. Once all other eligibility criteria are confirmed, must have a leukapheresis product of non-mobilized cells received and accepted by the manufacturing site.
    NOTE: Leukapheresis product will not be shipped to or assessed for acceptance by the manufacturing site until documented confirmation of all other clinical eligibility criteria is received.

    Other protocol-defined inclusion criteria may apply.
    -Leucemia linfoblástica aguda de células B que exprese CD19 (en sangre periférica o médula ósea con citometría de flujo)
    -Pacientes diagnosticados de LLA-B de novo de AR según el INC que recibieron tratamiento de primera línea y presenten enfermedad mínima residual ≥ 0.01% al final del tratamiento de consolidación (AR definido con los criterios del INC en el momento inicial de la presentación de la leucemia como edad ≥ 10 o recuento de leucocitos (WBC) ≥ 50 x 109 células/L). La enfermedad mínima residual de médula ósea al final del tratamiento de consolidación se recogerá antes de la selección y se evaluará con citometría de flujo de multiples parámetros utilizando el análisis del laboratorio central.
    - Edad de 1 a 25 años en el momento de la selección
    - Estado funcional de Lansky (edad < 16 años) o de Karnofsky (edad ≥ 16 años) ≥ 60% en la selección
    -Función orgánica adecuada durante el periodo de selección:
    - Función renal según la edad/sexo como se indica en el protocolo.
    ALT ≤ 5 veces el límite superior de normalidad (LSN) para la edad
    AST ≤ 5 veces el LSN para la edad
    Bilirrubina total < 2 mg/dL (para pacientes con síndrome de Gilbert, bilirrubina total < 4 mg/dL)
    Función pulmonar adecuada definida como:
    sin disnea o leve (≤ grado 1)
    saturación de oxígeno de > 90% en el aire ambiental
    Función cardíaca adecuada definida como LVSF ≥ 28% confirmado con ecocardiograma (ECO) o LVEF ≥ 45% confirmado con ECO o ventriculografía isotópica (MUGA) dentro
    de las 6 semanas de la selección.
    - Se permite quimioterapia de inducción o de consolidación previa descrita en el protocolo.
    - Los formularios de consentimiento informado por escrito (FCI) y de asentimiento firmados, si procede, deberán obtenerse antes de cualquier procedimiento del estudio.
    - Deberán cumplir los criterios institucionales para someterse a leucoféresis.
    -Cuando se hayan confirmado todos los criterios de elegibilidad, deberá haber un producto de leucoféresis de células no movilizadas recibido y aceptado por el centro de fabricación.
    NOTA: El producto de leucaféresis no será enviado o evaluado para su aceptación por el centro de fabricación hasta que se reciba la
    confirmación documentada de todos los otros criterios de elegibilidad clínicos.
    Cualquier otro criterio de inclusion definido en el protolo.
    E.4Principal exclusion criteria
    Patients eligible for this study must not meet any of the following criteria:
    1. M3 marrow (≥ 25% blasts by morphologic criteria) at the completion of first-line induction therapy
    2. M2 (i.e. ≥ 5% blasts by morphologic criteria) or M3 marrow or persistent extramedullary disease at the completion of first-line consolidation therapy. Patients with previous CNS disease are eligible if there is no active CNS involvement of leukemia at the time of enrollment.
    3. Philadelphia chromosome positive (Ph+) ALL
    4. Hypodiploid: less than 44 chromosomes and/or DNA index < 0.81, or other clear evidence of a hypodiploid clone
    5. Prior tyrosine kinase inhibitor therapy
    6. Subjects with concomitant genetic syndromes associated with bone marrow failure states: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down syndrome will not be excluded.
    7. Patients with Burkitt’s lymphoma/leukemia (i.e. patients with mature B-ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation).
    8. Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
    9. Has had treatment with any prior anti-CD19 therapy
    10. Treatment with any prior gene or engineered T cell therapy
    11. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to tisagenlecleucel infusion)
    12. Presence of active or prior hepatitis B or C as indicated by serology. Serology must be repeated, if the interval between testing at screening and tisagenlecleucel infusion exceeds 8 weeks.
    13. Human Immunodeficiency Virus (HIV) positivity as indicated by serology. Serology must be repeated, if the interval between testing at screening and tisagenlecleucel infusion exceeds 8 weeks.
    14. Subject had an investigational medicinal product within the last 30 days prior to screening
    NOTE: Investigational therapies must not be used at any time while on study until the first relapse following CTL019 infusion.
    15. If subjects are taking any of the medications defined in the protocol, their infusion (including a second infusion) must be delayed until the medications have been stopped (details according to in the protocol):
    a. Medications to be stopped > 72 hours prior to tisagenlecleucel infusion: Therapeutic systemic doses of steroids.
    b. Medications to be stopped at least 1 week prior to tisagenlecleucel infusion:
    • 6-thioguanine, asparginase (non-pegylated), vincristine, 6-mercaptopurine, and intrathecal methotrexate
    c. Medications to be stopped at least 2 weeks prior to tisagenlecleucel infusion:
    • Anthracyclines and cytarabine
    • Intravenous methotrexate.
    • Radiotherapy: Non-CNS site of radiation
    d. Medications to be stopped at least 4 weeks prior to tisagenlecleucel infusion: Pegylated-asparaginase
    e. Medications/Therapy to be stopped at least 8 weeks prior to tisagenlecleucel infusion:
    • Radiotherapy: Cranial radiation (for CNS 3 patient) therapy
    16. Pregnant or nursing (lactating) women
    NOTE: Female study participants of reproductive potential must have a negative serum pregnancy test performed within 24 hours before leukapheresis, lymphodepletion and prior to tisagenlecleucel infusion.
    17. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective method of contraception while taking study treatment and for at least 12 months after the tisagenlecleucel infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests. Highly effective contraception are detailed in the protocol.
    Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
    18. Sexually active males must use a condom during intercourse while taking study treatment and for at least 12 months after the tisagenlecleucel infusion and until CAR T-cells are no longer present by qPCR on two consecutive tests. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above.

    Other protocol-defined exclusion criteria may apply.
    1.Médula M3 (≥ 25% de blastos con criterios morfológicos) al final de la terapia de inducción de primera línea
    2.Médula M2 (es decir ≥ 5% de blastos con criterios morfológicos) o M3 o enfermedad extramedular persistente al final de la terapia de consolidación de primera línea. Los pacientes con enfermedad previa en el sistema nervioso central (SNC) son aptos si no se observa
    afectación activa de leucemia en el SNC en el momento de la inclusión
    3. LLA con cromosoma Filadelfia positivo (Ph+)
    4. Hipodiploide: menos de 44 cromosomas y/o índice de ADN < 0.81, u otra evidencia clara de un clon hipodiploide.
    5. Terapia previa con inhibidor de la tirosina quinasa
    6. Pacientes con síndromes genéticos concomitantes asociados con fallo en la función de médula ósea: como pacientes con anemia de Fanconi,
    síndrome de Kostmann, Síndrome de Shwachman u otro síndrome conocido de fallo medular. Los pacientes con síndrome de Down no
    serán excluidos.
    7. Pacientes con leucemia/linfoma de Burkitt (es decir, pacientes diagnosticados de LLA-B madura, leucemia con células B [sIg (inmunoglobulina de superficie) positiva y positividad restringida de kappa o lambda] TODAS, con morfología FAB L3 y/o translocación
    MYC)
    8. Neoplasia maligna previa, excepto carcinoma in situ cutáneo o del cuello del útero tratado con propósito curativo y sin evidencia de enfermedad activa.
    9. Que hayan sido tratados con terapia previa anti-CD19.
    10. Tratamiento previo con cualquier gen o terapia de células T diseñada.
    11. Infección bacteriana, viral o fúngica aguda, incontrolada, amenazante para la vida (por ejemplo, hemocultivo positivo ≤ 72 horas antes de la infusión de tisagenlecleucel).
    12. Presencia de hepatitis B o C activa o previa, determinado con serología (para los criterios detallados, véase Suplemento 3). La serología deberá repetirse, si el intervalo entre el análisis realizado en la selección y la infusión de tisagenlecleucel supera las 8 semanas.
    13. Positividad frente al virus de la inmunodeficiencia humana (VIH), indicado con serología. La serología deberá repetirse, si el intervalo entre el análisis realizado en la selección y la infusión de tisagenlecleucel supera las 8 semanas.
    14. Pacientes que hayan recibido un producto medicinal en investigación dentro de los últimos 30 días antes de la selección.
    NOTA: No deberán utilizarse terapias en investigación en ningún momento durante el estudio hasta la primera recaída después de la infusión de tisagenlecleucel.
    15. Si los pacientes están tomando alguna de las siguientes medicaciones su infusión (incluyendo una segunda infusión) deberá retrasarse hasta que las medicaciones se hayan suspendido de acuerdo con lo descrito en el protocolo:
    Medicaciones que han de suspenderse > 72 horas antes de la infusión de tisagenlecleucel: Dosis sistémicas terapéuticas de esteroides.
    Medicaciones que han de suspenderse por lo menos 1 semana antes de la infusión de tisagenlecleucel:
    • 6-tioguanina, asparginasa (no pegilada), vincristina, 6- mercaptopurina y metotrexato intratecal
    c. Medicaciones que han de suspenderse por lo menos 2 semanas antes de la infusión de tisagenlecleucel:
    • Antraciclinas y citarabina
    • Metotrexato intravenoso
    • Radioterapia: zona de radiación que no sea el SNC
    d. Medicaciones que han de suspenderse por lo menos 4 semanas antes de la infusión de tisagenlecleucel: asparaginasa pegilada
    e. Medicaciones/terapia que han/ha de suspenderse por lo menos 8 semanas antes de la infusión de tisagenlecleucel:
    • Radioterapia: terapia de radiación craneal (para sujetos SNC 3)
    16. Mujeres embarazadas o en periodo de lactancia
    NOTA: Las mujeres potencialmente fértiles deberán presentar una prueba de embarazo en suero negativa dentro de las 24 horas antes de
    la leucoféresis, depleción linfocitaria y antes de la infusión de tisagenlecleucel.
    17. Mujeres en edad fértil, definidas como todas las mujeres fisiológicamente capaces de quedarse embarazadas, salvo que utilicen métodos anticonceptivos altamente eficaces mientras reciban el tratamiento del estudio y durante por lo menos 12 meses después de la infusión de tisagenlecleucel y hasta que ya no se detecten células TCAR con reacción en cadena de la polimerasa cuantitativa (qPCR) en dos análisis consecutivos. Los métodos anticonceptivos altamente eficaces estan descritos en el protocolo.
    18. Los varones sexualmente activos deberán utilizar un preservativo durante el coito mientras reciban el tratamiento del estudio y durante por lo menos 12 meses después de la infusión de tisagenlecleucel y hasta que ya no se detecten células T-CAR con qPCR en dos análisis consecutivos.
    E.5 End points
    E.5.1Primary end point(s)
    5-year DFS rate. DFS is defined as the time from tisagenlecleucel infusion to morphologic relapse, occurrence of secondary malignancy or death due to any cause, whichever occurs first.
    Variable principal Tasa de SLE a los 5 años. La SLE se define como el tiempo desde la perfusión de tisagenlecleucel hasta la recidiva morfológica, aparición de una segunda neoplasia maligna o muerte por cualquier causa, lo que ocurriera primero.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After tisagenlecleucel infusion, efficacy will be assessed at Day 28, then every 3 months for the first year, every 6 months for the second year, then yearly until the EOS. Relapse and survival will be captured every 3 months throughout the study.
    Después de la perfusión de tisagenlecleucel, la eficacia se evaluará el día 28, luego cada 3 meses durante el primer año, cada 6 meses en el segundo año y luego anualmente hasta fin de estudio. La recaída y la supervivencia se capturarán cada 3 meses a lo largo del estudio.
    E.5.2Secondary end point(s)
    - Proportion of patients who are disease free without allogeneic SCT at 1 year
    - OS, i.e. the time from date of tisagenlecleucel infusion to the date of death due to any reason
    - Proportion of patients achieving MRD-negative CR or CRi at month 3 post-tisagenlecleucel infusion
    - Proportion of patients in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion
    - Proportion of patients who have tisagenlecleucel product successfully manufactured (meet all release criteria) over the total number of patients enrolled for the age ≥ 1 year and < 3 years at respective time points
    - PedsQL 4.0 and EuroQol EQ-5D in patients ≥ age 8 years; change from baseline
    - Cogstate computerized cognitive battery age standardized scores (5 tests: psychomotor function (DET), attention (IDN), working memory (ONB), visual learning (OCL) and executive function (GML) (in patients ≥ age 6 years)
    - Evaluation of adverse events, vital signs, laboratory and other parameters.
    - Prevalence and incidence of pre-existing and treatment induced immunogenicity
    - Pre-existing and treatment induced immunogenicity on clinical response, cellular kinetics (Cmax, AUC0-28d, Clast) and safety
    - Tisagenlecleucel transgene levels by qPCR in blood, bone marrow, and CSF if available
    - Expression of tisagenlecleucel detected by flow cytometry in blood and bone marrow
    - Cmax, Tmax, AUCs and other relevant cellular kinetic parameters in blood, bone-marrow, and CSF if available
    - B-cell recovery time and transgene levels over time
    - Dose-exposure-response relationship:
    • Response endpoints (e.g. DFS, OS, Month 3 response) and key safety events (e.g. CRS, neurological events, cytopenias) and relationships with dose
    • Response endpoints (e.g. DFS, OS, Month 3 response) and key safety events (e.g. CRS, neurological events, cytopenias) and relationship with relevant exposure parameters (e.g. AUC and Cmax)
    • Cellular kinetic parameters and relationship with dose
    - Proporción de pacientes que están libres de enfermedad sin TCM alogénico al cabo del primer año
    - OS, es decir, el tiempo desde la perfusión de tisagenlecleucel hasta la fecha de la muerte por cualquier causa
    - Proporción de pacientes que alcanzan una RC o RCi con EMR negativa a los 3 meses después de la perfusión de tisagenlecleucel
    - Proporción de pacientes con enfermedad residual mínima negativa a los 3 meses después de la perfusión.
    - Proporción de pacientes con RC o RCi con aplasia persistente de células B a lo largo del tiempo después de la perfusión de tisagenlecleucel
    - Proporción de pacientes que presentan un producto de tisagenlecleucel fabricado correctamente (que cumplen todos los criterios de liberación) sobre el número total de pacientes incluidos entre ≥ 1 año y < 3 años de edad en los respectivos momentos
    - PedsQL 4.0 y EuroQol EQ-5D en pacientes de ≥ 8 años de edad; cambio respecto a la basal
    - Puntuaciones estandarizadas por edad en las pruebas cognitivas computarizadas de Cogstate (5 pruebas: función psicomotora (DET), atención (IDN), memoria de trabajo (ONB), aprendizaje visual (OCL) y función ejecutiva (GML) (en pacientes de ≥ 6 años de edad)
    - Evaluación de los acontecimientos adversos, constantes vitales, pruebas analíticas y otros parámetros
    - Prevalencia e incidencia de inmunogenicidad preexistente e inducida por el tratamiento
    - Inmunogenicidad preexistente e inducida por el tratamiento en la respuesta clínica, la cinética celular (Cmax y AUC0-28d, Clast) y la seguridad
    - Niveles transgénicos de tisagenlecleucel evaluados mediante PCR cuantitativa en sangre, médula ósea y LCR si procede
    - Expresión de tisagenlecleucel detectada por citometría de flujo en sangre y la médula ósea
    - Cmax, Tmax, AUCs y otros parámetros cinéticos celulares relevantes en la sangre, la médula ósea y LCR si procede
    - Tiempo de recuperación de células B y niveles transgénicos a lo largo del tiempo
    - Relación dosis-exposición-respuesta:
    • Variables de respuesta (p. ej., DFS, OS, respuesta a los 3 meses), acontecimientos de seguridad principales(p. ej., CRS, acontecimientos neurológicos, citopenias) y relaciones con la dosis
    • Variables de respuesta (p. ej., DFS, OS, respuesta a los 3 meses), acontecimientos de seguridad principales (p. ej., CRS, acontecimientos neurológicos, citopenias) y relaciones con los parámetros de exposición relevantes (p. ej., AUC y Cmax)
    • Parámetros de cinética celular y relación con la dosis
    E.5.2.1Timepoint(s) of evaluation of this end point
    Subjects achieving CR or CRi at 1 year post infusion without SCT, overall survival, subjects achieving MRD negative CR or CRi at month 3 post infusion
    Pacientes que alcancen una RC o CRi al año después de la infusión sin TCM, supervivencia global, pacientes que alcancen una RC o RCi con EMR negativa a los 3 meses después de la infusión
    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Patient Reported Outcomes and Cogstate Neurocognitive Assessment in patients
    Medidas de calidad de vida relacionada con la salud (QoL) y mediciones neurocognitivas.
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 EEA15
    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
    Denmark
    Finland
    France
    Germany
    Italy
    Netherlands
    Norway
    Spain
    Sweden
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The study will end when approximately 80% of the all treated patients have been followed for at least 5 years or have DFS events, whichever occurs first (estimated in approximately 8 years after first patient first treatment (FPFT)).
    El estudio finalizará cuando aproximadamente al 80% de todos los pacientes tratados se les haya realizado un seguimiento de por lo menos 5 años o presenten acontecimientos de SLE, lo que ocurra primero (calculado en aproximadamente 8 años después del primer tratamiento del primer paciente (PTPP)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 125
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 10
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 45
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 70
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Pediatric patients
    Pacientes pediátricos
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 42
    F.4.2.2In the whole clinical trial 140
    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)
    Following the end of the study as defined in the protocol, per health authority requirements, patients are to be followed up to 15 years post-tisagenlecleucel infusion. Therefore, a post-study long-term follow-up for lentiviral vector safety monitoring will continue under a separate protocol.
    Una vez finalizado el estudio, tal como se define en el protocolo y de acuerdo con los requisitos de las autoridades sanitarias, los pacientes deben someterse a un seguimiento hasta 15 años después de la perfusión de tisagenlecleucel. Por lo tanto, después del estudio se realizará un seguimiento a largo plazo para monitorizar la seguridad de los vectores lentivirales con un protocolo aparte.
    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 Decision2018-09-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-07
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
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