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    Summary
    EudraCT Number:2017-005019-15
    Sponsor's Protocol Code Number:CCTL019C2202
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-08-10
    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 number2017-005019-15
    A.3Full title of the trial
    A Phase II, single arm, multicenter open label trial to determine the safety and efficacy of tisagenlecleucel in pediatric patients with relapsed or refractory mature B-cell non-Hodgkin lymphoma (NHL) (BIANCA)
    Estudio fase II, abierto, multicéntrico, de un brazo único, para determiner la seguridad y la eficacia de tisagenlecleucel en pacientes pediátricos diagnosticados de linfoma no Hodgkin (LNH) de células B maduras en recaída/refractario (r/r) (BIANCA)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to determine the safety and efficacy of tisagenlecleucel in children and adolescents with non-Hodgkin lymphoma (NHL)
    Estudio para determinar la seguridad y la eficacia de tisagenlecleucel en niños y adolescents diagnosticados de linfoma no Hodgkin (LNH)
    A.3.2Name or abbreviated title of the trial where available
    BIANCA
    A.4.1Sponsor's protocol code numberCCTL019C2202
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/266/2017
    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 number0034933044464
    B.5.5Fax numberNANANA
    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 adolescents patients with CD19positive r/r mature B-cell NHL who have relapsed after one or more prior therapies or are primary refractory.
    Pacientes niños y adolescentes con CD19+ LNH de células B r/r. que han recaído después de una o más terapias previas o son refractarios primarios
    E.1.1.1Medical condition in easily understood language
    B-cell NHL
    LNH de Células B
    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 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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the efficacy of tisagenlecleucel therapy as measured by ORR and determined by local investigator assessments in subjects with aggressive r/r B-cell NHL.
    Evaluar la eficacia de la terapia tisagenlecleucel medida con la TRG y determinada con evaluación del investigador local en pacientes con LNH de células B agresivo r/r.
    E.2.2Secondary objectives of the trial
    1-Evaluate the duration of response (DOR)
    2-Evaluate event free survival (EFS)
    3-Evaluate relapse free survival (RFS)
    4-Evaluate progression free survival (PFS)
    5-Evaluate overall survival (OS)
    6-Evaluate the safety of tisagenlecleucel therapy
    7-Characterize the in vivo cellular kinetics (levels, expansion, persistence) of tisagenlecleucel cells into target tissues (blood, bone marrow, lymph nodes, cerebral spinal fluid and other tissues if available), as measured by qPCR in relation to safety and efficacy.
    8-Characterize the presence of pre-existing and treatment induced immunogenicity and impact on cellular kinetics and response
    9-Assess the proportion of subjects who proceed to transplant post-tisagenlecleucel therapy until end of study.
    10-Retrospective assessment of potential CRS predictive models considering also data from other CTL019 trials
    Evaluar la duración de la respuesta (DR)
    Evaluar la supervivencia libre de evento (SLE)
    Evaluar la supervivencia libre de recaída (SLR)
    Evaluar la supervivencia libre de progresión (SLP)
    Evaluar la supervivencia global (SG)
    Evaluar la seguridad de la terapia tisagenlecleucel.
    Caracterizar la cinética celular in vivo (niveles, expansión, persistencia) de las células tisagenlecleucel en tejidos diana (sangre, médula ósea, ganglios linfáticos, líquido cefalorraquídeo y otros tejidos, si están disponibles), medida con PCRq en relación con la seguridad y eficacia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Signed informed consent and assent forms if applicable must be obtained prior to participation in the study.
    2.Histologically confirmed (local evaluation) mature B-cell non-Hodgkin lymphoma (B-cell NHL) including the following subtypes; Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), gray zone lymphoma (GZL), and follicular lymphoma (FL).
    a.Note: Subjects with bone marrow involvement of >25% lymphoma cells by bone marrow biopsy/aspirate evaluation, will be excluded. Patients with B-cell NHL associated with Nijmegen breakage syndrome will be allowed.
    b.Sufficient formalin-fixed, paraffin-embedded (FFPE) tumor sample must be available for correlative analyses. A recent tumor sample obtained for the purpose of the study must be submitted, however if not clinically feasible, an archival tumor biopsy from the most recent relapse may be submitted instead. Excisional biopsies should be submitted wherever possible; in cases where this is not possible a core needle biopsy is allowed. Fine needle aspiration (FNA) is not suitable.
    3.Patients <18 years of age and weighing at least 6 kg at the time of screening.
    4.Patients who have relapsed after one or more prior therapies (can include allogeneic and autologous hematopoietic stem cell transplant) or are primary refractory (have not achieved a CR or PR after the first line of therapy).
    5.Measurable disease by radiological criteria in all patients at the time of screening.
    6.Karnofsky (age more or equal to 16 years) or Lansky (age <16 years) performance status more or equal to 60.
    7.Adequate bone marrow reserve without transfusions (transfusion > 2 weeks prior to laboratory assessment is allowed) defined as:
    a.Absolute neutrophil count (ANC) >1000/mm3
    b.Absolute lymphocyte count (ALC) >300/mm3
    c.absolute number of CD3+ T cells >150/mm3
    d.Platelets more or equal to 50000//mm3
    e.Hemoglobin more or equal to 8.0 g/dl
    8.Adequate organ function:
    a.a serum creatinine (sCR) based on gender/age as described in detail the protocol
    b.AST (aspartate aminotransferase) and ALT (alanine aminotransferase)less or equal to 5 times the upper limit of normal (ULN) for age.
    c.Bilirubin <1.5 x ULN (for Gilbert’s Syndrome patients total bilirubin <4 mg/dL).
    d.Adequate pulmonary function
    i.Oxygen saturation of >91% on room air.
    ii.No or mild dyspnea ( less or equal to Grade 1)
    9.Must have a leukapheresis material of non-mobilized cells accepted for manufacturing. Note: Leukapheresis material will not be shipped to or assessed for acceptance by the manufacturing site until documented confirmation of all other eligibility criteria is received.

    Other protocol-defined inclusion criteria may apply.
    1. El formulario de asentimiento, si procede, y el formulario de consentimiento informado firmado deberán obtenerse antes de la participación en el estudio.
    2. Linfoma no Hodgkin de células B maduras (LNH de células B) incluidos los siguientes subtipos: linfoma de Burkitt (BL),
    linfoma de células B grandes difuso (DLBCL), linfoma de células B mediastínico primario (PMBCL), linfoma de la zona
    gris (GZL) y linfoma folicular (FL), histológicamente confirmado (evaluación local).
    Nota: los pacientes con afectación de médula ósea por células linfomatosas > 25% evaluada con aspirado/biopsia de medulla ósea, serán excluidos.
    Los pacientes con LNH de células B asociado con síndrome de Nijmegen podrán participar.
    a. Deberá disponerse de suficiente muestra de tumor fijada en formalina, embebida en parafina (FFPE) para análisis
    correlativos. Deberá proporcionarse una muestra de tumor reciente obtenida para el propósito del estudio, sin embargo, si no es clínicamente viable, puede presentarse una biopsia de tumor almacenado de la recaída más reciente. Deberían proporcionarse biopsias excisionales cuando sea posible; en los casos donde no sea posible, se permite una biopsia core.
    No se permite aspirado con aguja fina (FNA).
    3. Pacientes <18 años y que pesen por lo menos 6 kg en el momento de la selección.
    4. Pacientes que presenten recaída después de una o más terapias previas (puede incluir trasplante alogénico y autólogo de progenitores hematopoyéticos) o que sean refractarios primaries (no han alcanzado una RC o RP después de la terapia de primera línea).
    5. Enfermedad medible con criterios radiológicos en todos los pacientes en el momento de la selección. Para los detalles, remítase al Suplemento 1.
    6. Estado funcional de Karnofsky (edad mayor o igual 16 años) o Lansky (edad <16 años) mayor o igual 60.
    7. Reserva de médula ósea adecuada sin transfusiones (la transfusión > 2 semanas antes para evaluaciones de laboratorio se permite) definida como:
    a. Recuento de neutrófilos absoluto (RAN) >1000/mm3
    b. Recuento de linfocitos absoluto (ALC) >300/mm3
    c. Número absoluto de células T CD3+ >150/mm3
    d. Plaquetas mayor o igual 50000//mm3
    e. Hemoglobina mayor o igual 8.0 g/dl
    8. Función orgánica adecuada
    a. Creatinina sérica (sCR) en función del sexo/edad
    b. Aspartato aminotransferasa (AST) y alanina aminotransferasa
    (ALT) menor o igual 5 veces el límite superior de normalidad (LSN) para la edad.
    c. Bilirrubina total < 2 mg/dL (bilirrubina total <4 mg/dl para pacientes con síndrome de Gilbert)
    d. Función pulmonar adecuada
    i. Saturación de oxígeno de >91% en aire ambiente
    ii. Sin disnea o disnea leve (menor o igual a grado 1)
    9. Deberá disponerse de un material de leucoféresis de células no movilizadas para fabricación: Nota: el material de leucoféresis no se enviará a ni será evaluado para aceptación por el centro de fabricación hasta la confirmación documentada de que se cumplen todos los otros criterios de elegibilidad.
    Aplican otros criterios de inclusion definidos por protocolo.
    E.4Principal exclusion criteria
    1.Prior gene therapy or engineered T cell therapy
    2.Prior treatment with any anti-CD19 therapy
    3.Allogeneic hematopoietic stem cell transplant (HSCT) <3 months prior to screening and less or equal than 4 months prior to infusion
    4.Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD) in patients who received prior allogeneic HSCT.
    5.Prior diagnosis of malignancy other than study indication, and not disease free for 5 years
    6.Active, uncontrolled infection despite treatment at screening
    7.Presence of active or prior hepatitis B or C as indicated by serology. Repeat serology is required if the interval between serology performed at screening and tisagenlecleucel infusion exceeds 8 weeks.
    8.Human Immunodeficiency Virus (HIV) positive test. Repeat serology is required if the interval between serology performed at screening and tisagenlecleucel infusion exceeds 8 weeks
    9.Active neurological autoimmune or inflammatory disorders not related to B cell NHL (e.g., Guillain-Barre syndrome, Amyotrophic Lateral Sclerosis)
    10.Active CNS involvement by malignancy. Note: Patients with history of CNS disease that have been effectively treated will be eligible.
    11.Patients with B-cell NHL in the context of post-transplant lymphoproliferative disorders (PTLD) associated lymphomas.
    12.Patients with concomitant genetic syndromes associated with bone marrow failure status such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Note: Patients with Down syndrome will not be excluded.
    13.Intolerance to the excipients of the tisagenlecleucel cell product
    14.Cardiac disorder defined as:
    a.Cardiac or cardiac repolarization abnormality, including any of the following:
    i.History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to starting study treatment
    ii.Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
    b.LVEF <45% as determined by ECHO or MRA or MUGA
    c.NYHA functional class III or IV
    15.Subjects enrolled in this study are not permitted to participate in additional parallel investigational drug or device studies
    16.Pregnant or nursing (lactating) women.
    Note: Women of child-bearing potential must have a negative serum pregnancy test performed at screening, within 24 hours prior to leukapheresis, within 24 hours prior to lymphodepletion Serum or urine, within 24 hours prior to tisagenlecleucel infusion and at EOS.
    17.Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods 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.
    18.Sexually active males who do not agree to 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.



    Other protocol-defined exclusion criteria may apply.
    1. Terapia genética o terapia de células T diseñada previa.
    2. Tratamiento previo con una terapia anti-CD19.
    3. Trasplante alogénico de progenitores hematopoyéticos (HSCT) < 3 meses antes de la selección y menor o igual a 4 meses antes de la infusión.
    4. Presencia de enfermedad de injerto contra huésped (GVHD) aguda o crónica extensa de grado 2 a 4 en pacientes que recibieron HSCT alogénico previo. Suplemento 7.
    5. Diagnostico previo de neoplasia maligna que no sea la indicación del estudio y no libre de enfermedad durante 5 años.
    6. Infección incontrolada, activa a pesar del tratamiento en la selección.
    7. Presencia de hepatitis B o C activa o previa, determinado con serología. Se requiere la repetición de la serología si el intervalo entre la serología realizada en la selección y la infusión de tisagenlecleucel excede las 8 semanas. Para los detalles, véase el Suplemento 3.
    8. Resultados positivo en la prueba del virus de inmunodeficiencia humana (VIH). Se requiere la repetición de la serología si el intervalo entre la serología realizada en la selección y la infusión de tisagenlecleucel excede las 8 semanas.
    9. Trastornos inflamatorios o autoinmunes neurológicos activos no relacionados con el LNH de células B (por ejemplo, síndrome de Guillain-Barré, esclerosis lateral amiotrófica).
    10. Afectación activa del sistema nervioso central (SNC) por neoplasia maligna. Nota: Los pacientes con antecedentes de enfermedad del SNC que hayan sido tratados de forma eficaz son elegibles.
    11. Pacientes con LNH de células B en el contexto de trastornos linfoproliferativos postrasplante (PTLD) asociado con linfomas.
    12. Pacientes con síndromes genéticos concomitantes con estado de fallo de médula ósea como pacientes con anemia de Fanconi, síndrome de Kostmann, síndrome de Shwachman o cualquier otro síndrome de fallo de médula ósea conocido. Nota: los pacientes con síndrome de Down no serán excluidos.
    13. Intolerancia a los excipientes del producto de células tisagenlecleucel.
    14. Trastornos cardíacos definidos como:
    a. Anomalía cardíaca o de repolarización cardíaca, que incluya algo de lo siguiente:
    i. Antecedentes de infarto de miocardio (MI), angina de pecho o bypass coronario arterial por injerto (CABG)
    dentro de los 6 meses antes de iniciar el tratamiento del estudio.
    ii. Arritmias cardíacas clínicamente significativas (por ejemplo, taquicardia ventricular), bloqueo de rama
    izquierda completo, bloqueo auriculoventricular (AV) de grado alto (por ejemplo, bloqueo bifascicular, tipo II de
    Mobitz y bloqueo AV de tercer grado)
    b. Fracción de eyección ventricular izquierda (LVEF) < 45%, determinado con ecocardiograma (ECO) o angiografía por
    resonancia magnética (MRA) o ventriculografía isotópica (MUGA).
    c. Clase funcional III o IV de la Asociación de Cardiología de Nueva York (NYHA) (Chavey et al 2001).
    15. Los pacientes incluidos en este estudio no pueden participar en estudios paralelos adicionales con dispositivos o fármacos en investigación.
    16. Mujeres embarazadas o en periodo de lactancia.
    Nota: Las mujeres físicamente fértiles (WOCBP) deberán presentar una prueba de embarazo negativa realizada en la selección, dentro de las 24 horas antes de la leucoféresis, depleción linfocítica, infusión de tisagenlecleucel y en la EOS.
    17. Mujeres físicamente fértiles, definidas como todas las mujeres fisiológicamente capaces de quedarse embarazadas, a no ser que estén utilizando 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 T del receptor del antígeno quimérico (CAR) con PCRq en dos análisis consecutivos.
    18. Varones sexualmente activos que no utilicen 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 CAR-T con PCRq en dos análisis consecutivos.
    Aplican otros criterios de inclusion definidos por protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    Overall response rate (ORR), which includes complete response (CR) and partial response (PR) determined by local investigator assessments.
    Ratio de respuesta global, que incluye respuesta complete (RC) y respuesta parcial (RP) determinado a juicio del investigador local.
    E.5.1.1Timepoint(s) of evaluation of this end point
    as defined per protocol
    definido por protocolo
    E.5.2Secondary end point(s)
    1-DOR
    2-EFS
    3-RFS
    4-PFS
    5-OS
    6- Physical examination, vital signs, adverse events, , laboratory abnormalities, performance status and as applicable physical development
    7- Cellular kinetics parameters and/or other relevant parameters in peripheral blood, bone marrow, lymph nodes, cerebrospinal fluid and other tissues as appropriate, month 3 response, safety endpoint (CRS grade).
    8-Levels of pre-existing and treatment induced immunogenicity, cellular kinetic parameters, and efficacy (Month 3 response)
    9-Number of subjects that proceed to SCT after tisagenlecleucel infusion until EOS will be described
    10-Assess the ability for early prediction of cytokine release syndrome utilizing clinical and biomarker data
    1-DR
    2-SLE
    3-SLR
    4-SLP
    5-SG
    6-Exploración física, constantes vitales, acontecimientos adversos, anomalías de laboratorio, estado funcional y, cuando proceda, desarrollo físico.
    7-Parámetros cinéticos celulares y/u otros parámetros relevantes en sangre periférica, médula ósea, ganglios linfáticos, líquido cefalorraquídeo y otros tejidos, si procede, respuesta en el mes 3, variables de seguridad (grado del CRS).
    8-Niveles de inmunogenicidad inducida por el tratamiento y preexistente, parámetros cinéticos celulares y eficacia (respuesta en el mes 3).
    9-Se describirá el número de sujetos que sean sometidos a SCT después de la infusión de tisagenlecleucel hasta la EOT.
    10-Evaluar la capacidad de predicción precoz de síndrome de liberación de citoquinas utilizando los datos clínicos y de biomarcadores
    E.5.2.1Timepoint(s) of evaluation of this end point
    as defined per protocol
    definido por protocolo
    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 No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) 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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Canada
    Denmark
    Finland
    France
    Germany
    Italy
    Japan
    Netherlands
    Norway
    Spain
    Sweden
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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 study (EOS) assessments for each subject is completed within 2 weeks of a subject’s death, premature withdrawal of consent, or when all infused and evaluable subjects with aggressive B-cell NHL have completed Month 24 evaluation or discontinued early. A final Clinical Study Report will be produced once all subjects complete the study.
    Las evaluaciones de final del estudio (EOS) para cada sujeto se completarán dentro de las 2 semanas de la muerte de un sujeto, retirada prematura del consentimiento o cuando todos los pacientes con NHL agresivo de células B evaluables y que hayan recibido la infusión, hayan completado la evaluación del mes 24 o hayan sido retirados prematuramente. Se producirá un informe de estudio clínico final cuando todos los sujetos completen el estudio.
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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: 35
    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: 5
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    F.1.2Adults (18-64 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    pediatric patients
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 21
    F.4.2.2In the whole clinical trial 35
    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.
    Después de la EOS, a los pacientes se les pedirá que continúen en un seguimiento a largo plazo posterior al estudio (LTFU) en un protocolo de destino separado, durante hasta 15 años después de la infusión.
    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 Decision2018-11-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-08
    P. End of Trial
    P.End of Trial StatusOngoing
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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