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    Summary
    EudraCT Number:2013-003205-25
    Sponsor's Protocol Code Number:CCTL019B2202
    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:2015-08-06
    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 number2013-003205-25
    A.3Full title of the trial
    A Phase II, single arm, multicenter trial to determine the efficacy and safety of CTL019 in pediatric patients with relapsed and refractory B-cell acute lymphoblastic leukemia
    Ensayo de fase II, de un solo grupo, multicéntrico, para determinar la eficacia y la seguridad de CTL019 en pacientes pediátricos con leucemia linfoblástica aguda de células B en recaída y refractaria
    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 CTL019, an investigational gene therapy, in children and adolescent patients with a recurrent form of B-cell acute lymphoblastic leukaemia
    Un estudio clínico para determinar la eficacia y seguridad de CTL019, una terapia génica de investigación, en niños y pacientes adolescentes con una forma recurrente de células B de leucemia linfoblástica aguda
    A.3.2Name or abbreviated title of the trial where available
    Study of efficacy and safety of CTL019 in relapsed/refractory paediatric B cell ALL (Eliana)
    Estudio de la eficacia y la seguridad de CTL019 en pacientes pediátricos con LLA (Eliana)
    A.4.1Sponsor's protocol code numberCCTL019B2202
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02435849
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/103/2015
    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 Services 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 pointDepartamento Médico Oncología (GMO)
    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 number34900353036
    B.5.5Fax number34932479903
    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 nameCTL019
    D.3.2Product code CTL019
    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 INNCélulas Linfocitos T diferenciadas adultas autólogas de sangre periférica expandidas infectadas con un vector lentiviral expresando un CAR
    D.3.9.1CAS number CTL019
    D.3.9.2Current sponsor codeCTL019
    D.3.9.3Other descriptive nameCélulas Linfocitos T diferenciadas adultas autólogas de sangre periférica expandidas infectadas con un vector lentiviral expresando un CAR
    D.3.9.4EV Substance CodeSUB176601
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number2000000 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) Yes
    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 RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name RoActemra
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited, UK
    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.3.9.2Current sponsor codeTOCILIZUMAB
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Fludarabina
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameFludarabina
    D.3.4Pharmaceutical form Concentrate for solution for injection/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 INNFLUDARABINE
    D.3.9.1CAS number 21679-14-1
    D.3.9.2Current sponsor codeFLUDARABINE
    D.3.9.3Other descriptive nameFLUDARABINE
    D.3.9.4EV Substance CodeSUB07678MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product 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 No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Genoxal
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameCiclofosfamida
    D.3.4Pharmaceutical form Solution for injection/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 INNCYCLOPHOSPHAMIDE
    D.3.9.1CAS number 50-18-0
    D.3.9.2Current sponsor codeCYCLOPHOSPHAMIDE
    D.3.9.3Other descriptive nameCYCLOPHOSPHAMIDE
    D.3.9.4EV Substance CodeSUB06859MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product 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 No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Citarabina
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameCitarabina
    D.3.4Pharmaceutical form Solution for injection/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 INNCYTARABINE
    D.3.9.2Current sponsor codeCYTARABINE
    D.3.9.3Other descriptive nameCYTARABINE
    D.3.9.4EV Substance CodeSUB06880MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product 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 No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Etoposido
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameEtoposido
    D.3.4Pharmaceutical form Concentrate for solution for injection/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 INNETOPOSIDE
    D.3.9.2Current sponsor codeETOPOSIDE
    D.3.9.3Other descriptive nameETOPOSIDE
    D.3.9.4EV Substance CodeSUB07337MIG
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product 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 No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 7
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Privigen
    D.2.1.1.2Name of the Marketing Authorisation holderCSL BEHRING S.A.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameImmunoglobulina humana normal
    D.3.4Pharmaceutical form Solution 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 INNPrivigen
    D.3.9.2Current sponsor codeHUMAN NORMAL IMMUNOGLOBULIN
    D.3.9.3Other descriptive nameHUMAN NORMAL IMMUNOGLOBULIN (IV)
    D.3.9.4EV Substance CodeSUB12041MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Paediatric patients with B-cell acute lymphoblastic leukaemia who are chemo-refractory, relapsed after allogeneic SCT, or are otherwise ineligible for allogeneic SCT.
    Pacientes pediátricos con LLA de células B leucemia linfoblástica aguda que son quimio-refractarios, que han recaído después de transplante alogénico, o son por otro motivo no elegibles para transplante alogénico.
    E.1.1.1Medical condition in easily understood language
    Paediatric patients with a recurrent form of B-cell acute lymphoblastic leukaemia
    Pacientes pediátricos con leucemia linfoblástica aguda recurrente 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 18.1
    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 18.1
    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
    Evaluate the efficacy of CTL019 therapy as measured by overall remission rate (ORR) during the 6 months after CTL019 administration, which includes CR and CR with incomplete blood count recovery (CRi) as determined by IRC assessment
    Evaluar la eficacia de la terapia con CTL019 medida por la tasa de remisión global (TRG) durante 6 meses después de la administración de CTL019, lo que incluye la remisión completa (RC) y la RC con recuperación incompleta del recuento de las células sanguíneas (RCi) según ha determinado la evaluación por un comité de revisión independiente (IRC).
    E.2.2Secondary objectives of the trial
    - Evaluate the percentage of patients who achieve a best overall response (BOR) of CR or CRi with a MRD negative bone marrow by central analysis using qPCR
    - Evaluate the percentage of patients who achieve CR or CRi at Month 6 without SCT between CTL019 infusion and Month 6 response assessment
    - Evaluate the percentage of patients who achieve CR or CRi and then proceed to SCT while in remission before Month 6 response assessment
    - Evaluate the duration of remission (DOR)
    - Evaluate the relapse-free survival (RFS)
    - Evaluate the event-free survival (EFS)
    - Evaluate the overall survival (OS)
    - Evaluate the safety of CTL019 therapy
    - Characterize the in vivo cellular pharmacokinetic (PK) profile (levels, persistence, trafficking) of CTL019 cells
    - Describe the prevalence and incidence of immunogenicity to CTL019
    - Evaluar el porcentaje de pacientes que logran RC o RCi en el Mes 6 sin TCM entre la infusión de CTL019 y la evaluación de la respuesta en el Mes 6.
    - Evaluar el porcentaje de pacientes que logran RC o RCi y luego pasan a TCM mientras están en remisión antes de la evaluación de la respuesta en el Mes 6.
    -Evaluar la duración de la remisión (DOR).
    -Evaluar la supervivencia libre de recaída (SLR), la supervivencia libre de acontecimientos (SLA) y la supervivencia global (SG).
    - Evaluar la respuesta el Día 28 +/- 4 días
    - Evaluar el impacto de la carga tumoral basal sobre la respuesta
    - Evaluar la calidad de la respuesta
    -Evaluar la eficacia y la seguridad de la terapia con CTL019
    -Caracterizar el perfil farmacocinético (PK) celular in vivo (niveles, persistencia, transporte) de las células CTL019 en tejidos diana (sangre, médula ósea, líquido cefalorraquídeo (LCR) y otros tejidos si están disponibles).
    - Describir la prevalencia y la incidencia de inmunogenicidad a CTL019.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A multicenter study of apheresis collection of peripheral blood mononuclear cells (PBMC) in patients with CD19 expressing malignancies who could be eligible for a CTL019 clinical research trial.
    V.02 dated January 8, 2015.
    Estudio multicéntrico de recogida de células mononucleadas de sangre periférica por aféresis en pacientes con neoplasias malignas que expresan CD19 que pueden ser candidatos a ensayos de investigación clínica de CTL019.
    V. 02 de fecha 8 de Enero de 2015.
    E.3Principal inclusion criteria
    Inclusion Criteria:
    Relapsed or refractory pediatric B-cell ALL.
    a.2nd or greater Bone Marrow (BM) relapse OR.
    b.Any BM relapse after allogeneic stem cell transplantation (SCT) and must be ? 6 months from SCT at the time of CTL019 infusion OR
    c. Primary refractory as defined by not achieving a CR after 2 cycles of a standard chemotherapy regimen or chemorefractory as defined by not achieving a CR after 1 cycle of standard chemotherapy for relapsed leukemia OR
    d.Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy (TKI), or if TKI therapy is contraindicated OR.
    e.Ineligible for allogeneic SCT.
    2.For relapsed patients, documentation of CD19 tumor expression in bone marrow or peripheral blood by flow cytometry within 3 months of study entry.
    3.Adequate organ function defined as:
    a.Renal function defined as: A serum creatinine based on age/gender as follows: Maximum Serum Creatinine (mg/dL) - Age/Male/Female: 1 to < 2 years/0.6/0.6; 2 to < 6 years/0.8/0.8; 6 to < 10 years/1.0/1.0; 10 to < 13 years/1.2/1.2; 13 to < 16 years/1.5/ 1.4; ? 16 years/1.7/1.4.
    b.Alanine Aminotransferase (ALT) ? 5 times the upper limit of normal (ULN) for age.
    c.Bilirubin < 2.0 mg/dL.
    d.?Grade1 dyspnea and pulse oxygenation > 91% on room air.
    e.Left Ventricular Shortening Fraction (LVSF) ? 28% confirmed by echocardiogram (ECHO), or Left Ventricular Ejection Fraction (LVEF) ? 45% confirmed by echocardiogram or Multiple Uptake Gated Acquisition (MUGA).
    4.Bone marrow with ? 5% lymphoblasts by morphologic assessment at screening.
    5.Life expectancy > 12 weeks.
    6.Age 3 at the time of screening to age 21 at the time of initial diagnosis
    7.Karnofsky (age ? 16 years) or Lansky (age < 16 years) performance status ? 50 at screening.
    8.Must have an apheresis product of non-mobilized cells received and accepted by the manufacturing site.
    Other protocol defined inclusion criteria may apply.
    1.LLA de células B en recaída o refractaria en pacientes pediátricos
    a.Segunda o más recaídas en médula ósea (MO), O
    b.Cualquier recaída en MO después de trasplante de células madre (TCM) alogénico y ? 6 meses desde el TCM y el momento de la infusión de CTL019, O
    c.Enfermedad refractaria primaria definida por el hecho de no lograr RC después de 2 ciclos de una pauta estándar de quimioterapia o quimiorrefractaria definida por el hecho de no lograr RC después de 1 ciclo de quimioterapia estándar para la leucemia en recaída, O
    d.Los pacientes con LLA con cromosoma Filadelfia (Ph+) son elegibles si no toleran o no han respondido a 2 líneas de terapia con inhibidores de tirosina cinasa (TKI) o si la terapia con TKI está contraindicada, O
    e.No elegibles para TCM alogénico debido a:
    ?Enfermedad concomitante
    ?Otras contraindicaciones a TMC alogénico que condicionan la pauta
    ?Falta de un donante adecuado
    ?TCM previo
    ?Rechazo de TCM alogénico como opción terapéutica después de discusión documentada sobre el papel del TCM con un médico especialista en trasplante de médula ósea (TMO) que no forme parte del equipo del estudio
    2.En pacientes con recaída, documentación de la expresión tumoral CD19 en médula ósea o en sangre periférica mediante citometría de flujo en el plazo de 3 meses de la entrada en el estudio
    3.Función orgánica adecuada definida como:
    a.Función renal definida como:
    ?Creatinina sérica basada en la edad/sexo
    b.Alanino aminotransferasa (ALT) ? 5 veces el límite superior de normalidad (LSN) para la edad
    c.Bilirrubina < 2,0 mg/dl
    d.Nivel de reserva pulmonar mínima definida como disnea ? grado 1 y oximetría de pulso > 91% en aire ambiente
    e.Fracción de acortamiento ventricular izquierdo (FAVI) ? 28% confirmado por ecocardiograma (ECO) o fracción de eyección ventricular izquierda (FEVI) ? 45% confirmada por ecocardiograma o ventriculografía isotópica (MUGA)
    4.Médula ósea con ? 5% de linfoblastos por evaluación morfológica en la selección
    5.Esperanza de vida > 12 semanas
    6.Tres años de edad en el momento de la selección hasta 21 años de edad en el momento del diagnóstico inicial
    7.Estado funcional de Karnofsky (edad ? 16 años) o de Lansky (edad < 16 años) ? 50 en la selección
    8. Antes de cualquier procedimiento del estudio, se debe obtener el formulario de consentimiento informado por escrito firmado y el formulario de asentimiento, si procede
    9.Se deben cumplir los criterios del hospital para la práctica de leucoféresis o disponer de un producto de aféresis conservado aceptable
    10.Una vez confirmados todos los demás criterios de elegibilidad, se debe disponer de un producto de aféresis de células no movilizadas recibidas y aceptadas por el centro de fabricación. Nota: El producto de aféresis no se enviará al centro de fabricación ni será evaluado para su aceptación por el centro de fabricación hasta que se reciba la confirmación documentada de los demás criterios de elegibilidad.
    E.4Principal exclusion criteria
    Exclusion Criteria:
    1.Isolated extra-medullary disease relapse
    2.Patients with concomitant genetic syndrome: 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.
    3.Patients with Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation)
    4.Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease
    5.Treatment with any prior gene therapy product
    6.Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
    7.Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening
    8.Human Immunodeficiency Virus (HIV) positive test within 8 weeks of screening
    9.Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD)
    10.Active CNS involvement by malignancy, defined as CNS-3 per NCCN guidelines. Note: Patients with history of CNS disease that has been effectively treated will be eligible
    11.Patient has an investigational medicinal product within the last 30 days prior to screening
    12.Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion
    13. Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants, unless they are using highly effective methods of contraception for a period of 1 year after the CTL019 infusion. Highly effective contraception methods include:
    a.Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are NOT acceptable methods of contraception
    b.Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    c.Male sterilization (at least 6 months prior to screening). For female patients on the study the vasectomized male partner should be the sole partner for that patient.
    d. BOTH of the following forms of contraception must be utilized:
    - Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
    - Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
    e.Use of IUDs are excluded due to increased risks of infection and bleeding in this population.
    f.In case of use of oral contraception, women must be stable on the same pill for a minimum of 3 months before taking study treatment.

    Women who are not of reproductive potential (defined as either <11 years of age, Tanner Stage 1, post-menopausal for at least 24 consecutive months or have undergone hysterectomy, salpingotomy, and/or bilateral oophorectomy) are eligible without requiring the use of contraception. Acceptable documentation includes written or oral documentation communicated by clinician or clinician's staff of one of the following:
    1.Demographics show age <11
    2.Physical examination indicates Tanner Stage 1
    3.Physician report/letter
    4.Operative report or other source documentation in the patient record
    5.Discharge summary
    6.Follicle stimulating hormone measurement elevated into the menopausal range
    Other protocol-defined exclusion may apply.
    1.Recaída de enfermedad extramedular aislada
    2.Pacientes con un síndrome genético concomitante: anemia de Fanconi, síndrome de Kostmann, síndrome de Shwachman o cualquier otro síndrome de insuficiencia medular conocido. No se excluirán los pacientes con síndrome de Down.
    3.Los pacientes con linfoma/leucemia de Burkitt (es decir, pacientes con LLA de células B maduras, leucemia con LLA de células B [inmunoglobulina de superficie (IgS) positiva y positividad restringida a kappa o lambda], con morfología L3 French-American-British [FAB] y/o traslocación MYC)
    4.Neoplasia maligna previa, excepto carcinoma in situ de la piel o del cuello uterino tratado con intención curativa y sin evidencia de enfermedad activa
    5.Tratamiento previo con cualquier producto de terapia génica
    6.Haber recibido tratamiento previo con cualquier terapia anti-CD19/anti-CD3 o con cualquier otra terapia anti-CD19
    7.Hepatitis B activa o latente o hepatitis C activa (prueba en el plazo de 8 semanas de la selección) o cualquier infección no controlada en la selección
    8.Positividad al virus de la inmunodeficiencia humana (VIH) en el plazo de 8 semanas de la selección
    9.Presencia de enfermedad de injerto contra huésped (EICH) crónica de grado 2-4 aguda o extensa
    10.[Retirado de la versión 01 del protocolo modificado]
    11.Afectación activa por la neoplasia maligna del sistema nervioso central (SNC), definida como SNC-3 según las guías de la National Comprehensive Cancer Network (NCCN). Nota: Los pacientes con antecedentes de enfermedad del SNC que se hayan tratado eficazmente serán elegibles
    12.Paciente que haya recibido un medicamento en investigación en los últimos 30 días antes de la selección
    13.Mujeres embarazadas o en período de lactancia NOTA: las mujeres participantes en el estudio con potencial reproductivo deberán obtener un resultado negativo en la prueba de embarazo en suero u orina realizada en las 48 horas previas a la infusión
    14.Mujeres en edad fértil (definidas como todas las mujeres fisiológicamente capaces de quedarse embarazadas) y todos los varones participantes, salvo que estén utilizando métodos anticonceptivos altamente eficaces durante un período de 1 año después de la infusión de CTL019. Los métodos anticonceptivos altamente eficaces incluyen:
    a.Abstinencia total (cuando esté en consonancia con el estilo de vida habitual y preferido del paciente). La abstinencia periódica (p. ej., calendario, ovulación, métodos sintotérmicos, postovulación) y el coitus interruptus NO son métodos anticonceptivos aceptables.
    b.Esterilización de la mujer (ha sido sometida a ooforectomía bilateral quirúrgica, con o sin histerectomía) o ligadura de trompas al menos seis semanas antes de tomar el tratamiento del estudio. Si sólo se ha realizado ooforectomía, sólo cuando se ha confirmado el estado reproductor de la mujer mediante el seguimiento de la evaluación del nivel hormonal.
    c.Esterilización del varón (al menos 6 meses antes de la selección). Para las pacientes mujeres participantes en el estudio, la pareja varón vasectomizado debería ser la única pareja de dicha paciente.
    d.Deberán utilizarse los DOS métodos anticonceptivos siguientes:
    ?Uso de métodos anticonceptivos hormonales orales, inyectados o implantados u otras formas de anticoncepción hormonal que tengan eficacia comparable (tasa de fallo <1%), por ejemplo, anillo hormonal vaginal o anticoncepción hormonal transdérmica.
    ?Métodos anticonceptivos de barrera: Preservativo o capuchón oclusivo (diafragma o capuchón en bóveda/cervical) con espuma/gel/película/crema espermicida/supositorio vaginal
    e.El uso de dispositivos intrauterinos (DIUs) está excluido debido al aumento del riesgo de infección y sangrado en esta población
    f.En caso de utilizar anticonceptivos orales, las mujeres deberán haber utilizado la misma píldora a una dosis estable durante un mínimo de 3 meses antes del procedimiento del estudio.
    Las mujeres sin potencial reproductivo (definidas o bien como <11 años, Estadio 1 de Tanner, posmenopáusicas durante al menos 24 meses consecutivos o que hayan sido sometidas a histerectomía, salpingectomía bilateral, y/u ooforectomía bilateral) son elegibles y no necesitan utilizar métodos anticonceptivos. La documentación aceptable incluye documentación escrita u oral comunicada por el clínico o personal clínico de uno de los siguientes:
    a.Los datos demográficos indican edad <11 años
    b.La exploración física indica Estadio 1 de Tanner
    c.Informe/carta del médico
    d.Informe operativo u otra documentación fuente en la historia clínica del paciente
    e.Resumen del alta
    f.Hormona foliculoestimulante (folitropina) elevada en el rango menopáusico
    15.Se excluyen las siguientes medicaciones:
    a.Esteroides:
    b.Terapia celular alogénica
    c.Terapias contra la EICH
    d.Quimioterapia
    e.Profilaxis de la enfermedad del SNC
    f.Terapia anti-células T:
    E.5 End points
    E.5.1Primary end point(s)
    Overall Remission Rate (ORR): Efficacy of CTL019 therapy - ORR includes Complete Remission (CR) and CR with incomplete blood count recovery (CRi) as determined by independent review committee (IRC) assessment.
    Tasa global de remisión (TRG): Eficacia de la terapia CTL019 - TRG incluye la remisión completa (RC) y RC con recuperación de hemograma incompleta (CRI) según lo determinado por el comité de revisión independiente (IRC) de evaluación.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The endpoint is assessed throughout the 60 months study
    Los criterios de valoración son evaluados a lo largo de los 60 meses de duración del estudio.
    E.5.2Secondary end point(s)
    - Percentage of patients with Best Overall Response (BOR) of CR or CRi with MRD negative bone marrow by qPCR during the 6 months after CTL019 infusion
    - Percentage of patients who achieve CR or CRi at Month 6 without SCT between CTL019 infusion and Month 6 response assessment
    - Percentage of patients who achieve CR or CRi and proceed to SCT while in remission prior to Month 6 response assessment
    - Duration of remission
    - Relapse-free survival
    - Event-free survival
    - Overall survival
    - In vivo cellular PK profile (levels, persistence, trafficking) of CTL019 cells
    - Prevalence/incidence of immunogenicity to CTL019
    - Safety: type, frequency and severity of adverse events and laboratory abnormalities
    - Porcentaje de pacientes con mejor respuesta global (BOR) de CR o CRi con MRD médula ósea negativa por qPCR durante los 6 meses después de la infusión CTL019
    - Porcentaje de pacientes que alcanzan CR o CRi en el mes 6 sin SCT entre CTL019 infusión y Mes 6
    - Porcentaje de pacientes que alcanzan CR o CRi y proceden a SCT mientras que la evaluación en remisión antes de la respuesta del mes 6
    - Duración de la remisión
    - La supervivencia libre de recaída
    - La supervivencia libre de eventos
    - La supervivencia global
    - perfil PK celular en vivo (niveles, la persistencia, la trata) de células CTL019
    - La prevalencia / incidencia de inmunogenicidad a CTL019
    - Seguridad: el tipo, la frecuencia y gravedad de los eventos adversos y anomalías de laboratorio
    E.5.2.1Timepoint(s) of evaluation of this end point
    The endpoints are assessed throughout the 60 months study duration.
    Los criterios de valoración son evaluados a lo largo de los 60 meses de duración del estudio.
    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 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 EEA7
    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
    France
    Germany
    Italy
    Japan
    Norway
    Spain
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of study is defined as the last patients last visit (LPLV) which is the last patient's Month 60 evaluation or the time of premature withdrawal.
    El fin del estudio se define como la última visita del último paciente (LPLV), que es la última evaluación en el Mes 60 del paciente, o el momento de la retirada prematura.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    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 years6
    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: 50
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 35
    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) Yes
    F.1.2.1Number of subjects for this age range: 10
    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
    In cases where the patient?s representative gives consent, the patient will be informed about the study to the extent possible given his/her understanding.
    En los casos en que el representante del paciente da su consentimiento, el paciente será informado sobre el estudio a la medida de lo posible dada su comprensión.
    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 17
    F.4.2.2In the whole clinical trial 60
    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)
    As a single administration study, patients are followed on study for 5 years post-infusion for safety and efficacy evaluations. A long term post-study follow-up for lentiviral vector safety will continue under a separate destination protocol. Patients will continue to be followed until 15 years post-CTL019 infusion per health authority guidelines.
    Como estudio de administración única, los pacientes son seguidos en el estudio durante 5 años después de la infusión para las evaluaciones de seguridad y eficacia. A largo plazo posterior al estudio de seguimiento para la seguridad del vector lentiviral continuará bajo un protocolo de destino independiente. Los pacientes continuarán siendo seguidos hasta los 15 años posteriores a la infusión de CTL019 según las directrices de las autoridades sanitarias.
    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 Decision2015-12-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-19
    P. End of Trial
    P.End of Trial StatusOngoing
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