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    EudraCT Number:2017-002116-14
    Sponsor's Protocol Code Number:CCTL019G2201J
    National Competent Authority:France - ANSM
    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
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    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    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
    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/young adult patients with B-cell acute lymphoblastic leukemia who are minimal residual disease positive at the end of consolidation therapy
    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.
    A.4.1Sponsor's protocol code numberCCTL019G2201J
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/270/2017
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma AG
    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.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma S.A.S.
    B.5.2Functional name of contact pointInformation&Communication Médicales
    B.5.3 Address:
    B.5.3.1Street Address2 et 4 rue Lionel Terray
    B.5.3.2Town/ cityRueil-Malmaison
    B.5.3.3Post code92500
    B.5.4Telephone number+33 1 5547 6600
    B.5.5Fax number+33 1 5547 6100
    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 Information not present in EudraCT
    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 and EU/3/16/1745
    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.3.9.1CAS number 1823078-37-0
    D.3.9.2Current sponsor codeCTL019
    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. cell therapy medicinal product No
    D. therapy medical product Yes
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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.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.
    E.1.1.1Medical condition in easily understood language
    High-risk B-cell acute lymphoblastic leukemia
    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.
    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
    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.
    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.
    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.
    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.
    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
    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
    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
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) 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
    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)).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days7
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 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. of subjects for this age range: 10
    F.1.1.5Children (2-11years) Yes
    F. of subjects for this age range: 45
    F.1.1.6Adolescents (12-17 years) Yes
    F. 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. 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 state7
    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.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Children's Oncology Group
    G.4.3.4Network Country United States
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-01-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-25
    P. End of Trial
    P.End of Trial StatusOngoing
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