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    EudraCT Number:2016-001991-31
    Sponsor's Protocol Code Number:CCTL019B2001X
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-01-25
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2016-001991-31
    A.3Full title of the trial
    Phase IIIb study for relapsed/refractory pediatric/young adult acute lymphoblastic leukemia patients to be treated with CTL019.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to provide the opportunity to be treated with CTL019, an investigational gene therapy, for children and adolescent patients with a recurrent form of B-cell acute lymphoblastic leukaemia after the closure of the Novartis single-arm phase II pivotal registration trial (Study CCTL019B2202) and to collect additional safety information.
    A.3.2Name or abbreviated title of the trial where available
    Phase IIIb study for CTL019.
    A.4.1Sponsor's protocol code numberCCTL019B2001X
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis 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 AG
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressForum 1, Novartis Campus
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4056
    B.5.4Telephone number+4161 324 1111
    B.5.5Fax number+4161 324 8001
    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 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 INNTisagenlecleucel
    D.3.9.2Current sponsor codeCTL019
    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 number 2000000 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
    Paediatric/young adult patients with B-cell acute lymphoblastic leukaemia who are chemo-refractory, relapsed after allogeneic SCT, or are otherwise ineligible for allogeneic SCT.
    E.1.1.1Medical condition in easily understood language
    Paediatric/young adult patients with a recurrent form of B-cell acute lymphoblastic leukaemia.
    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
    This expanded treatment protocol (ETP) will provide pediatric/young adult patients with relapsed or refractory B-cell ALL the opportunity to be treated with CTL019 after the closure of the Novartis single-arm phase II clinical trial (Study CCTL019B2202) and to collect additional safety information.
    E.2.2Secondary objectives of the trial
    - Evaluate the efficacy of CTL019 therapy as measured by complete remission rate, which includes CR and CR with incomplete blood count recovery (CRi).
    - 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.
    - Evaluate the relapse-free survival.
    - Evaluate the event-free survival.
    - Evaluate the overall survival.
    - Evaluate the response at Day 28 +/- 4 days.
    - Evaluate the impact of baseline tumor burden on response.
    - Evaluate the quality of response using minimal residue disease assessments.
    - Describe the prevalence and incidence of immunogenicity to CTL019.
    - Characterize the in vivo cellular kinetic profile of CTL019 cells in the blood.
    - Evaluate the relationship between exposure to CTL019 with CRS grades.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for inclusion in this program have to meet all of the following criteria:
    1. Relapsed or refractory B-cell ALL in pediatric or young adult patients:
    a. Second or greater bone marrow relapse, OR
    b. Any bone marrow relapse after allogeneic 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 (TKI) therapy, or if TKI therapy is contraindicated, OR
    e. Ineligible for allogeneic SCT because of:
    - Comorbid disease,
    - Other contraindications to allogeneic SCT conditioning regimen,
    - Lack of suitable donor,
    - Prior SCT,
    - Declines allogeneic SCT as a therapeutic option after documented discussion about the role of SCT with a bone marrow transplantation physician who is not a member of the CTL019 study team.
    2. For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of study entry. For relapsed or refractory patients previously treated with blinatumomab, CD19 tumor expression must be demonstrated (via flow cytometry) at Screening.
    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. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 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) within 7 days of screening.
    4. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening.
    5. Life expectancy > 12 weeks.
    6. Age 3 years at the time of screening to age 21 years at the time of initial diagnosis.
    7. Karnofsky (age ≥ 16 years) or Lansky (age < 16 years) performance status ≥ 50 at screening.
    8. Patients previously treated with blinatumomab who have detectable leukemia and documented CD19+ expression (via flow cytometry) and confirmed absence of CD19- leukemic blasts at Screening may be included. In this case, at least 1-week washout period must be applied from last dose of blinatumomab to start of leukapheresis. Patients previously treated with blinatumomab with no detectable MRD (i.e. MRD negative demonstrated by leukemic blasts < 0.01%) will be excluded.
    Note: blinatumomab must not be administered as a bridging therapy prior to CTL019 infusion while the patient is awaiting manufacture of CTL019
    9. Signed written informed consent and assent forms if applicable must be obtained prior to any study procedures.
    10. Must meet the institutional criteria to undergo leukapheresis or have an acceptable, stored leukapheresis product.
    11. Once all other eligibility criteria are confirmed, must have a leukapheresis product of nonmobilized 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 eligibility criteria is received.

    Other protocol-defined inclusion criteria may apply.
    E.4Principal exclusion criteria
    Exclusion Criteria:
    1. Isolated extra-medullary disease relapse.
    2. Patients with concomitant genetic syndrome
    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. Prior treatment with any anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy, except for patients pre-treated with blinatumomab who fulfill inclusion criterion no. 8.
    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.
    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. Uncontrolled acute life threatening bacterial, viral or fungal infection at Screening.
    12. Previous or concurrent malignancy with the following exceptions:
    a. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry).
    b. In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study.
    c. A primary malignancy which has been completely resected and in CR for ≥ 5 years.
    13. Intolerance to the excipients of the CTL019 cell product (i.e. dimethyl sulfoxide).
    14. Cardiac arrhythmia not controlled with medical management.
    15. Patients enrolled in this study are not permitted to participate in additional parallel investigational drug or device studies.
    16. Patient has an investigational medicinal product within the last 30 days prior to screening.
    17. Pregnant or nursing (lactating) women.
    18. The following medications are excluded:
    a. Steroids;
    b. Allogeneic cellular therapy;
    c. GVHD therapies;
    d. Chemotherapy;
    e. CNS disease prophylaxis;
    f. Radiotherapy;
    g. Anti-T cell antibodies
    19. Women of child-bearing potential and all male participants, unless they are using effective methods of contraception for a period of 1 year after the CTL019 infusion.
    - Sexually active women must continue to use contraception for greater than 12 months after the CTL019 infusion and until CAR T cells are no longer present by quantitative PCR (q-PCR) on 2 consecutive tests.
    - Sexually active males must use a condom during intercourse for 12 months after CTL019 infusion and until CAR T cells are no longer present by q-PCR on 2 consecutive tests, as they should not father a child in this period. A condom is required to be used also by vasectomized men (as well as during intercourse with a male partner) as white blood cells (WBCs) are a normal part of semen and transmission of CTL019 transduced cells may occur.
    Effective contraception methods include:
    a. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient.
    b. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 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 hormonal vaginal ring or transdermal hormone contraception.
    - Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/fil/cream/vaginal suppository.
    e. Use of IUDs are excluded due to increased risks of infection and bleeding in this population. However, IUD inserted prior to consent may remain in place, and a second method of contraception is mandated.
    Additionally, drugs that induce cytochrome P450 (CYP) enzymes can increase the clearance of sex hormones that are eluted by the IUD and reduce contraceptive efficacy, given the poly-pharmacy for these patients this presents a real risk of IUD failure and resultant conception.
    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.
    Other protocol-defined exclusion criteria may apply.
    E.5 End points
    E.5.1Primary end point(s)
    Evaluate the safety of CTL019 therapy.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The endpoint is assessed throughout the 12 months study duration.
    E.5.2Secondary end point(s)
    - Percentage of patients who achieve complete remission or complete remission with incomplete blood count recovery (i.e. CR or CRi) 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 then proceed to SCT while in remission prior to Month 6 response assessment.
    - Duration of remission.
    - Relapse-free survival.
    - Event-free survival.
    - Overall survival.
    - Response at Day 28 +/- 4 days.
    - Impact of baseline tumor burden on response.
    - Quality of response using MRD assessments.
    - Safety: type, frequency and severity of adverse events, laboratory abnormalities, vital signs, ECGs, pulse oximetry, echocardiogram and B-cell levels.
    - Describe the prevalence and incidence of immunogenicity to CTL019.
    - Characterize the in vivo cellular kinetic profile (levels, persistence, trafficking) of CTL019 cells in the blood.
    - Evaluate the relationship between exposure to CTL019 with CRS grades.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The endpoints are assessed throughout the 12 months study duration.
    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 No
    E.6.7Pharmacodynamic No
    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. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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
    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 is defined as the last patient's last visit (LPLV) which is the last patient's Month 12 evaluation or the time of premature withdrawal. The EOS is anticipated to occur around Quarter 3, 2020.

    Semiannual & annual evaluations will be performed for up to 15 years on all patients under a separate LTFU protocol (i.e. CCTL019A2205B). All patients who either complete this study or prematurely discontinue from this study will be enrolled in the LTFU protocol.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    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: 25
    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. of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    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. 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.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 55
    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 program, patients are followed on program for 1 year post-infusion for safety and efficacy evaluations. A long-term post-study follow-up for lentiviral vector safety will continue under a separate protocol. Patients will continue to be followed until 15 years post-CTL019 infusion per health authority guidelines.
    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 Decision2017-01-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-23
    P. End of Trial
    P.End of Trial StatusOngoing
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