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    Summary
    EudraCT Number:2013-003205-25
    Sponsor's Protocol Code Number:CCTL019B2202
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-08-04
    Trial results View 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 ConcernedAustria - BASG
    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
    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
    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)
    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 Pharma Services AG
    B.1.3.4CountrySwitzerland
    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 Pharma GmbH
    B.5.2Functional name of contact pointDrug Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressJakov-Lind-Straße 5 / Top 3.05
    B.5.3.2Town/ cityWien
    B.5.3.3Post code1020
    B.5.3.4CountryAustria
    B.5.4Telephone number+43 1 86657 0
    B.5.5Fax number+43 1 86657 6458
    B.5.6E-mailaustria.dra@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 Yes
    D.2.1.1.1Trade name Kymriah
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Euproharm 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 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 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-T
    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 CodeSUB176601
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number2x10^6 CTL019 to 2.5x10^8 CTL019
    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.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.
    E.1.1.1Medical condition in easily understood language
    Paediatric 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 21.0
    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 21.0
    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
    Evaluate the efficacy of CTL019 therapy from all manufacturing facilities as measured by overall remission rate (ORR) during the 3 months after CTL019 administration, which includes CR and CR with incomplete blood count recovery (CRi) as determined by IRC assessment

    E.2.2Secondary objectives of the trial
    - Percentage of patients who achieve a best overall response of CR or CRi with a MRD negative bone marrow by central analysis using flow cytometry among all patients who receive CTL019 from all manufacturing facilities
    - Quality of response using MRD disease assessments before treatment and at day 28 +/- 4 days after treatment using central assessment by flow cytometry and before SCT by local assessment (flow or PCR)
    - Percentage of pts who achieve CR or CRi at Month 6 without SCT between CTL019 infusion and Month 6 response assessment
    - Percentage of pts who achieve CR or CRi and then proceed to SCT while in remission before Month 6 response assessment
    - Duration of remission, relapse-free survival, the event-free survival and overall survival
    - Safety of CTL019 therapy
    - Assess the efficacy, safety and in vivo cellular pharmacokinetics of
    patients infused with CTL019 manufactured by Fraunhofer Institute
    E.2.3Trial contains a sub-study No
    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) within 7 days of screening.
    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 leukapheresis product of non-mobilized cells received and accepted by the manufacturing site.
    Other protocol defined inclusion criteria may apply.

    E.4Principal exclusion criteria
    Exclusion Criteria:
    1.Isolated extra-medullary disease relapse
    2.Patients 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.
    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. The following medications are excluded:
    a. Steroids: Therapeutic systemic doses of steroids must be stopped > 72 hours prior to CTL019 infusion. However, the following physiological replacement doses of steroids are allowed: < 12 mg/m2/day hydrocortisone or equivalent
    b. Allogeneic cellular therapy: Any donor lymphocyte infusions (DLI) must be completed > 6 weeks prior to CTL019 infusion
    c. GVHD therapies: Any systemic drug used for GVHD must be stopped > 4 weeks prior to CTL019 infusion to confirm that GVHD recurrence is not observed (e.g. calcineurin inhibitors, methotrexate or other chemotherapy drugs, mycophenolyate, rapamycin, thalidomide, or immunosuppressive antibodies such as anti-CD20 (rituximab), anti-TNF, anti-IL6 or anti-IL6R, systemic steroids)
    d. Chemotherapy:
    • Tyrosine kinase inhibitors and hydroxyurea must be stopped > 72 hours prior to CTL019 infusion
    • The following drugs must be stopped > 1 week prior to CTL019 infusion and should not be administered concomitantly or following lymphodepleting chemotherapy: vincristine, 6-mercaptopurine, 6-thioguanine, methotrexate < 25 mg/m2, cytosine arabinoside < 100 mg/m2/day, asparaginase (non-pegylated)
    • The following drugs must be stopped >2 weeks prior to CTL019 infusion: salvage chemotherapy (e.g. clofarabine, cytosine arabinoside > 100 mg/m2, anthracyclines, cyclophosphamide, methotrexate ≥ 25 mg/m2), excluding the required lymphodepleting chemotherapy drugs
    • Pegylated-asparaginase must be stopped > 4 weeks prior to CTL019 infusion
    e. CNS disease prophylaxis: CNS prophylaxis treatment must be stopped > 1 week prior to CTL019 infusion (e.g. intrathecal methotrexate)
    f. Radiotherapy
    • Non-CNS site of radiation must be completed > 2 weeks prior to CTL019 infusion
    • CNS directed radiation must be completed > 8 weeks prior to CTL019 infusion
    e.g. Anti T-cell Antibodies: Administration of any T cell lytic or toxic antibody (e.g. alemtuzumab) within 8 weeks prior to CTL019 is prohibited since residual lytic levels may destroy the infused CTL019 cells and/or prevent their in vivo expansion. If such an agent has been administered within 8 weeks prior to CTL019, contact the Sponsor, consider consultation with an pharmacology expert, and consider measuring residual drug levels, if feasible, prior to CTL019 infusion.
    14.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 qPCR on two 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 qPCR on two 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 WBCs are a normal part of semen and transmission of CTL019 transduced cells may occur.
    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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint is assessed during the 3 months after CTL019 administration.
    E.5.2Secondary end point(s)
    - Percentage of patients with BOR of CR or CRi with MRD negative bone marrow by flow cytometry during the 3 months after CTL019 infusion among all patients who are infused with CTL019 from all manufacturing facilities
    - 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    The endpoints are assessed throughout the 60 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 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.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    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
    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: 55
    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) No
    F.1.1.6.1Number of subjects for this age range: 20
    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.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 65
    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.
    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 Decision2015-10-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-11-17
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