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    Summary
    EudraCT Number:2014-003060-20
    Sponsor's Protocol Code Number:CCTL019C2201
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-08-06
    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 ConcernedNorway - NOMA
    A.2EudraCT number2014-003060-20
    A.3Full title of the trial
    A phase II, single arm, multicenter trial to determine the efficacy and safety of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
    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 therapy, an investigational genetherapy, in adult patients with a recurrent form of diffuse large B-cell lymphoma (DLBCL).
    A.3.2Name or abbreviated title of the trial where available
    Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients
    A.4.1Sponsor's protocol code numberCCTL019C2201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02445248
    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 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 Norge AS
    B.5.2Functional name of contact pointMedisinsk informasjon
    B.5.3 Address:
    B.5.3.1Street AddressPostboks 4284 Nydalen
    B.5.3.2Town/ cityOslo
    B.5.3.3Post code0401
    B.5.3.4CountryNorway
    B.5.4Telephone number+4723052000
    B.5.5Fax number+4723052001
    B.5.6E-mailmedisinsk.informasjon@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 No
    D.2.5.1Orphan drug designation number
    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 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 number1x10^8 to 5x10^8
    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
    Adult patients ≥ 18 years with relapsed or refractory DLBCL, having failed 2 or more lines of therapy and not eligible for HSCT
    E.1.1.1Medical condition in easily understood language
    Lymphoma is a cancer of lymphocytes, a type of white blood cell. The study enrols adult patients with recurrence of a subtype of a lymphoma termed 'diffuse large B cell lymphoma'.
    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 HLT
    E.1.2Classification code 10012819
    E.1.2Term Diffuse large B-cell lymphomas
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10012818
    E.1.2Term Diffuse large B-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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
    E.2.2Secondary objectives of the trial
    - Evaluate safety of CTL019
    - Evaluate time to response
    - Evaluate duration of overall response (DOR)
    - Evaluate event free survival (EFS)
    - Evaluate progression free survival (PFS)
    - Evaluate overall survival (OS)
    - Evaluate efficacy and safety in histological and molecular subgroups
    - Characterize the in vivo cellular PK profile
    - Describe the prevalence and incidence of immunogenicity to CTL019
    - Describe presence of RCL
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Written informed consent must be obtained prior to any screening procedures
    2) Histologically confirmed DLBCL at last relapse (by central pathology review before enrollment).
    3) Relapsed or refractory disease after ≥2 lines of chemotherapy, including rituximab and anthracycline, and either having failed autologous HSCT, or being ineligible for or not consenting to autologous HSCT
    4) Measurable disease at time of enrollment
    5) Life expectancy ≥12 weeks
    6) ECOG performance status that is either 0 or 1 at screening
    7) Adequate organ function:
    - Renal function defined as: A serum creatinine of ≤1.5 x ULN OR eGFR ≥ 60 mL/min/1.73 m2
    - Liver function defined as:
    • ALT ≤ 5 times the ULN for age
    • Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert–Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 x ULN and
    direct bilirubin ≤ 1.5 x ULN . Must have a minimum level of
    pulmonary reserve defined as ≤ Grade 1 dyspnea and
    pulse oxygenation > 91% on room air . Hemodynamically
    stable and LVEF ≥ 45% confirmed by echocardiogram or
    MUGA .
    - Adequate bone marrow reserve defined as:
    • Absolute neutrophil count (ANC) > 1.000/mm3
    • Absolute lymphocyte count (ALC) ≥ 300/mm3
    • Platelets ≥ 50.000//mm3
    • Hemoglobin > 8.0 g/dl .
    8) Must have an apheresis product of non-mobilized cells accepted for manufacturing.
    9) Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for at least 12 months following CTL019 infusion and until CAR T cells are no longer present by PCR on two consecutive tests.
    E.4Principal exclusion criteria
    1) Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
    2) Treatment with any prior gene therapy product
    3) Active CNS involvement by malignancy
    4) Prior allogeneic HSCT
    5) Eligible for and consenting to autologous HSCT -
    6) Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of
    infusion
    7) 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 progression following CTL019 infusion
    8) The following medications are excluded:
    • Steroids: Therapeutic doses of steroids must be stopped > 72 hours
    prior to leukapheresis and > 72 hours prior to CTL019 infusion. However, the following physiological replacement doses of steroids are allowed: <6 – 12 mg/m2/day hydrocortisone or equivalent
    • Immunosuppression: Any immunosuppressive medication must be stopped ≥ 2 weeks prior to leukapheresis and ≥ 2 weeks prior to CTL019 infusion. This could include check point inhibitors (monoclonal antibodies and small molecule modulators).
    • Antiproliferative therapies other than lymphodepleting chemotherapy within two weeks of leukapheresis and 2 weeks prior to infusion
    - Short acting drugs used to treat leukemia or lymphoma (e.g. tyrosine kinase inhibitors, and hydroxyrurea) must be stopped > 72 hour prior to leukapheresis and > 72 hours prior to CTL019 infusion
    - Other cytotoxic drugs, including low dose daily or weekly maintenance chemotherapy, must not be givien within 2 weeks prior to leukapheresis and within 2 weeks prior to CTL019 infusion.
    - Fludrabine may be associated with prolonged lymphopenia. This should be taken into consideration when evaluating the optimal timing for leukapheresis
    • Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respective antibody, whichever is longer
    • CNS disease prophylaxis must be stopped > 1 week prior to
    CTL019 infusion (e.g. intrathecal methotrexate)
    9) Prior radiation therapy within 2 weeks of infusion
    10) Active replication of or prior infection with latent hepatitis B or active hepatitis C (HCV RNA positive)
    11) HIV positive patients
    12) Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion)
    13) Unstable angina and/or myocardial infarction within 6
    months prior to screening
    14) Previous or concurrent malignancy with the following exceptions:
    • Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
    • In situ carcinoma of the cervix or breast, treated curatively and
    without evidence of recurrence for at least 3 years prior to the study
    • A primary malignancy which has been completely resected and in complete remission for ≥ 5 years - Investigational medicinal product within the last 30 days prior to screening
    15) Pregnant or nursing (lactating) women
    16) Intolerance to the excipients of the CTL019 cell product
    17) Cardiac arrhythmia not controlled with medical management
    18) Patients on oral anticoagulation therapy
    19) Prior treatment with any adoptive T cell therapy
    20) Patients with active neurological auto immune or inflammatory
    disorders (e.g. Guillain-Barré Syndrome, Amyotrophic Lateral Sclerosis)

    Other protocol-related inclusion/exclusion may apply.
    E.5 End points
    E.5.1Primary end point(s)
    Overall Response Rate(ORR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    monitored throughout five years
    E.5.2Secondary end point(s)
    - Number of participants with adverse evensts (AEs)
    - Number of participants with serious adverse evensts (SAEs)
    - Time to response (TTR)
    - Duration of overall response (DOR)
    - Event free survival (EFS)
    - Progression free survival (PFS)
    - Overall survival (OS)
    - ORR, PFS, OS, EFS, DOR and AEs in histological and molecular subtypes
    - Characterize the in vivo cellular PK profile (levels, persistence, trafficking) of CTL019 transduced cells into target tissues (blood, bone marrow, cerebral spinal fluid (CSF) and other tissues if available)
    - Prevalence and Incidence of immunogenicity to CTL019
    - RCL by VSV-g q-PCR
    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.8.2.4Number of treatment arms in the trial1
    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
    Canada
    France
    Germany
    Italy
    Japan
    Netherlands
    Norway
    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 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 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 23
    F.4.2.2In the whole clinical trial 100
    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 Decision2015-09-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-12-22
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