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    Summary
    EudraCT Number:2017-004385-94
    Sponsor's Protocol Code Number:CCTL019E2202
    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:2018-09-05
    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 ConcernedFrance - ANSM
    A.2EudraCT number2017-004385-94
    A.3Full title of the trial
    A Phase II, single arm, multicenter open label trial to determine the efficacy and safety of tisagenlecleucel (CTL019) in adult patients with refractory or relapsed follicular lymphoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of tisagenlecleucel in adult patients with refractory or relapsed follicular lymphoma
    A.3.2Name or abbreviated title of the trial where available
    Efficacy and safety of tisagenlecleucel in adults with refractory or relapsed follicular lymphoma
    A.4.1Sponsor's protocol code numberCCTL019E2202
    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.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 AG
    B.4.2CountrySwitzerland
    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.5.3.4CountryFrance
    B.5.4Telephone number+33 1 55 47 66 00
    B.5.5Fax number+33 1 55 47 61 00
    B.5.6E-mailicm.phfr@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 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.3.8INN - Proposed INNtisagenlecleucel
    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 number60000000 to 600000000
    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) 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
    Adult patients with refractory or relapsed follicular lymphoma
    E.1.1.1Medical condition in easily understood language
    Cancer of lymphocytes (cells present in blood)
    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 10016903
    E.1.2Term Follicle centre lymphomas, follicular grade I, II, III
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10061170
    E.1.2Term Follicle centre lymphoma, follicular grade I, II, III
    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 tisagenlecleucel therapy as measured by CRR determined by IRC
    E.2.2Secondary objectives of the trial
    - Evaluate the efficacy of tisagenlecleucel as measured by additional efficacy measures, including ORR, DOR, PFS and OS
    - Evaluate safety of tisagenlecleucel
    - Characterize the in vivo cellular kinetics (levels, expansion, persistence) of tisagenlecleucel transduced cells into target tissues (blood, bone marrow, and other tissues if available) and CD3+ tisagenlecleucel cells in peripheral blood, summarized by clinical response
    - Characterize the incidence and prevalence of tisagenlecleucel immunogenicity (humoral and cellular)
    - Characterize the impact of pre-existing and treatment induced immunogenicity (cellular and humoral) on cellular kinetics, efficacy and safety
    - Describe the effect of tisagenlecleucel therapy on Patient reported outcomes (PRO)

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Written informed consent prior to any screening procedures
    •≥18 years of age at the time of ICF signature
    •FL (Grade 1, 2, 3A) confirmed histologically by central pathology review before tisagenlecleucel infusion.
    •FL meeting one of the following criteria:
    oRefractory to a second line or later line of systemic therapy (including anti-CD20 antibodies and alkylating agents) or relapsed within 6 months after completion of a second line or later line of systemic therapy
    oRelapsed during anti-CD20 antibody maintenance (following at least two lines of therapies as above) or within 6 months after maintenance completion
    oRelapsed after autologous HSCT
    •Radiographically measurable disease at screening defined as:
    •At least one nodal lesion greater than 20 mm in the long axis, regardless of the length of the short axis AND/OR
    •Extranodal lesions (outside lymph node or nodal mass, including liver and spleen) greater than 10 mm in long AND short axis
    E.4Principal exclusion criteria
    •Evidence of histologic transformation
    •Follicular Lymphoma Grade 3B
    •Prior anti-CD19 therapy
    •Prior gene therapy
    •Prior adoptive T cell therapy
    •Prior allogeneic hematopoietic stem cell transplant
    •Active CNS involvement by malignancy
    E.5 End points
    E.5.1Primary end point(s)
    Complete response rate (CRR) determined by an Independent Review Committee (IRC) in the efficacy analysis set (EAS) based on Lugano 2014 classification response criteria (Cheson et al 2014).
    E.5.1.1Timepoint(s) of evaluation of this end point
    When approximately 50 patients have received treatment and have either completed 6 months from study day 1 infusion or discontinued earlier; when 90 patients have received treatment and have either completed 6 months from study day 1 infusion or discontinued earlier.
    E.5.2Secondary end point(s)
    - ORR, including complete response (CR) and partial response (PR) determined by IRC in the FAS based on Lugano 2014 classification.
    - DOR, defined as time from achievement of CR or PR to relapse or death due to FL, based on IRC
    - DOR for CR only, defined as time from achievement of CR to relapse or death due to FL, based on IRC
    - PFS, defined as time from tisagenlecleucel infusion to first documented disease progression or death due to any cause, based on IRC
    - OS, defined as time from tisagenlecleucel infusion to death due to any cause
    - Type, frequency and severity of adverse events and laboratory abnormalities
    - Summary of qPCR detected tisagenlecleucel transgene concentrations in peripheral blood, bone marrow and other tissues by time point and clinical response status
    - Summary of cellular kinetic parameters: Cmax, Tmax, AUC0-28 and AUC0-84d, T1/2, and/or other relevant parameters in peripheral blood; bone marrow and other tissues by clinical response as appropriate
    - Summary of exposure and cellular kinetic parameters of CD3+ tisagenlecleucel cells in peripheral blood detected by flow cytometry
    - Summary of pre-existing and treatment induced immunogenicity (cellular and humoral) of tisagenlecleucel
    - Levels of pre-existing and treatment induced immunogenicity
    - Cellular kinetic parameters (Cmax, AUCs, Tlast), concentration-time profile tisagenlecleucel by immunogenicity category (positive/negative)
    - Efficacy (ORR, DOR, PFS)
    - Safety (B-cell levels, CRS grades, neurologic events)
    - Summary scores of PRO measured by SF-36 version 2, EQ-5D-3L and FACT-Lym quality of life questionnaires
    E.5.2.1Timepoint(s) of evaluation of this end point
    When approximately 50 patients have received treatment and have either completed 6 months from study day 1 infusion or discontinued earlier; when 90 patients have received treatment and have either completed 6 months from study day 1 infusion or discontinued earlier; the end of the study (Part of the secondary endpoints).
    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 Yes
    E.6.13.1Other scope of the trial description
    Patient Reported Outcomes
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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
    Netherlands
    Norway
    Spain
    United Kingdom
    United States
    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
    When all patients have completed Month 24 evaluation or discontinued prematurely.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days9
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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 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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 23
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 54
    F.4.2.2In the whole clinical trial 113
    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)
    Semiannual and annual evaluations will be performed for up to 15 years from the date of infusion on all patients under a separate long term follow-up (LTFU) protocol as recommended by Health Authority guidance for patients treated with gene therapies. All patients who either complete or prematurely discontinue from the study will be enrolled in this destination protocol at the time of study completion/discontinuation.
    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 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 Opinion2018-10-24
    P. End of Trial
    P.End of Trial StatusOngoing
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