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    Summary
    EudraCT Number:2016-001991-31
    Sponsor's Protocol Code Number:CCTL019B2001X
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-09-18
    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 number2016-001991-31
    A.3Full title of the trial
    Expanded treatment protocol 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
    Expanded treatment protocol 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.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 5547 6600
    B.5.5Fax number+33 1 5547 6100
    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
    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 number2000000 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.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
    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 100000012975
    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 100000012975
    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 not part of the program team.
    2. For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of program 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. 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. Signed written informed consent and assent forms if applicable must be obtained prior to
    any program procedures.
    9. Must meet the institutional criteria to undergo leukapheresis or have an acceptable, stored
    leukapheresis product.
    10. 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: 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.
    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. Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants, unless they are using highly effective methods of contraception for a period of 1 year after the CTL019 infusion. Highly effective contraception methods include:
    a. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are NOT acceptable methods of contraception.
    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. 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 hormone vaginal ring or transdermal hormone contraception.
    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.
    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.

    Women who are not of reproductive potential (defined as either <11 years of age, Tanner Stage 1, post-menopausal for at least 24 consecutive months or have undergone hysterectomy, salpingotomy, and/or bilateral oophorectomy) are eligible without requiring the use of contraception. Women who are not yet of reproductive potential are to agree to use acceptable forms of contraception when they reach reproductive potential if within 1 year of CTL019 or if CAR cells are present in the blood by polymerase chain reaction (PCR). Acceptable documentation includes written or oral documentation communicated by clinician or clinician’s staff of one of the following:
    - Demographics show age <11,
    - Physical examination indicates Tanner Stage 1,
    - Physician report/letter,
    - Operative report or other source documentation in the patient record,
    - Discharge summary,
    - Follicle stimulating hormone measurement elevated into the menopausal range.

    14. The following medications are excluded (more details are provided in the protocol):
    a. Steroids,
    b. Allogeneic cellular therapy,
    c. GVHD therapies,
    d. Chemotherapy,
    e. CNS disease prophylaxis,
    f. Radiotherapy,
    g. Anti T-cell antibodies.

    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.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 concerned2
    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
    Austria
    Belgium
    Canada
    France
    Germany
    Italy
    Japan
    Norway
    Spain
    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.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months9
    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.1.1.5.1Number of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number 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.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 state10
    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 Decision2017-06-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-13
    P. End of Trial
    P.End of Trial StatusCompleted
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