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    Summary
    EudraCT Number:2017-002849-30
    Sponsor's Protocol Code Number:CCTL019B2101J/CHP-959
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2017-11-16
    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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2017-002849-30
    A.3Full title of the trial
    A Phase I/IIA Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCRzeta and 4-1BB Signaling Domains in Patients With Chemotherapy Resistant Or Refractory CD19+ Leukemia and Lymphoma.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to determine the safety and efficacy of CD19 redirected autologous T cells, an investigational gene therapy, in children and young adults patients with a recurrent form of B-cell leukaemia and lymphoma.
    A.4.1Sponsor's protocol code numberCCTL019B2101J/CHP-959
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01626495
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/337/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Pennsylvania
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPennsylvania Department of Health
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportNovartis Pharmaceuticals
    B.4.2CountryUnited States
    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 AG
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4056
    B.5.3.4CountrySwitzerland
    B.5.6E-mailclinicaltrial.enquiries@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 nameCART-19 T Cells
    D.3.2Product code CART-19
    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.3.9.2Current sponsor codeCTL019
    D.3.9.3Other descriptive nameCD19 redirected autologous T cells
    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 number1.5E+07 to 5E+09
    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
    Chemotherapy resistant or refractory CD19+ B-cell Leukemia and Lymphoma.
    E.1.1.1Medical condition in easily understood language
    Recurrent form of CD19+ Leukemia and 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 LLT
    E.1.2Classification code 10063621
    E.1.2Term Acute lymphoblastic leukaemia 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 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 HLGT
    E.1.2Classification code 10025320
    E.1.2Term Lymphomas non-Hodgkin's B-cell
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. Determine the safety , survival and feasibility of administration of chimeric antigen receptor T cells transduced with the anti-CD19 lentiviral vector (referred to as “CART-19” cells), in pediatric and adult patients who either:
    a. have not received a prior allogeneic SCT or have 0% residual donor engraftment (“no allo” cohort), or
    b. have relapsed after prior allogeneic SCT with any degree of residual donor engraftment (“allo” cohort).
    2. Determine duration of in vivo survival of CART-19 cells. RT-PCR analysis of whole blood will be used to detect and quantify survival of CART-19 TCR: 4-1BB and TCR cells over time.
    E.2.2Secondary objectives of the trial
    1. For patients with detectable disease, measure anti-tumor response due to CART-19 cell infusions.
    2. To determine if the 4-1BB transgene is superior to the TCR-zeta only transgene as measured by the relative engraftment levels of CART-19 TCR-zeta :4-1BB and TCR-zeta cells over time.
    3. For patients with stored or accessible tumor cells (such as patients with active CLL, ALL, etc) determine tumor cell killing by CART-19 cells in vitro.
    4. Determine if cellular or humoral host immunity develops against the murine anti-CD19, and assess correlation with loss of detectable CART-19 (loss of engraftment).
    5. Determine the relative subsets of CART-19 T cells (Tcm, Tem, and Treg)
    6. Determine safety and efficacy in a test cohort of patients with CNS3 disease.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Eligible diseases: CD19+ leukemia or lymphoma
    a. ALL without curative options for therapy, including those not eligible for allogeneic SCT because of: age, comorbid disease, other contraindications to TBI-based conditioning (required for ALL SCT), lack of suitable donor, prior SCT, Declines allo SCT (in CR3) as a therapeutic option after documented discussion about the role of SCT with a BMT physician not part of the study team (see note below).
    Patient may be in any complete response, or patient may have active disease but responding or stable after most recent therapy.
    b. Follicular lymphoma, previously identified as CD19+
    -At least 2 prior combination chemotherapy regimens
    -Stage III-IV disease.
    -Less than 1 year between last chemotherapy and progression
    -Disease responding or stable after most recent therapy (chemotherapy, MoAb).
    c. CLL
    - At least 2 prior chemotherapy regimens
    - Less than 1 year between last chemotherapy and progression 
    - Not eligible or appropriate for conventional allogeneic SCT.
    -Disease responding or stable after most recent therapy (chemotherapy, MoAb)
    d. Mantle cell lymphoma
    -Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT.
    -Disease responding or stable after most recent therapy (chemotherapy, MoAb).
    -Relapsed after prior autologous SCT.
    e. B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least 1 prior therapy and not eligible for allogeneic SCT.
    f. Diffuse large cell lymphoma or other high-grade NHL, previously identified as CD19+
    -Residual disease after primary therapy and not eligible for autologous SCT.
    -Relapsed after prior autologous SCT.
    -Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT.
    2. Age 1 to 24 years. Patients ages 22-24 will only be enrolled if they are currently being treated at CHOP or another pediatric facility/oncologist.
    3. Expected survival > 12 weeks
    4. Creatinine < 2.5 mg/dl and less than 2.5x normal for age
    5. ALT <= 5x normal
    6. Bilirubin <2.0 mg/dl
    7. Any relapse after prior SCT will make patient eligible regardless of other prior therapy.
    8. Patients with relapsed disease after prior allogeneic SCT (myeloablative or non-myeloablative) will be eligible if they meet all other inclusion criteria and
    a. Have no active GVHD and require no immunosuppression
    b. Are more than 4 months from transplant (6 months at infusion)
    9. For those patients who require leukapheresis for T cell collection (i.e. no previously collected product exists), adequate venous access for apheresis or eligible for appropriate catheter placement, and no other contraindications for leukapheresis.
    10. Voluntary informed consent is given.
    11. Patients with CNS3 disease will be eligible if CNS disease is responsive to therapy
    E.4Principal exclusion criteria
    - Pregnant or lactating women. Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion.
    - Uncontrolled active infection.
    - Active hepatitis B or hepatitis C infection.
    - Concurrent use of systemic steroids at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of inhaled steroids, or hydrocortisone for physiological replacement in patients with adrenal insufficiency are permitted as well.
    - Previous treatment with any gene therapy products.
    - Any uncontrolled active medical disorder that would preclude participation as outlined.
    - HIV infection.
    - CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity
    - Acute or chronic GVHD requiring systemic therapy (topical allowed).
    E.5 End points
    E.5.1Primary end point(s)
    Number of Participants with Severe/Adverse Events as a Measure of Safety and Tolerability (Safety of CAR+ T cell infusion and observed side effects)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time Frame: 24 weeks
    E.5.2Secondary end point(s)
    •Ability of two different types of CAR+ T cells to expand and persist in the patient
    - The change in the ratio of the vector transduced cells to each other between baseline and week four will be evaluated.
    - Observation and monitoring of patients will continue on a monthly basis until week 24 post dosing)
    •Impact of CAR+ T cell infusion on cancer
    - patients with measurable disease will be assessed for the response of their disease to the CAR+ T cell treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    Ability of two different types of CAR+ T cells to expand and persist in the patient : Time Frame: 24 weeks
    Impact of CAR+ T cell infusion on cancer :Time Frame: 4 weeks
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase I/IIa study
    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 Will this trial be conducted at a single site globally? Yes
    E.8.4 Will this trial be conducted at multiple sites globally? No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years5
    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: 77
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 2
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 37
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 29
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 9
    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
    Subjects under age incapable of giving consent personally.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 86
    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)
    Following 6 months of intensive follow-up, subjects will be evaluated quarterly for two years with a medical history, a physical examination, and blood tests. Subjects will then continue to be followed for disease-free survival (as applicable) and overall survival every 3 months until they withdraw consent or until two years post the last subject infusion. After they completed participation in this study, subjects will be asked to participate in a separate 15 year long-term follow-up protocol.
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
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