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    Summary
    EudraCT Number:2021-006556-14
    Sponsor's Protocol Code Number:RHCART1A
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-04-11
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2021-006556-14
    A.3Full title of the trial
    CLIC-1901 CAR T-cells for treatment of patients with relapsed/refractory CD19-positive ALL and NHL (DAN-CART 1901)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of genetically modified patient immune cells in treatment of refractory leukemia and lymphoma of B-cell origin
    CLIC-1901 CAR T-celler som behandling af patienter recidiveret/behandlingsresistent CD19-positiv ALL og NHL (DAN-CART 1901)
    A.3.2Name or abbreviated title of the trial where available
    DAN-CART 1901
    A.4.1Sponsor's protocol code numberRHCART1A
    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 SponsorRigshospitalet
    B.1.3.4CountryDenmark
    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 supportRigshospitalet
    B.4.2CountryDenmark
    B.4.1Name of organisation providing supportDanish Childhood Cancer Foundation
    B.4.2CountryDenmark
    B.4.1Name of organisation providing supportCapital Region of Denmark
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRigshospitalet
    B.5.2Functional name of contact pointKatrine Kielsen
    B.5.3 Address:
    B.5.3.1Street AddressBlegdamsvej 9
    B.5.3.2Town/ cityCopenhagen
    B.5.3.3Post code2100
    B.5.3.4CountryDenmark
    B.5.4Telephone number0045354596903
    B.5.6E-mailkatrine.kielsen@regionh.dk
    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 nameDK-CLIC -1901
    D.3.4Pharmaceutical form Injection/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 INNDK-CLIC-1901
    D.3.9.3Other descriptive nameCD19CAT-41BBZCAR T-CELLS (CD19CAR T-CELLS)
    D.3.9.4EV Substance CodeSUB182373
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number1000000
    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 No
    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
    Acute Lymphoblastic Leukemia and B-cell Non Hodgkin Lymphoma
    E.1.1.1Medical condition in easily understood language
    Leukemia- blood cancer
    Lymphoma - lymph cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10066109
    E.1.2Term Precursor B-lymphoblastic leukemia acute
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10012855
    E.1.2Term Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation)
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10060669
    E.1.2Term B-cell chronic lymphocytic leukemia/prolymphocytic leukemia/small lymphocytic lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10036524
    E.1.2Term Precursor B-lymphoblastic lymphomas
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10026798
    E.1.2Term Mantle cell lymphomas
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10020068
    E.1.2Term High grade B-cell lymphomas Burkitt-like lymphoma
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10036711
    E.1.2Term Primary mediastinal large B-cell lymphomas
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 24.0
    E.1.2Level PT
    E.1.2Classification code 10085128
    E.1.2Term Follicular 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
    To test safety and feasibility of treatment with CLIC-1901 CAR T-cell in relapsed or refractory CD19-expressing hematological malignancies.
    E.2.2Secondary objectives of the trial
    To test efficacy of treatment with CLIC-1901 CAR T-cells and analyse factors contributing to to non-efficacy
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Relapsed/refractory hematologic disease (in peripheral blood, bone marrow or lymph node biopsy by flow cytometry) defined as one of the following:
    a. CD19 expressing B-cell acute lymphoblastic leukemia (B-ALL) with one of the following:
    • Second or greater bone marrow (BM) relapse.
    • Any relapse after allogeneic haematopoietic stem cell transplantation (HSCT).
    • Primary refractory, defined as not achieving complete remission (CR) after 2 cycles of standard chemotherapy regimen, or chemo refractory, defined as not achieving CR after 1 cycle of standard chemotherapy for relapsed leukemia.
    • Philadelphia chromosome-positive ALL intolerant of or with 2 failed lines of tyrosine kinase inhibitor (TKI) therapy or if TKI therapy is contraindicated.
    • Ineligible for allogeneic HSCT due to comorbidity, contraindications to conditioning regimen, lack of a suitable donor, prior HSCT, or declined allogeneic HSCT after documented detailed discussion of this treatment option with the given patient.

    b. Histologically confirmed B-cell non-Hodgkin’s lymphoma including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, High-grade B cell lymphoma with or without double hit, primary mediastinal large B-cell lymphoma, mantle cell lymphoma, Richter-transformed chronic lymphocytic lymphoma (CLL) or transformed follicular lymphoma with one of the following:
    • Second or greater relapse.
    • Relapse after autologous or allogeneic haematopoietic stem cell transplantation (HSCT).
    • Primary refractory, defined as not achieving partiel remission (PR) at time of interim-scanning or as defined in frontline protocol.

    2. Age of 1-70 years
    3. Life expectancy ≥ 12 weeks after enrollment
    4. Adequate organ function defined as:
    a. Lansky (<16 years) or Karnofsky (>16 years) score > 50%
    b. FEV1 or DLCOc ≥ 40 % of expected and oxygen saturation > 90% without oxygen supply
    c. LVEF > 45% and no symptoms of ischemic heart disease
    d. Bilirubin < 2 x upper normal limit for age (except for patient diagnosed with Gilbert syndrome)
    e. ALT < 5 x upper normal limit for age
    f. EDTA clearance >40mL/min (adults) or >30% of normal limit for age (children)
    5. Signed statement of consent after receiving oral and written study information
    6. Agreement to utilize highly effective contraception methods from time of leukapheresis until a minimum of 12 months after CAR-T infusion for all female patients of childbearing potential and all male patients with a female partner of childbearing potential. Highly effective contraception is defined as: total abstinence, female sterilization (oophorectomy, total hysterectomy or tubal ligation), male sterilization or use of oral, injected or implanted hormonal methods of contraception or placement or an intrauterine system/device.
    E.4Principal exclusion criteria
    o Prior malignancy (except for non-melanoma skin cancer) with on-going evidence of active disease or expected 5-year survival below 50% (as best estimation by treating oncologist)
    o Patients with concomitant genetic syndrome, such as Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known familial bone marrow failure syndrome
    o Prior treatment with any gene therapy product
    o Treatment with any investigational agent within 30 days prior to enrollment
    o Treatment with allogeneic haematopoietic stem cell transplantation within 6 months or donor lymphocyte infusion within 6 weeks from CAR-T infusion
    o Acute or chronic graft-versus-host disease with the need for systemic corticosteroid treatment within 4 weeks prior to enrollment
    o Acute or chronic infections with HIV
    o Active infection with, hepatitis B or hepatitis C
    o Active severe bacterial, viral or fungal infection
    o Active Central Nervous System (CNS) involvement by malignancy, defined by CNS-3 per NCCN guidelines for ALL, or any evidence of lymphoma on lumbar puncture or brain imaging (if performed).
    o Pre-existing significant central neurological disorder defined as CTCAE grade 3-4 (other than CNS involvement of underlying hematological malignancy)
    o History of anaphylaxis to gentamicin or its derivates
    o Pregnant or breastfeeding women
    E.5 End points
    E.5.1Primary end point(s)
    o CRS: registration according to international grading system[31]. Endpoints include proportion of patients experiencing CRS of all grades and CRS grade 3-4.
    o Neurotoxicity: registration according to international grading system[31]. Endpoints include proportion of patients experiencing neurotoxicity of all grades and neurotoxicity grade 3-4.
    o Treatment with tocilizumab and/or glucocorticoids.
    o Prolonged cytopenia, including time to reach acceptable levels of neutrophils (≥1,.0 in three consecutive days), thrombocytes (≥100 in three consecutive days) and hemoglobin after CAR T-cell infusion.
    o Episodes of neutropenic fever (temperature >38.5 °C and neutrophils <0.5) .
    o Admission at the intensive care unit (ICU) or pediatric intensive care unit (PICU)
    o Death from any cause
    E.5.1.1Timepoint(s) of evaluation of this end point
    28 days, 90 days, 180 days, 365 days and 730 days
    E.5.2Secondary end point(s)
    o Response rates defined as complete response, partial response, stable response or progressive disease
    o Overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM) and treatment with allogeneic hematopoietic stem cell transplantation (HSCT)
    E.5.2.1Timepoint(s) of evaluation of this end point
    at time points 28 days, 90 days, 180 days, 365 days and 730 days.
    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 Yes
    E.6.13.1Other scope of the trial description
    Biological and immunological markers during treatment with CLIC-1901 cells
    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 No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    Due to GMO, all patients will be followed for 15 years, however for safety, not as part of the study
    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
    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: 20
    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: 1
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 1
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 8
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 8
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state20
    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)
    None
    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 Decision2022-04-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-07-08
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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