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    Summary
    EudraCT Number:2018-001018-14
    Sponsor's Protocol Code Number:UCART123_03
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-04-02
    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 ConcernedUK - MHRA
    A.2EudraCT number2018-001018-14
    A.3Full title of the trial
    Phase I, open label dose-escalation study to evaluate the safety, expansion, persistence and clinical activity of multiple infusions of UCART123 (allogeneic engineered T-cells expressing anti-CD123 chimeric antigen receptor) in patients with adverse genetic risk Acute Myeloid Leukaemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate the safety and efficacy of UCART123 in adults with high risk Acute Myeloid Leukaemia
    A.4.1Sponsor's protocol code numberUCART123_03
    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 SponsorCELLECTIS SA
    B.1.3.4CountryFrance
    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 supportCELLECTIS SA
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCELLECTIS SA
    B.5.2Functional name of contact pointRegulatory and Compliance Affairs
    B.5.3 Address:
    B.5.3.1Street Address8 rue de la Croix Jarry
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75013
    B.5.3.4CountryFrance
    B.5.4Telephone number+33181691713
    B.5.6E-mailclinicaltrialinfo@cellectis.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 nameUCART123
    D.3.4Pharmaceutical form 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 INNCD123-CAR+_TCRαβ–_T-cells
    D.3.9.3Other descriptive nameUCART123
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number2.8E6 to 27E6
    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
    Adverse genetic Acute Myeloid Leukaemia
    E.1.1.1Medical condition in easily understood language
    Blood Cancer
    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 10000878
    E.1.2Term Acute myeloblastic leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To evaluate the safety and tolerability of a multiple infusion schedule of UCART123 in
    patients with CD123+ adverse genetic risk AML who do not achieve morphologic or
    cytogenetic complete remission after induction chemotherapy.
    2. To determine the Maximum Tolerated Dose (MTD) of UCART123.
    E.2.2Secondary objectives of the trial
    To assess the efficacy and tolerability of UCART123 in patients with CD123+ adverse genetic
    risk AML who do not achieve morphologic or cytogenetic complete remission after induction
    chemotherapy, by measuring:
    • Rate and severity of cytokine release syndrome,
    • Rate and severity of UCART123 related adverse events,
    • Rate of morphological CR at Day 28 after each UCART123 infusion,
    • Rate of cytogenetic CR at Day 28 after each UCART123 infusion,
    • Rate of CR without MRD at Day 28 after each UCART123 infusion, and
    • Leukaemia-free survival (LFS) and overall survival (OS).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Aged between 18 and 65 years;
    2. Weight ≥42 kg;
    3. Patients newly diagnosed with CD123 positive adverse genetic risk acute myeloid leukaemia (AML), including patients with CD123 positive AML secondary to MDS, who do not achieve complete remission, and whose bone marrow blast content is < 20% after 1 or 2 courses of standard intensive induction chemotherapy. Adverse genetic risk is defined as per ELN guidelines (Döhner et al., 2017).
    4. Patients must have received either a “3+7” regimen (consisting of 3 days of an IV anthracycline: daunorubicin at least 60 mg/m²; idarubicin 12 mg/m²; or mitoxantrone 12 mg/m², and 7 days of continuous infusion cytarabine (100-200 mg/m²)) ; or FLAG-Ida regimen (consisting of fludarabine 30 mg/m² from Day 2 to Day 6, cytarabine 1500-2000 mg/m² IV, Day 2 to Day 6; idarubicin 10 mg/m², Day 2 to Day 4);
    5. Availability of a suitable sibling or unrelated HLA matched donor;
    6. Adequate organ function defined as:
    i. Creatinine clearance ≥60mL/minute (assessed as glomerular filtration rate using the Cockcroft & Gault formula or MDRD); and
    ii. Alanine aminotransferase <3 × upper limit of normal (ULN) or aspartate aminotransferase <3 × upper limit of normal (ULN); and
    iii. Bilirubin < 2 times ULN (except for patients with documented history of Gilbert’s syndrome confirmed by UGT1A1 mutation); and
    iv. Cardiac ejection fraction >50% as assessed by echocardiography; and
    v. Must have a minimum level of pulmonary reserve defined as Grade <2 dyspnoea and pulse oxygenation ≥92% on room air.
    7. Women of childbearing potential must have a negative highly sensitive serum pregnancy test performed within 7 days prior to enrolment. Within the frame of this study, female patients of childbearing potential and male patients with partners of childbearing potential must use a highly effective method of birth control, as well as their partners, from the screening period for a duration of 12 months after UCART123 administration.
    Nonchildbearing potential is defined as being postmenopausal for at least 1 year, or women with documented infertility (natural or acquired). Highly effective birth control methods include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, and sexual abstinence
    E.4Principal exclusion criteria
    1. Patients with ≥20% blasts in bone marrow after 1 or 2 courses of standard intensive induction chemotherapy;
    2. Patients with AML transformed from previously diagnosed myeloproliferative disorder;
    3. Patients with APL;
    4. Evidence of uncontrolled CNS leukaemia or evidence of CNS leukaemia on CSF examination;
    5. AML relapsing after first complete remission;
    6. Prior allogeneic stem cell transplant;
    7. Therapy-related AML;
    8. Favourable or intermediate risk AML;
    9. Prior gene or experimental cellular therapy;
    10. Active uncontrolled infection or organ dysfunction that in the opinion of the investigator precludes intensive induction chemotherapy or cellular therapy;
    11. Use of other investigational products within five half-lives or within 14 days prior to start of lymphodepletion, whichever is longer; participation in non-interventional registries or epidemiological studies is allowed. In addition, treatment-related toxicities should have resolved to no more than Grade 1;
    12. Use of rituximab and other anti-CD20 antibodies known to have the same epitope as rituximab or anti-CD20 antibodies for which the epitope is unknown within 3 months or 5 half-lives prior to enrolment, whichever is longer. Any contraindication to or safety concern preventing the potential use of rituximab;
    13. Patients may not receive ≥ 20 mg of prednisone or equivalent between Day -7 and Day 28 of UCART123 administration. Hydrocortisone required for mineralocorticoid replacement therapy is authorized at all times as
    needed clinically. Topical, inhaled, or nasal route of steroids are permitted;
    14. Known infection with human immunodeficiency virus or human T-cell leukaemia/lymphoma virus type 1;
    15. A known hypersensitivity to any of the test materials or related compounds including murine and bovine products;
    16. Any planned medical/surgical treatment that might interfere with the ability to comply with the study requirements; or
    17. Evidence of another uncontrolled malignancy within 2 years prior to Screening (except in situ non-melanoma skin cell cancers and in situ cervical carcinoma).
    E.5 End points
    E.5.1Primary end point(s)
    -Safety Endpoint
    • Evaluation of DLT, Incidence, nature, and severity of adverse events and serious adverse events (SAEs) throughout the study (CTCAE v4.03; Lee et al., 2014 for CRS; Cairo and Bishop 2004 for TLS, New consensus criteria 2016 for GvHD).
    E.5.1.1Timepoint(s) of evaluation of this end point
    • DLT at Day 28 post first UCART123 infusion and adverse events are assessed throughout the study
    E.5.2Secondary end point(s)
    -Efficacy Endpoints
    • Antileukemic activity, as measured by European Leukaemia Net (ELN) Response Criteria in AML (Döhner et al., 2017).
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Antileukemic Response will be assessed following each UCART123 administration at Day 14 and Day 28, at EOT visit and as clinically relevant
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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
    Exploratory objectives
    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
    Safety and Efficacy Trial
    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 EEA3
    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 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
    15 years long-term follow-up participation.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years18
    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 years19
    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: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 18
    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)
    Post 15 years follow up, surviving patients will continue their standard of care
    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 Decision2018-09-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-15
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2019-12-05
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