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    Summary
    EudraCT Number:2019-003686-17
    Sponsor's Protocol Code Number:WiNK
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-04-27
    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 ConcernedGermany - PEI
    A.2EudraCT number2019-003686-17
    A.3Full title of the trial
    A prospective phase I/IIa, open-label, multicentre trial to evaluate the safety and efficacy of oNKord®, an off-the-shelf, ex vivo-cultured allogeneic NK cell preparation, in subjects with acute myeloid leukaemia who are in complete morphologic remission with measurable residual disease and without a strong indication for stem cell transplantation.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial to evaluate the safety and efficacy of oNKord® in participants with acute myeloid leukaemia who are in complete morphologic remission with measurable residual disease and without a strong indication for stem cell transplantation.
    A.4.1Sponsor's protocol code numberWiNK
    A.5.4Other Identifiers
    Name:SMS-oncology study numberNumber:SMS-0341
    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 SponsorGlycostem Therapeutics BV
    B.1.3.4CountryNetherlands
    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 supportGlycostem Therapeutics BV
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSMS-oncology
    B.5.2Functional name of contact pointPavlina Topalova
    B.5.3 Address:
    B.5.3.1Street AddressWalaardt Sacréstraat 401-403
    B.5.3.2Town/ citySchiphol
    B.5.3.3Post code1117 BM
    B.5.3.4CountryNetherlands
    B.5.4Telephone number00310204350580
    B.5.5Fax number00310204350589
    B.5.6E-mailregulatory@sms-oncology.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/3/14/1395
    D.3 Description of the IMP
    D.3.1Product nameoNKord®
    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 INNALLOGENEIC EX VIVO-GENERATED NATURAL KILLER CELLS FROM CD34+ UMBILICAL CORD BLOOD PROGENITOR CELLS
    D.3.9.3Other descriptive nameALLOGENEIC EX VIVO-GENERATED NATURAL KILLER CELLS FROM CD34+ UMBILICAL CORD BLOOD PROGENITOR CELLS
    D.3.9.4EV Substance CodeSUB198925
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number325000000 to 1000000000
    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 Yes
    D.3.11.3.2Gene therapy medical product No
    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 Yes
    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 myeloid leukaemia
    E.1.1.1Medical condition in easily understood language
    A type of blood cancer with cancer cells in the bone marrow.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid 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
    The primary objectives are:
    • The primary safety objective is to evaluate the safety and tolerability of up to three infusions of oNKord®
    • The primary efficacy objective is to assess the cumulative incidence of MRD response, following the infusion of oNKord® at the RP2D


    E.2.2Secondary objectives of the trial
    The secondary objectives are:
    • In Stage A, to determine the RP2D of oNKord®
    • To evaluate the safety and tolerability of the overall trial treatment (combination of the Cy/Flu conditioning regimen and up to three oNKord® infusions)
    • To further assess the efficacy of the overall trial treatment (combination of the Cy/Flu conditioning regimen and oNKord® at RP2D) on EFS, duration of MRD response, CIR and OS
    • To evaluate the effect of the overall trial treatment (combination of the Cy/Flu conditioning regimen and oNKord® at RP2D) on quality of life (QoL)

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible to participate in this trial, subjects must meet ALL of the following eligibility criteria:
    1. Male or female subjects ≥ 18 years old
    2. Subjects with a diagnosis of AML and related precursor neoplasms according to the WHO 2016 classification (excluding acute promyelocytic leukaemia), including secondary AML after an antecedent haematological disease (e.g. myelodysplastic syndrome) and therapy-related AML
    3. Subjects who have achieved CMR, including CRi and complete clinical remission, with MRD documented at screening, as assessed by centralized MFC, after one or two courses of remission induction chemotherapy and who have completed consolidation chemotherapy or who achieved CMR with documented MRD with hypomethylating agents or other relevant appropriate therapies
    4. Life expectancy ≥ 6 months at screening
    5. Adequate renal and hepatic functions within 14 days of study screening, unless clearly disease related, as indicated by the following laboratory values:
    a. Serum creatinine ≤ 3 times the upper limit of normal (ULN) and estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73m2
    b. Serum total bilirubin < 2.0 mg/dl, unless due to Gilbert’s syndrome
    c. Alanine transaminase (ALT) ≤ 2.5 x ULN
    6. Karnofsky Status ≥ 50%
    7. Male subjects with partners who are women of childbearing potential must use an effective contraceptive method during the trial and for a minimum of 6 months after trial treatment, or have undergone successful vasectomy at least 6 months prior to entry into the trial (confirmed by semen analysis).
    8. Female subjects of childbearing potential must have a negative serum pregnancy test at screening and agree to use an effective contraceptive method during the trial and for a minimum of 6 months after trial treatment.
    9. Able to understand and willing to provide written informed consent
    to participate in the trial
    10. Affiliation to a national health insurance scheme (according to
    applicable local requirements)
    E.4Principal exclusion criteria
    Subjects who meet any of the following criteria at screening will be excluded from trial entry:
    1. Subjects proceeding to allogeneic HSCT, i.e. subject is a suitable candidate for allogeneic HSCT according to the investigator's assessment and donor is expected to be available in a timely manner
    2. Subjects having received prior allogeneic HSCT
    3. Subjects with acute promyelocytic leukaemia
    4. Diagnosis of any previous or concomitant malignancy is an exclusion criterion, except when the subject completed treatment (chemotherapy and/or surgery and/or radiotherapy) with curative intent for this malignancy at least 6 months prior to enrolment
    5. Blast crisis of chronic myeloid leukaemia
    6. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, uncontrolled hypertension, active or uncontrolled infection) including abnormal laboratory values, that could compromise compliance with the trial protocol or cause unacceptable safety risks
    7. Antibodies against HLA (anti-HLA) present
    8. Seronegativity for Epstein-Barr Virus (EBV)
    9. Known allergy to any of the components of oNKord® (e.g., dimethyl sulfoxide [DMSO]) or to any of the drugs to be administered in the preparative regimen to oNKord® infusion
    10. Contraindication to any of the drugs to be administered in the conditioning regimen or oNKord® infusion. This includes Cy, Flu, and medications associated with prophylaxis of AEs
    11. Cardiac dysfunction as defined by:
    a. Myocardial infarction within the last 3 months of trial entry, or
    b. Reduced left ventricular function with an ejection fraction < 40% as measured by multi-gated acquisition (MUGA) scan or echocardiogram (echo) within 28 days before screening, or
    c. Unstable angina, or
    d. New York Heart Association (NYHA) Class IV congestive heart failure, or
    e. Unstable cardiac arrhythmias
    12. Pulmonary dysfunction as defined by oxygen saturation < 90% on room air. Pulmonary function test (PFT) is required only in the case of symptomatic or prior known impairments within 28 days before screening - with pulmonary function < 50% corrected diffusing capacity of the lung for carbon monoxide (DLCO) and forced expiratory volume in 1 second (FEV1)
    13. Major surgery within 4 weeks prior to screening or a major wound that has not fully healed
    14. Vaccination with live, attenuated vaccines within 4 weeks prior to screening
    15. Immunosuppressive drugs for concomitant disease. Subject must be able to be off prednisone or other immunosuppressive medications for at least 3 days prior to the start of Cy/Flu regimen
    16. History of stroke or intracranial haemorrhage within 6 months prior to screening
    17. Active infections (viral, bacterial or fungal) that requires specific therapy. Acute anti-infectious therapy must have been completed within 14 days prior to trial treatment
    18. History of human immunodeficiency virus (HIV) or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
    19. Current concomitant chemotherapy, radiation therapy, or immunotherapy
    20. Positive pregnancy test or breastfeeding for women of childbearing potential
    21. Participation in another interventional clinical trial within 4 weeks prior to trial enrolment or participation in a concomitant interventional clinical trial
    22. Any serious concomitant medical condition, medication or therapy which could, in the opinion of the Investigator, compromise participation in the trial
    23. Subjects under legal protection measure (guardianship, trusteeship
    or safeguard of justice) and/or inability or unwillingness to comply with
    the requirements and procedures of this trial
    E.5 End points
    E.5.1Primary end point(s)
    Safety and Tolerability:
    To evaluate the safety and tolerability of oNKord® using the cumulative incidence of the adverse events of special interest (AESI), including:
    • Grade 3-to 4 infusion-related toxicity of oNKord®, as rated by the National Cancer Institute (NCI)’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
    • Acute GVHD grade III and IV
    • CRS ≥ Grade 2, as rated by the ASTCT Consensus Grading for Cytokine Release Syndrome
    • ICANS ≥ Grade 2, as rated by the ASTCT Consensus Grading for Neurologic Toxicity Associated with Immune Effector Cells (see Appendix C)
    Efficacy:
    To evaluate the efficacy of oNKord® using:
    • The cumulative incidence of MRD response as assessed by multiparameter flow cytometry (MFC) in bone marrow at 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord® infusion. Subjects with responses are defined as MRD negative subjects still in CMR at any time during the follow-up period of the trial after receiving oNKord® at RP2D
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety & tolerability: at screening, D-6 D-5, D-4, D-3, D0, D1, (D5, D8,) D9, D14 + each follow-up visit
    Efficacy: The cumulative incidence of MRD response at 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord® infusion.
    E.5.2Secondary end point(s)
    Safety and Tolerability:
    To evaluate the safety and tolerability of the overall trial treatment (Cy/Flu in combination with up to three oNKord® infusions) using the cumulative incidence of AESIs, including:
    • Grade 3-to 4 infusion-related toxicity of the overall trial treatment, as rated by CTCAE v5.0
    • Acute GVHD grade III and IV / Extensive chronic GVHD
    • CRS ≥ Grade 2, as rated by the ASTCT Consensus Grading for Cytokine Release Syndrome
    • ICANS ≥ Grade 2, as rated by the ASTCT Consensus Grading for Neurologic Toxicity Associated with Immune Effector Cells
    • Haemorrhagic cystitis
    • Death related to the overall trial treatment
    • Incidence and severity of viral, fungal, and bacterial infections with onset during the first two months following conditioning initiation, including viral reactivations, and Infection Related Mortality (IRM) defined as death due to infectious disease
    Efficacy:
    To evaluate the efficacy of the overall trial treatment (Cy/Flu in combination with oNKord® at RP2D) by assessing:
    • EFS, defined as the time from enrolment until disease relapse (morphologic and/or clinical relapse) after CMR or death due to any cause, whichever occurs first
    • CIR, defined as the cumulative incidence of relapse throughout the course of the trial
    • Duration of MRD response, defined as duration between MRD negativity to returning to MRD positivity, as assessed by MFC
    • OS, defined as the time from enrolment until death from any cause
    • Changes in QoL using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and SF-36 questionnaires, assessed at 1, 3 and 12 months post-treatment compared to baseline
    Exploratory Endpoints
    • Analysis of biomarkers predictive of response may include:
    o Analysis of responders and non-responders, as assessed by the efficacy primary endpoint, in relation to secondary efficacy endpoints
    o Targeted DNA sequencing of commonly mutated genes in AML, performed by next generation sequencing (NGS) on bone marrow samples, compared to diagnosis tumour genetic profiling (if available), and associated to response/ non-response
    o Assessment of oNKord® immunogenicity
    o Number of oNKord® infusions and corresponding enumeration of oNKord®-derived NK-cells in combination with relevant cytokine levels, including chimerism as determined by genomic assays and/or flow cytometry
    o MRD negativity, baseline physical and functional conditions associated to occurrence of relapse and survival
    • Determination of the biological parameters related to oNKord® derived NK-cells may include analysis of the in-vivo lifespan (immunophenotyping), cytolytic activity (persistence of oNKord® derived NK-cell functionality after infusions), and extent of oNKord® derived NK-cell expansion at multiple time points after oNKord® infusion(s)
    • Cumulative incidence of molecular response on MRD as assessed by error-corrected NGS at various timepoints post oNKord® infusion(s) in bone marrow and peripheral blood
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety & tolerability: at screening, D-6 D-5, D-4, D-3, D0, D1, (D5, D8,) D9, D14 + each follow-up visit
    Efficacy:
    - QOL: assessed at 1, 3 and 12 months post-treatment compared to baseline
    -OS: until death
    -Duration MRD response at 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord® infusion.
    -CIR; throughout the course of the trial
    -EFS: enrolment until disease relapse
    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 Yes
    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
    dose-escalation stage + Expansion stage
    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.8.2.4Number of treatment arms in the trial1
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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
    Belgium
    France
    Germany
    Netherlands
    Switzerland
    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
    The end of the trial is defined as the date at which the last data point for the primary endpoint from the last subject is received.




    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 months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    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: 17
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 16
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 33
    F.4.2.2In the whole clinical trial 33
    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)
    After participation, subjects will be managed in accordance with clinical practice (as per local guidelines and standard of care). At the Investigator request, a rescue dose of oNKord® might be made available in case of return to positive MRD status at 2,3,6,9 or 12 months, after MRD negativity at 1 month post oNKord® infusion(s), as the subject is still in CMR
    Subject to further informed consent, all subjects who received oNKord® can participate in an observational study for further follow-up
    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 Decision2020-08-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-31
    P. End of Trial
    P.End of Trial StatusOngoing
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