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    Summary
    EudraCT Number:2022-001080-27
    Sponsor's Protocol Code Number:CD45RADLIHaplo
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2022-04-12
    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 number2022-001080-27
    A.3Full title of the trial
    A multi-center phase I/II trial of memory T cell donor lymphocyte infusions after transplantation of CliniMACS TCRα/β and CD19 depleted stem cell grafts from haploidentical donors for hematopoietic cell transplantation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multicenter phase I/II study for the use of infusions of donor memory T cells after haploidentical stem cell transplantation with TCRαβ and CD19-depleted stem cells.
    A.4.1Sponsor's protocol code numberCD45RADLIHaplo
    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 SponsorUniversity Hospital Tuebingen
    B.1.3.4CountryGermany
    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 supportUniversity Hospital Tuebingen
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationZentrum fuer klinische Studien (ZKS)
    B.5.2Functional name of contact pointProjectmanagement
    B.5.3 Address:
    B.5.3.1Street AddressFrondsbergstr. 23
    B.5.3.2Town/ cityTuebingen
    B.5.3.3Post code72070
    B.5.3.4CountryGermany
    B.5.4Telephone number0049070712985635
    B.5.5Fax number004907071292508
    B.5.6E-mailzks-pm@med.uni-tuebingen.de
    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 nameAllogeneic T-cell concentrate CD45RA depleted
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    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) 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 Yes
    D.3.11.13.1Other medicinal product typeallogeneic CD3+ CD45RA- T-Lymphocytes
    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
    Patients suffering from hematological malignancies and eligible for haploidentical allogeneic stem cell transplantation. Patients will be included prior start of conditioning for SCT. Inclusion criteria for IMP infusions will be rechecked on day 30 after SCT.
    E.1.1.1Medical condition in easily understood language
    Patients suffering from hematological malignancies and eligible for haploidentical allogeneic stem cell transplantation.
    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 10066481
    E.1.2Term Hematological malignancy
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    ­Phase I dose escalation:
    Safety and toxicity of CD45RA depleted DLI as defined by infusional toxicities and acute GVHD grad III-IV.
    - Infusional toxicity: maximum toxicity on the days of transfusion evaluated by measuring vital signs prior to and at different times after transfusion

    Acute graft-versus-host disease grade III–IV defined as GVHD occurring within 100 days after SCT
    Severity graded according to Seattle (Glucksberg) criteria:
    - Incidence of acute GVHD grade III-IV
    - Time until occurrence of acute GVHD grade III-IV

    Phase II extension phase:
    - Number of CD3+/CD4+ T cells
    - Immune reconstitution on Day +100
    E.2.2Secondary objectives of the trial
    ­- Incidence of acute graft versus host disease GVHD) grade II-IV until Day 100 post transplantation
    ­- Incidence and severity of chronic GVHD after 1 year
    ­- Incidence of NRM after 1 year
    ­­- Overall survival at Day 100 and after 1 year
    ­- Disease-free survival at Day 100 and after 1 year
    ­- Incidence of relapse at Day 100 and after 1 year
    ­- Number and percentage of patients who are off immunosuppression at one year post transplant
    - Donor chimerism
    ­- Reconstitution of T, B, NK and T regulatory (Treg) cell subsets by immune cell phenotyping
    ­- TCR V ß Spectrotyping , TREC analysis
    ­- T-cell activity
    ­- Infections: Incidence of CMV, ADV, EBV and aspergillus, as well as other viral, bacterial and fungal infections
    ­- Incidence, severity and type of adverse events/serious adverse events
    ­
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Adult and paediatric patients with hematological malignancies in complete remission (CR), partial remission (PR) or with stable disease
    - Acute myeloid leukemia (AML):
    Patients with high-risk AML in CR1
    Patients with relapsed or primary therapy-refractory AML
    - Acute lymphoid leukemia (ALL):
    Patients with high-risk ALL in CR1
    Patients with relapsed or primary refractory ALL
    - Hodgkin’s disease: Patients with relapsed or primary refractory Hodgkin’s disease
    - Non-Hodgkin’s lymphoma: Patients with relapsed or primary refractory Non-Hodgkin’s lymphoma
    - Myelodysplastic Syndrome (MDS)/ Myeloproliferative Syndrome (MPS):
    Patients with refractory MDS/MPS
    - Multiple myeloma (MM): Patients with relapsed or refractory multiple myeloma

    • No signs of acute GVHD on day 30 (day of infusion of DLI/IMP) after haploidentical HHCT
    • Patients aged ≥1 year to ≤65 years
    For safety reasons, dose escalation part within this study should only be performed for adults and older children (>6 years). The second part of the study, with already evaluated safe dose level, also younger children (≥1 year) can be included.
    E.4Principal exclusion criteria
    • Age >65 years or <1 year
    • Patients with progressive disease prior HCT
    • <3 months after preceding hematopoietic cell transplantation (HCT)
    • Treatment with T-cell or IL-2 targeted medication (e.g. alemtuzumab, basiliximab) within 60 days prior to study product infusion
    • Continuous treatment with prednisolone (or alternative glucocorticosteroid e.g. dexamethasone, short term use ≤3 days for other indication as GVHD allowed) within two weeks prior study product infusion (DLI).
    • Known allergy/hypersensitivity to any component of the study product
    • Treatment with another investigational drug within one month before inclusion
    • History of neurological impairment (active seizures, severe peripheral neuropathy, signs of leukencephalopathy, active CNS infection)
    Note: For patients with HLH or Malignant Osteopetrosis or other patients with heavy pretreatment with irradiation or intrathecal chemotherapy pre-transplant CNS MRI and neurological consultation are mandatory.
    • Fungal infections with radiological and clinical progression
    • Liver function abnormalities with bilirubin >2 mg/dL and elevation of transaminases higher than 400 U/L
    • Chronic active viral hepatitis
    • Ejection fraction <40% or Shortening fraction <20% on echocardiography. Patients with > grade II hypertension by CommonToxicity Criteria (CTC)
    • Creatinine clearance below threshold defined for stem cell transplantation according to local clinical standard
    • Respiratory failure necessitating supplemental oxygen
    • HIV infection
    • Female patients who are pregnant or breast feeding, or adults of reproductive potential not willing to use an effective method of birth control during study treatment and for at least 12 months thereafter
    Note: Women of childbearing potential must have a negative serum pregnancy test at study entry.
    • Concurrent severe or uncontrolled medical disease (e.g. uncontrolled diabetes, congestive heart failure, myocardial infarction within 6 months prior to the study, unstable and uncontrolled hypertension, chronic renal disease, or active uncontrolled infection) which by assessment of the treating physician could compromise participation in the study
    • Patients with a history of psychiatric illness or a condition which could interfere with their ability to understand the requirements of the study (this includes alcoholism/drug addiction)
    • Patients unwilling or unable to comply with the protocol or unable to give informed consent
    E.5 End points
    E.5.1Primary end point(s)
    Assessment of safety and tolerability of CD45RA depleted DLI will be measured by acute infusional toxicity such as allergic reactions and AEs >4 but also as described by the incidence of acute graft-versus-host disease grade III–IV defined as GVHD occurring within 100 days after HCT.

    The primary endpoint for part 2 of the study will be the immune reconstitution on Day +100 as assessed as by the log count of CD4+ T cells.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The main analysis will be presented after completion of the 100 days post-transplantation visit, i.e. when all patients have either completed the 100 days period after transplantation, are lost to follow-up or have died within this period. Additional analyses will be done on the 1-year follow-up data, i.e. when all patients have completed the 1-year period after transplantation, are lost to follow-up or have died within these periods.
    E.5.2Secondary end point(s)
    Secondary endpoints include the rate of NRM, chronic GVHD, reconstitution and functionality of relevant cells of the immune system (T, B and NK cell subsets as well as T regulatory cells), relapse rate, overall and disease-free at 1 year after transplantation.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The main analysis will be presented after completion of the 100 days post-transplantation visit, i.e. when all patients have either completed the 100 days period after transplantation, are lost to follow-up or have died within this period. Additional analyses will be done on the 1-year follow-up data, i.e. when all patients have completed the 1-year period after transplantation, are lost to follow-up or have died within these periods.
    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) 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 concerned10
    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 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.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    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: 2
    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: 10
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 10
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients aged ≥8 weeks to ≤65 years are enrolled
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    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 Decision2022-11-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-08-10
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
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