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    Summary
    EudraCT Number:2017-002848-32
    Sponsor's Protocol Code Number:M-2017-322
    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:2017-10-02
    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 ConcernedGermany - PEI
    A.2EudraCT number2017-002848-32
    A.3Full title of the trial
    A phase I/II safety, dose finding and feasibility trial of MB-CART19.1 in patients with relapsed or refractory CD19 positive B cell malignancies.
    Eine Phase-I/II-Studie mit MB-CART19.1 zur Beurteilung der Sicherheit und Machbarkeit sowie zur Dosisfindung bei Patienten mit wiederkehrenden oder therapie-unempfindlichen CD19 positiven B-Zell Erkrankungen.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase I/II safety, dose finding and feasibility trial of MB-CART19.1 in patients with relapsed or refractory CD19 positive B cell malignancies.
    Eine Phase-I/II-Studie mit MB-CART19.1 zur Beurteilung der Sicherheit und Machbarkeit sowie zur Dosisfindung bei Patienten mit wiederkehrenden oder therapie-unempfindlichen CD19 positiven B-Zell Erkrankungen.
    A.3.2Name or abbreviated title of the trial where available
    MB-CART19.1 r/r CD19+ BCM
    MB-CART19.1 r/r CD19+ BCM
    A.4.1Sponsor's protocol code numberM-2017-322
    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 SponsorMiltenyi Biomedicine GmbH
    B.1.3.4CountryGermany
    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 supportMiltenyi Biomedicine GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMiltenyi Biomedicine GmbH
    B.5.2Functional name of contact pointClinical Trial Manager
    B.5.3 Address:
    B.5.3.1Street AddressFriedrich-Ebert-Straße 68
    B.5.3.2Town/ cityBergisch Gladbach
    B.5.3.3Post code51429
    B.5.3.4CountryGermany
    B.5.4Telephone number+49220483066648
    B.5.5Fax number+49220483066699
    B.5.6E-mailAlexandra.Merckling@miltenyi.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 nameMB-CART19.1
    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) 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
    Pediatric and adult patients with relapsed/refractory (r/r) CD19-expressing B cell acute lymphoblastic leukemia (ALL) and Non-Hodgkin lymphoma (NHL), including chronic lymphocytic leukemia (CLL).
    E.1.1.1Medical condition in easily understood language
    Pediatric and adult patients with relapsed or refractory CD19 positive B cell malignancies.
    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 10063625
    E.1.2Term Acute lymphoblastic leukemia recurrent
    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 PT
    E.1.2Classification code 10003902
    E.1.2Term B-cell lymphoma recurrent
    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 PT
    E.1.2Classification code 10003903
    E.1.2Term B-cell lymphoma refractory
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10008977
    E.1.2Term Chronic lymphocytic leukemia recurrent
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10008978
    E.1.2Term Chronic lymphocytic leukemia refractory
    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
    Part I (Phase I):
    To determine the recommended dose of MB-CART19.1

    Part II (Phase II):
    To assess the response to adoptive cell therapy using autologous MB-CART19.1
    E.2.2Secondary objectives of the trial
    Part I (Phase I):
    - Preliminary evidence of response to MB-CART19.1 treatment
    - Phenotype and persistence of MB-CART19.1

    Part II (Phase II):
    - Safety and toxicity assessment of MB-CART19.1
    - Phenotype and persistence of MB-CART19.1
    - To determine duration of response, relapse rate, disease-free and overall survival after treatment with MB-CART19.1
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients must have r/r CD19-expressing ALL or NHL and meet the following disease-specific criteria:

    ALL:
    a patients with >5% blasts in BM (M2 or M3) after at least one standard chemotherapy and one salvage regimen who are ineligible for allogeneic stem cell transplant (alloSCT) or have refractory disease activity precluding alloSCT at this time, or
    b patients who have relapsed post alloSCT at least 100 days post-transplant, with no evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to leukapheresis.
    c patients with Ph+ ALL if they are intolerant to tyrosine kinase inhibitor (TKI) therapy, or if they have r/r disease after treatment with at least 2 different TKIs.
    d ALL patients with combined bone marrow and CNS and/or testicular relapse are eligible only if the extramedullary disease has been successfully cleared by conventional therapy at the time of inclusion (e.g. intrathecal chemotherapy, orchiectomy).

    Pediatric aggressive NHL (1-17 years):
    e patients after at least one salvage chemotherapy as bridge to alloSCT or
    f patients ineligible for alloSCT or
    g patients who have relapsed post alloSCT at least 100 days post-transplant, with not evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to leukapheresis.
    h patients with CNS disease (excluding isolated CNS lymphoma) are eligible only if disease has been successfully cleared by intrathecal chemotherapy at the time of inclusion.

    Adult NHL:
    i patients after at least one standard chemotherapy and one salvage regimen as bridge to alloSCT or
    j patients who are ineligible for alloSCT or
    k patients who have relapsed post alloSCT at least 100 days post-transplant, with no evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to leukapheresis.
    l patients with CNS disease (excluding isolated CNS lymphoma) are eligible only if disease has been successfully cleared by intrathecal chemotherapy at the time of inclusion.

    CLL:
    m patients with r/r disease after established and approved treatment options have failed.
    n patients not eligible or appropriate for conventional alloSCT

    2. CD19 expression must be detected on the malignant cells by flow cytometry (leukemia, malignant effusion in NHL) or immunohistochemistry (NHL); Results of previous assessments after the last treatment with CD19 targeted therapies but preceding inclusion of the patient in this trial are acceptable, if available;
    3. Age ≥1 year (if deemed fit by treating investigator);
    4. Absolute CD3+ T cell count ≥100/µl;
    5. ECOG performance score of 0-2 if >16 years old, or Lansky performance score of >50 if ≤16 years old at screening;
    6. No active Hepatitis B, Hepatitis C, HIV1/2;
    7. No childbearing potential or negative pregnancy test at screening and before chemotherapy in women with childbearing potential;
    8. Signed and dated informed consent/assent by patients and/or, in case of patients <18 years by parents, before conduct of any trial-specific procedure.
    E.4Principal exclusion criteria
    1. Isolated CNS or testicular relapse in ALL;
    2. Isolated CNS lymphomas;
    3. Active solid brain metastases or history of solid brain metastases
    4. Current autoimmune disease, or history of autoimmune disease with potential CNS involvement;
    5. Active clinically significant CNS dysfunction (including but not limited to uncontrolled seizure disorders, cerebrovascular ischemia or hemorrhage, dementia, paralysis);
    6. History of an additional malignancy other than non-melanoma skin cancer or carcinoma in situ unless disease free for ≥3 years;
    7. Pulmonary function: Patients with pre-existing severe lung disease or an oxygen requirement of >28% O2 supplementation or active pulmonary infiltrates on chest X-ray;
    8. Cardiac function: Pediatric patients: Fractional shortening <28% or left ventricular ejection fraction <50% by echocardiography, adult patients: left ventricular ejection fraction <50% by echocardiography;
    9. Renal function: GFR ≤29 mL/min/1.73 m2 by CKD-EPI for patients 18 yrs (Levey et al. 2009) or creatinine clearance ≤29 mL/min/1.73 m2 by Schwartz formula (Schwartz et al. 1976) for patients <18 yrs of age;10. Liver function: Patients with a serum bilirubin >3 times upper limit of normal or an AST or ALT > 5 times upper limit of normal, unless due to leukemic liver infiltration in the estimation of the investigator;
    11. Rapidly progressive disease that in the estimation of the investigator would compromise ability to complete study therapy;
    12. Pregnant or breast-feeding females;
    13. Medications:
    a Systemic chemotherapies, corticosteroids with the exception of physiologic replacement dosing, tyrosine kinase inhibitors (TKI) within 7 days prior to leukapheresis,
    b. Fludarabine/clofarabine or immunosuppressive drugs and antibodies (e.g. rituximab, calcineurin inhibitors, blinatumomab) or donor lymphocyte transfusions or radiation therapy within 30 days prior to leukapheresis,
    c Alemtuzumab within 3 months prior to leukapheresis,
    d Exception: Intrathecal chemotherapy is allowed at any time prior to treatment, but should be discontinued in ALL and BL 10 days prior to MB-CART19.1 infusion to limit risk of neurotoxicities;
    14. Hypersensitivity against any drug or its ingredients/impurities that is scheduled or likely to be given during trial participation, e.g. as part of the mandatory lymphodepletion protocol, pre-medication for infusion, rescue medication/salvage therapies for treatment related toxicities;
    15. Intake of concomitant medication contraindicated for other reasons than hypersensitivity within 30 days prior to leukapheresis, e.g. live vaccines and fludarabine
    16. Contraindication of trial related procedures as judged by the investigator, e.g. lumbar punctures for CSF sampling;
    17. Female patients of child-bearing potential not willing to practice a highly effective form of birth control from the time of leukapheresis and for 12 months after dosing the IMP;
    18. Male patients of fathering potential not willing to practice a highly effective form of birth control from the time of enrollment and for 12 months after dosing the IMP;
    19. Concurrent participation in another interventional trial that could interact with this trial, e.g. CAR T trials;
    20. Other investigational treatment within 4 weeks before IMP infusion;
    21. Cerebral dysfunction, legal incapacity of adult patients;
    22. Committal to an institution on judicial or official order.
    E.5 End points
    E.5.1Primary end point(s)
    Part I (Phase I):
    Determination of the recommended dose of MB-CART19.1, determined on the basis of the maximum tolerated dose (MTD), defined as the highest dose level of the two to three dose levels tested at which < 33% of patients experience DLT until day 28 after infusion of MB-CART19.1 and on the basis of the safety and efficacy data.
    Safety and toxicity assessment of MB-CART19.1 per adverse events (AE) reporting classified according to CTCAE (Common Terminology Criteria for Adverse Events) version 5.0 defined by <33% of patients experiencing DLT, or maximal administered dose.

    Part II (Phase II):
    Determination of the Overall Response Rate (ORR)
    - ORR in ALL patients is defined as the rate of complete remission (CR, CRh) on day 28;
    - ORR in NHL patients is defined as the rate of overall response (CR or PR) on day 28 and on month 3 in patients not in CR on day 28.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Adverse events will be documented at least 1,2, and 4 h post start of infusion. Furthermore on days 1, 2, 7,10, 14 and 28, on weeks 8, 12 and 16 as well as on months 6,8, 10 and 12 after the treatment and yearly during the long-term follow up . Adverse events observed by the investigator or reported spontaneously by the patient will also be recorded at any time.
    E.5.2Secondary end point(s)
    Part I (Phase I):
    - Overall incidence and severity of adverse events;
    - Response to treatment for each timepoint:
    - Overall response rate (ORR) in ALL patients defined as the rate of complete remission (CR, CRh) on day 28;
    - Rate of ALL patients achieving MRD response (<10-4);
    - ORR in NHL patients defined as the rate of overall response (CR or PR) on day 28 and at month 3 in patients not in CR on day 28;
    - Occurrence of B cell depletion;
    - Phenotype and persistence of MB-CART19.1.
    - Further safety assessments;

    Part II (Phase II):
    - Safety and toxicity of MB-CART19.1 per adverse events (AE) reporting classified according to CTCAE version 5.0;
    - Proportion of patients meeting the inclusion criteria and none of the exclusion criteria for who an autologous MB-CART19.1 product can be generated;
    - Rate of ALL patients achieving MRD response (<10-4);
    - Duration of response, relapse rate and time to relapse;
    - Disease-free and overall survival at 1 year after adoptive immunotherapy with MB-CART19.1 in patients not receiving alloSCT;
    - Occurrence of B cell depletion;
    - Phenotype and persistence of MB-CART19.1.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Clinical Response assessments:
    PB, BM and CSF for cytomorphology and MRD analysis: screening, day -5 or day -6 (only in patients with CNS-2 or 3 status at screening), day 28, week 12, months 6 and 12.

    PET-CT/PET-MRI; MRI whole Body (NHL adults): screening, week 12;
    MRI/CT (NHL): day 28, months 6, 12, long-term FU

    MRI (Children): Screening
    Day 28, week 12, month 6, 12, long-term FU

    B-cell Depletion:
    Pre-dose (day 0), days 7, 10, 14 and 28, weeks 8, 12 and 16, months 6, 8, 10 and 12 after infusion and annually during long-term FU

    Persistence / Phenotyping of infused MB-CART19.1:
    Day -5, pre-dose (day 0), days 2, 7, 10, 14 and 28, weeks 8 and 12, months 6 and 12 after dosing and annually during the long-term FU.
    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 No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    dose escalation
    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 concerned12
    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
    Letzter Besuch letzter Patient
    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 months7
    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: 18
    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: 4
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 8
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 13
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 17
    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 state48
    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)
    Up to 5 years after dosing regular long-term follow-up visits will be performed.
    Participation in another clinical trial not allowed up to week 4 for ALL patients and up to week 12 for NHL patients.
    Subsequent alloSCT is allowed at the discretion of the responsible investigator.
    Patients with a partial response or a subsequent relapse will be treated on a palliative care regimen. If they are eligible for alloSCT, they may move on to transplant, again at the discretion of the Investigator.
    Bis 5 Jahre nach der Dosierung erfolgen regelmäßige Nachuntersuchungen.
    Teilnahme an anderen klinischen Prüfungen bis 4 Wochen (ALL Patienten) oder 12 Wochen (NHL Patienten) nicht erlaubt.
    Der behandelnde Arzt entscheidet über eine darauf folgende alloSCT.
    Patienten mit partiellem Ansprechen oder Relapse werden entweder palliativ oder mit einer alloSCT behandelt, wiederum nach Entscheidung durch den Arzt.
    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 Decision2018-05-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-22
    P. End of Trial
    P.End of Trial StatusOngoing
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