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    Summary
    EudraCT Number:2019-004491-19
    Sponsor's Protocol Code Number:GMALL-MOLACT2-PONA
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2020-06-03
    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 - BfArM
    A.2EudraCT number2019-004491-19
    A.3Full title of the trial
    A confirmatory multicenter, single-arm study to assess the efficacy, safety, and tolerability of ponatinib (Iclusig®) in adult patients with minimal residual disease (MRD) in Philadelphia-Chromosome positive acute lymphoblastic leukemia
    Eine multizentrische, einarmige Studie zur Bestimmung der Wirksamkeit, Sicherheit und Verträglichkeit des Tyrosinkinaseinhibitors Ponatinib bei erwachsenen Patienten mit minimaler Resterkrankung (MRD) einer Philadelphia-Chromosom-positiver akuter lymphatischen Leukämie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A confirmatory multicenter, single-arm study to assess the efficacy, safety, and tolerability of ponatinib (Iclusig®) in adult patients with minimal residual disease (MRD) in Philadelphia-Chromosome positive acute lymphoblastic leukemia
    Eine multizentrische, einarmige Studie zur Bestimmung der Wirksamkeit, Sicherheit und Verträglichkeit des Tyrosinkinaseinhibitors Ponatinib bei erwachsenen Patienten mit minimaler Resterkrankung (MRD) einer Philadelphia-Chromosom-positiver akuter lymphatischen Leukämie
    A.3.2Name or abbreviated title of the trial where available
    GMALL-MOLACT2-PONA
    A.4.1Sponsor's protocol code numberGMALL-MOLACT2-PONA
    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 SponsorUniversitätsklinikum Frankfurt
    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 supportIncyte Biosciences International Sàrl
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitätsklinikum Frankfurt
    B.5.2Functional name of contact pointStudienzentrale Hämatologie
    B.5.3 Address:
    B.5.3.1Street AddressTheodor Stern Kai 7
    B.5.3.2Town/ cityFrankfurt/Main
    B.5.3.3Post code60590
    B.5.3.4CountryGermany
    B.5.4Telephone number+49696301-6365
    B.5.5Fax number+49696301-7463
    B.5.6E-mailgmall@em.uni-frankfurt.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 Yes
    D.2.1.1.1Trade name Iclusig®
    D.2.1.1.2Name of the Marketing Authorisation holderIncyte Biosciences Distribution B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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/3/09/715
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNINN-ponatinib
    D.3.9.1CAS number 943319-70-8
    D.3.9.3Other descriptive namePONATINIB
    D.3.9.4EV Substance CodeSUB91901
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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) 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 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
    minimal residual disease (MRD) in Philadelphia-Chromosome positive
    acute lymphoblastic leukemia (Ph+ALL)
    minimale Resterkrankung (MRD) einer Philadelphia-Chromosompositiven
    akuten lymphatischen Leukämie
    E.1.1.1Medical condition in easily understood language
    minimal residual disease (MRD) in Philadelphia-Chromosome positive
    acute lymphoblastic leukemia (Ph+ALL)
    minimale Resterkrankung (MRD) einer Philadelphia-Chromosompositiven
    akuten lymphatischen Leukämie
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10080018
    E.1.2Term Philadelphia positive acute lymphocytic 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
    To evaluate the efficacy of ponatinib to induce molecular remission in patients
    E.2.2Secondary objectives of the trial
    Other secondary objectives:
    To evaluate
    - Remission duration, relapse-free survival and overall survival
    - Relapse localisation and relapse characteristics
    - Efficacy of ponatinib in patients
    - Safety and tolerability of ponatinib in patients
    - Effect of ponatinib on duration of MRD response and molecular remission
    - Effect of ponatinib on the kinetics on MRD response
    - Outcome of SCT after ponatinib including mortality rate
    - Outcome of patients without SCT after ponatinib
    - Patient’s quality of life during and after therapy

    Exploratory objectives
    - Effect of pre-defined dose reductions, recommendations and local handling practices on safety, tolerability and treatment realisation of ponatinib
    - Resource utilization and practical treatment organisation
    - To assess potential biologic predictors of response to ponatinib, toxicity and relapse risk after ponatinib
    - To analyse the spectrum and kinetics in MRD-positive patients receiving ponatinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with Philadelphia-Chromosome/BCR-ABL1 positive ALL in complete hematological remission defined as less than 5% blasts in bone marrow after at least three intense chemotherapy blocks (e.g., GMALL induction I-II/consolidation I for patients < 55 years or after consolidation II for patients > 55 years) who received treatment with at least one tyrosine kinase inhibitor
    2. Presence of minimal residual disease (MRD) in molecular failure or with molecular relapse documented after an interval of at least 2 weeks from last systemic chemotherapy (Definition of Molecular failure/Mo-lecular Relapse: BCR-ABL1/ABL1>10E-04 and BCR-ABL1 copies > 10)
    3. Molecular evaluation for BCR-ABL1 performed
    4. Bone marrow function as defined below:
    ANC (Neutrophils) ≥ 1,000/μL
    Platelets ≥ 50,000/μL (transfusion permitted)
    HB level ≥ 9g/dl (transfusion permitted)
    5. ECOG performance status ≤2
    6. Normal QTcF interval ≤450 ms for males and ≤470 ms for females
    7. Normal serum levels > LLN (lower limit of normal) of potassium and magnesium, or corrected to within normal limits with supplements, prior to the first dose of study medication
    8. Adequate renal, hepatic and pancreatic function
    9. Minimum life expectancy of ≥3 months
    10. Negative pregnancy test and agree to use effective form of contraception (as applicable)
    11. Age ≥18 years
    12. Ability to understand and willingness to sign a written informed consent
    13. Signed and dated written informed consent is available
    14. Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)
    E.4Principal exclusion criteria
    1. Ph-negative ALL
    2. Presence of circulating blasts or current extramedullary involvement by ALL
    3. Current detection of ALL blast cells in cerebro-spinal fluid
    4. Any cancer chemotherapy or immunotherapy after sampling for the MRD test which leads to study inclu-sion (except for intrathecal prophylaxis and continued tyrosine kinase inhibitor)
    5. Autologous hematopoietic stem cell transplantation (SCT) or allogeneic SCT
    6. Treatment with any investigational product within four weeks prior to study treatment or within five terminal elimination half-lives of a preceding investigational medicinal product or of its relevant me-tabolite. The longer period of time will apply
    7. History of malignancy other than ALL diagnosed within 5 years prior to start of protocol-specified ther-apy with the exception of:
    a. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    b. Adequately treated cervical carcinoma in situ without evidence of disease
    c. Adequately treated breast ductal carcinoma in situ without evidence of disease
    d. Prostatic intraepithelial neoplasia without evidence of prostate cancer
    8. Active infection, any other concurrent disease or medical condition that are deemed to interfere with the conduct of the study as judged by the investigator
    9. Pregnant and nursing women
    10. Woman of childbearing potential and is not willing to use highly effective methods (as defined in the pro-tocol) of contraception while receiving study treatment and for an additional 3 months after the last dose of study treatment (Pearl-Index <1%). Women of childbearing potential are defined as mature women without hysterectomie or surgical sterilization or women without menopause. Menopause means without menstruation for natural reasons for one year
    11. Male who has a female partner of childbearing potential, and is not willing to use highly effective forms (as defined in the protocol) of contraception while receiving study treatment and for at least an additional 3 months after the last dose of study treatment (Pearl-Index <1%)
    12. Tyrosine kinase inhibitor (TKI) treatment within 3 days prior to receiving the first dose of ponatinib
    13. Treatment with medications that are known to be associated with torsades de pointes
    14. Prior treatment with ponatinib
    15. History or presence of clinically significant bleeding or coagulation disorder unrelated to completed ALL treatment elements, e.g asparaginase treatment
    16. History of pancreatitis within 1 year of study start or history of chronic pancreatitis, serum lipase and amylase ≥1.5 x ULN
    17. Known impaired cardiac function, including any of the following:
    a. LVEF < 40%
    b. Complete left bundle branch block
    c. Right bundle branch block plus left anterior hemiblock, bifascicular block
    d. History of or presence of clinically significant ventricular or atrial tachyarrhythmias
    e. Clinically significant resting bradycardia (< 50 beats per minute)
    f. Congenital long QT syndrome or QTcF >470 msec on screening ECG. If QTc > 470 msec and electrolytes are not within normal ranges before ponatinib dosing, electrolytes should be cor-rected and then the patient rescreened for QTcF criterion.
    g. Previous myocardial infarction
    h. Other clinically significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
    i. History of or presence of clinically relevant peripheral vascular disease or other vascular ste-nosis or occlusion,
    j. Any history of ischemic stroke or transient ischemic attacks (TIAs)
    18. Inadequate hepatic functions defined as ASAT or ALAT > 2.5 times the institutional upper limit of normal (ULN) or > 5 times ULN if considered due to leukemia
    19. Total bilirubin >1.5 fold the institutional ULN unless considered to be due to organ involvement by the leukemia or to M. Gilbert / M. Meulengracht
    20. Concurrent severe diseases which exclude the administra-tion of therapy
    21. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)
    22. Major surgery within 14 days prior to first dose of ponatinib
    23. Ongoing or active infection
    24. Malabsorption syndrome or other gastrointestinal illness that could affect absorption of ponatinib
    25. Any other condition or illness that would compromise safety
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients who achieve molecular remission after one cycle of treatment with ponatinib
    E.5.1.1Timepoint(s) of evaluation of this end point
    at the end of each treatment cycle (day 29) and
    during the efficacy follow-up visits at least 3-monthly (calculated from
    cycle 1 day 1) within the first year and 6-monthly within the second year
    until completion of a 18 months period after treatment start with
    ponatinib
    E.5.2Secondary end point(s)
    Secondary Endpoints
    - Probability of continuous molecular remission (remission duration) at 18 months follow-ing initiation of ponatinib
    - Probability of hematological relapse-free survival rate at 18 months following initiation of ponatinib
    - Probability of overall survival at 18 months following initiation of ponatinib
    - Frequency of different relapse localisations in proportion to total hematological relapses
    - Biological evaluation of hematological and extramedullary relapses including ABL-TKD mutation status
    - Overall incidence and severity of adverse events in patients (CTC-AE 4.0)
    - Proportion of patients who achieve molecular remission after one cycle of treatment with ponatinib
    - Probability of continuous MRD response and molecular remission and duration of mo-lecular remission at 18 months following initiation of ponatinib
    - Time to molecular remission measured by time-point of first achievement
    Evaluation of overall survival, remission duration, relapse-free survival and treatment re-lated mortality (at day 100 and later) in patients with SCT in complete remission after ponatinib
    - Evaluation of overall survival, remission duration, relapse-free survival and treatment re-lated mortality in patients without SCT in complete remission after ponatinib
    - Measurement of Quality of Life with EORTC instruments (EORTC QLQ C30 and EQ 5D) at different time points during treatment

    Exploratory endpoints
    - Incidence of dose reductions, incidence of treatment interruptions, days of interruption, withdrawals, total days of treatment and realisation rate calculated as delivered total dose/scheduled total dose
    - Hospitalisation days
    - Evaluation of ABL1-TKD mutations at different time-points during first treatment cycle, in primary materials and in comparison of primary materials and relapse material.
    E.5.2.1Timepoint(s) of evaluation of this end point
    at the end of each treatment cycle (day 29) and
    during the efficacy follow-up visits at least 3-monthly (calculated from
    cycle 1 day 1) within the first year and 6-monthly within the second year
    until completion of a 18 months period after treatment start with
    ponatinib
    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 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 concerned20
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    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 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: 5
    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 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)
    Transfer of patients to alloHSCT after one cycle or after subsequent
    cycles is considered as per protocol discontinuation. Patients who are
    not eligible for allo SCT will receive a second cycle, and will receive
    afterwards the standard protocol combined with a tyrosine kinase
    inhibitor (investigators choice).
    Ein Transfer der Patienten zur allogenen Stammzelltransplantation
    nach 1 oder 2 Zyklen wird protokollgemäß als Beendigung der Studie
    bewertet. Patienten, die nicht allogen transplantiert warden könne,
    erhalten einen 2. Zyklus und warden anschließend nach dem Standard
    Protokoll weiterbehandelt in Kombination mit einem TKI. Die Auswahl
    des TKI erfolgt durch den behandelnden Arzt.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia (GMALL)
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-09-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-09
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
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