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    Summary
    EudraCT Number:2018-002301-61
    Sponsor's Protocol Code Number:2215-CL-0603
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-07-16
    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 number2018-002301-61
    A.3Full title of the trial
    A Phase 1/2, Multicenter, Open-Label, Single Arm, Dose Escalation
    and Expansion Study of Gilteritinib (ASP2215) Combined with
    Chemotherapy in Children, Adolescents and Young Adults with FMS-like
    Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD)
    Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of Gilteritinib combined with chemotherapy to treat Children, Adolescents and Young Adults with Relapsed or Refractory Acute Myeloid Leukemia (AML) with a FLT3 gene mutation.
    A.4.1Sponsor's protocol code number2215-CL-0603
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/194/2019
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstellas Pharma Global Development, Inc. (APGD)
    B.1.3.4CountryUnited States
    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 supportAstellas Pharma Global Development, Inc. (APGD)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstellas Pharma Europe B.V.
    B.5.2Functional name of contact pointClinical Trial Unit Reg. Affairs
    B.5.3 Address:
    B.5.3.1Street AddressSylviusweg 62
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 BE
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31 71 545 5050
    B.5.5Fax number+31 71 545 5840
    B.5.6E-mailCTU@astellas.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/3/17/1961
    D.3 Description of the IMP
    D.3.1Product nameGilteritinib
    D.3.2Product code ASP12215
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Yes
    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 INNGILTERITINIB
    D.3.9.1CAS number 1254053-43-4
    D.3.9.2Current sponsor codeASP2215
    D.3.9.4EV Substance CodeSUB177203
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.IMP: 2
    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/3/17/1961
    D.3 Description of the IMP
    D.3.1Product nameGilteritinib
    D.3.2Product code ASP2215
    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 INNGILTERITINIB
    D.3.9.1CAS number 1254053-43-4
    D.3.9.2Current sponsor codeASP2215
    D.3.9.4EV Substance CodeSUB177203
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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
    FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or
    Refractory Acute Myeloid Leukemia (AML)
    E.1.1.1Medical condition in easily understood language
    AML is cancer of myeloid line of blood cells characterized by rapid growth of abnormal white blood cells that accumulate in bone marrow and interfere with production of normal blood cells
    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
    Phase 1 (Dose Escalation Phase):
    To determine the maximum tolerated dose (MTD) and/or optimally safe and biologically active recommended phase 2 dose (RP2D) of gilteritinib given in sequential combination with fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) in children, adolescents and young adults with relapsed/refractory (R/R) FMS like tyrosine kinase 3 (FLT3)/internal tandem duplication (ITD) and/or tyrosine kinase domain (TKD)] acute myeloid leukemia (AML).
    Phase 2 (Dose Expansion Phase):
    To determine complete remission (CR) rates and composite complete remission (CRc) rates after 2 cycles of gilteritinib in sequential combination with FLAG in children, adolescents and young adults in R/R FLT3/ITD AML in first relapse.
    E.2.2Secondary objectives of the trial
    The secondary objectives are:
    ● To assess the safety, tolerability and toxicities of gilteritinib when given in sequential combination with FLAG in children, adolescents, and young adults with R/R FLT3/ITD AML.
    ● To evaluate FLT3 inhibition due to gilteritinib treatment
    ● To characterize gilteritinib pharmacokinetics.
    ● To perform serial measurements of minimal residual disease (MRD) and examine the relationship with study endpoints.
    ● To obtain preliminary estimates of 1-year event-free survival (EFS) and overall survival (OS) rate.
    ● To assess the acceptability and palatability of the formulation.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved informed consent and privacy language as required per national regulations (e.g., Health Insurance
    Portability and Accountability Act Authorization for US sites) must be obtained from the subject or subject’s parent or legal guardian and if required child assent prior to any study-related procedures.
    2. Phase 1: Subject is positive for FLT3 (ITD and/or TKD) mutation in bone marrow or blood as determined by the local institution except for sites in the USA. USA sites – subject is positive for the FLT3 (ITD) mutation.
    Phase 2: Subject is positive for the FLT3 (ITD) mutation in bone marrow
    or blood as determined by the local institution.
    3. Subject is aged ≥ 6 months and < 21 years of age at the time of signing informed consent and/or assent, as applicable.
    * For phase 2: Enrollment of subjects from 6 months to less than 1 year (Group 3) and 1 year to less than 2 years (Group 2) will be dependent on the establishment of RP2D in the respective for age groups during phase 1.
    4. Subject has a diagnosis of AML according to The French–American–British (FAB) classification with ≥ 5% blasts in the bone marrow, with or without extramedullary disease (except subjects with active central nervous system [CNS] leukemia).
    a) In the phase 1 portion of the study, subject must be in first or greater relapse or refractory to induction therapy with no more than 1 attempt at remission induction.
    b) For the phase 2 portion of the study, subject must be in first relapse.
    5.Subject has fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
    6. For subject undergoing hematopoietic stem cell transplant (HSCT), at least 90 days must have elapsed since HSCT and subject must not have active graft-versus-host disease (GVHD).
    7. Subject has Karnofsky score ≥ 50 (if the subject is of ≥ 16 years of age) or Lansky score of ≥ 50 (if the subject is < 16 years of age). A score < 50 is acceptable if related to the subject's leukemia in the investigators judgment.
    8. Subject must meet the following criteria as indicated on the clinical
    laboratory tests.
    • Serum AST and ALT ≤ 3.0 x upper limit normal (ULN) for age
    • Total serum bilirubin ≤ 1.5 x ULN for age
    • Serum creatinine ≤ 1.5 x ULN for age or an estimated glomerular filtration rate of
    > 60 mL/min/1.73 m2.
    9. A female subject is eligible to participate if she is not pregnant and at least 1 of the following conditions applies:
    a) Not a woman of childbearing potential (WOCBP) as defined in [Appendix 12.3 Contraception Requirements]
    OR
    b) WOCBP who agrees to follow the contraceptive guidance as defined in throughout the treatment period and for at least 180 days after the final study drug administration.
    10. Female subject must agree not to breastfeed starting at Screening, and throughout the study period and for 60 days after the final study drug administration.
    11. Female subject must not donate ova starting at Screening and throughout the study, and for 180 days after the final study drug administration.
    12.A male subject with female partner(s) of childbearing potential must agree to use contraception as detailed in [Appendix 12.3 Contraception Requirements] during the treatment period and for at least 180 days after the final study drug administration.
    13. A male subject must not donate sperm during the treatment period and for at least 120 days after the final study drug administration.
    14. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 180 days after the final study drug administration.
    15. Subject and subject's parent(s) or legal guardian agrees not to participate in another interventional study while on treatment.
    16. Live Vaccines: At least 6 weeks must have elapsed since the administration of the last dose of a live vaccine and prior to initiation of study treatment (cycle 1 day -1).


    E.4Principal exclusion criteria
    1. Subject has active CNS leukemia.
    2. This criterion has been removed.
    3. Subject has uncontrolled or significant cardiovascular disease, including:
    -Diagnosed or suspected congenital long QT syndrome or any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or TdPtorsades de pointes); any history of arrhythmia will be discussed with the sponsor’s medical monitor prior to subject’s entry into the study
    - Prolonged QTcF interval on pre-entry ECG (≥ 450 ms)
    - Any history of second or third degree heart block (may be eligible if the subject currently has a pacemaker)
    - Heart rate < 50 beats/minute on pre-entry ECG
    - Uncontrolled hypertension
    - Complete left bundle branch block
    4. Subject has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The subject needs to be off pressors and have negative blood cultures for 48 hours.
    5. Subject is receiving or plans to receive concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
    6. Subject has active clinically significant GVHD or is on treatment with systemic corticosteroids and is receiving > 0.5 mg/kg of prednisone (or equivalent) daily dose for GVHD.
    7. Subject has active malignant tumors other than AML.
    8. Subject has any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise subject safety or compliance; interfere with consent, study participation, follow-up or interpretation of study results.
    9. Subject has hypokalemia and/or hypomagnesemia at Screening (defined as values below institutional lower limit of normal [LLN]). Repletion of potassium and magnesium levels during the screening period is allowed.
    10. Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A/P-glycoprotein (P-gp).
    11. Subject is known to have human immunodeficiency virus infection.
    12. Subject has active hepatitis B or C, or other active hepatic disorder.
    ● Subjects with positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B DNA are not eligible.
    ● Subjects with negative HBsAg, positive hepatitis B core antibody and negative hepatitis B surface antibody will be eligible if hepatitis B DNA undetectable.
    ● Subjects with antibodies to hepatitis C virus will be eligible if hepatitis C RNA is undetectable.
    13. This criterion has been removed.
    14. Subject must wait for at least 5 half-lives after stopping therapy with any investigational agent and before starting gilteritinib.
    15. Subject has known or suspected hypersensitivity to gilteritinib, cytarabine, fludarabine, G-CSF or any components of the formulations used.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1:
    Determination of MTD and/or RP2D based on the DLT and biologic activity according to PIA.
    Phase 2:
    o CRc rates (overall best response) after 2 cycles of therapy.
    o CR rates after 2 cycles of therapy ( only for FDA)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1:
    DLT observation period will be 28 days from the start of cycle 1 day 1; for the first cycle only.

    Phase 2:
    CRc and CR rates after 2 cycles of therapy.
    E.5.2Secondary end point(s)
    -Inhibition of phosphorylated FLT3 (pFLT3) measured by PIA assay
    -Gilteritinib plasma concentration
    -Pharmacokinetic parameters (e.g., oral clearance [CL/F], apparent volume of distribution [Vd/F], maximum concentration [Cmax], time of maximum concentration [tmax], area under the concentration-time curve [AUC]) of gilteritinib
    -Safety, tolerability and toxicity assessments of gilteritinib when given in combination with and FLAG
    -EFS rate
    -OS rate
    -MRD assessment
    -Acceptability and palatability assessment of the liquid formulation
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 2 cycles of therapy
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    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 Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Acceptability and palatability assessment of the liquid formulation
    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
    first use in children
    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 Yes
    E.8.1.7.1Other trial design description
    sequential combination with FLAG
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    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
    Canada
    Germany
    Italy
    Japan
    Spain
    United Kingdom
    United States
    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
    LPLV
    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 months11
    E.8.9.1In the Member State concerned days16
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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 Yes
    F.1.1Number of subjects for this age range: 80
    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: 5
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 29
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 46
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 34
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Male and female children and adolescents from 6 months to less than 21 years of age.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 45
    F.4.2.2In the whole clinical trial 114
    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)
    None
    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 Decision2019-11-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-12
    P. End of Trial
    P.End of Trial StatusOngoing
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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