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    EudraCT Number:2018-002675-17
    Sponsor's Protocol Code Number:NCT-2017-0545
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-08-13
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2018-002675-17
    A.3Full title of the trial
    Quizartinib and High-dose Ara-C plus Mitoxantrone in Relapsed/Refractory AML with FLT3-ITD
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment with Quizartinib and High-dose Ara-C plus Mitoxantrone for patients with relapsed or refractory acute myeloid leukemia with FLT3-internal tandem duplication
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberNCT-2017-0545
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03989713
    A.5.4Other Identifiers
    Name:Trial CodeNumber:HeLeNe- 18-03
    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 SponsorRuprecht-Karls-University of Heidelberg Medical Faculty represented in law by Heidelberg University Hospital
    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 supportHeidelberg University Hospital
    B.4.1Name of organisation providing supportDaiichi Sankyo Europe GmbH
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHeidelberg University Hospital
    B.5.2Functional name of contact pointRiachrd F. Schlenk
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 130/3
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69120
    B.5.4Telephone number+49 (0)6221 56 6228
    B.5.5Fax number+49 (0)6621 56 5863
    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 nameQuizartinib
    D.3.2Product code AC220
    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.3.9.4EV Substance CodeSUB193517
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Relapsed/Refractory AML with FLT3-ITD
    E.1.1.1Medical condition in easily understood language
    relapsed or refractory acute myeloid leukemia with FLT3-internal tandem duplication
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assess CR and CRi after salvage therapy with Q-HAM according the ELN 2017 criteria
    E.2.2Secondary objectives of the trial
    Assess event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), cumulative incidence of relapse (CIR) and death (CID) and patient reported outcomes (PRO) according to continuation therapy strategy (preemptive vs. prophylactic)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with acute myeloid leukemia according to the 2016 WHO classification (except acute promyelocytic leukemia) who are either
    A) refractory to induction therapy or
    B) relapsed after first line treatment including chemotherapy, autologous and/or allo-HCT (details below).
    2. Positive for FLT3-ITD (defined as a ratio of mutant to wild-type alleles of at least 0.05; measured within 4 weeks before inclusion)#
    3. ECOG performance status ≤ 2. See appendix 18.1
    4. Adequate renal function defined as creatinine clearance >50 mL/min (calculated using the standard method for the institution)
    5. Discontinuation of prior AML treatment for at least
    • 10 days for cytotoxic agents and
    • 28 days for investigational drug treatment
    before the start of study treatment (except hydroxyurea to control hyperleukocytosis)
    6. Age ≥ 18 years and ≤ 75 years
    7. Pregnancy and childbearing potential:
    • Non-pregnant and non-nursing women
    • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 48 hours prior to randomization (“Women of childbearing potential” is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months).
    • WOCBP must agree to avoid getting pregnant while on therapy: WOCBP must either commit to continued abstinence from heterosexual intercourse or begin one acceptable method of birth control (IUD, tubal ligation, or partner’s vasectomy) during study and 6 months after end of study/treatment.
    • Men must use a latex condom during any sexual contact with WOCBP, even if they have undergone a successful vasectomy and must agree to avoid to father a child during study and 6 months after end of study/treatment
    8. Signed written informed consent
    9. Ability of patient to understand character and consequences of the clinical trial

    A) Refractory to induction therapy is defined as no CR, or CRi, or PR (according to standard criteria) [1] after 1 or 2 intensive induction cycles of at least 7 days of cytarabine 100-200mg/m² continuously or an equivalent regimen with cytarabine with total dose not less than 700mg/m² per cycle and 2 days of an anthracycline (e.g. daunorubicin, idarubicin).
    B) Relapsed after first line therapy is defined as relapsed AML (according to standard criteria) [1] after a first line therapy including at least one intensive induction and consolidation therapy including (but not limited to) allo-HCT.
    # Secondary exclusion if FLT3-ITD cannot be verified by central testing. Patient already receiving Quizartinib may continue taking it and will be excluded after the first treatment cycle.
    E.4Principal exclusion criteria
    1. Acute promyelocytic leukemia (AML FAB M3 with t(15;17)(q22;q12) / PML-RARA)
    2. Patients with known CNS leukemia
    3. Isolated extramedullary manifestation of AML
    4. Patients with a “currently active” second malignancy other than non-melanoma skin cancer. Patients are not considered to have a “currently active” malignancy if they have completed therapy for more than one year and are considered by their physician to be at less than 30% risk of relapse within one year
    5. Hyperleukocytosis (leukocytes > 30,000/µl) at the time of study entry. 1)
    6. Uncontrolled or significant cardiovascular disease, including any of the following:
    o History of heart failure NYHA class 3 or 4
    o Left ventricular ejection fraction (LVEF) ≤ 40% by echocardiogram (ECHO)
    o History of uncontrolled angina pectoris or myocardial infarction within 12 months prior to screening
    o History of second (Mobitz II) or third degree heart block or any cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
    7. Inadequate liver function: ALT and AST ≥ 2.5 x ULN), total bilirubin ≥ 1.5 x ULN; Alkaline phosphatase ≥ 2.5 x ULN. Known liver cirrhosis or history of veno-occlusive disease (VOD) or history of Sinusoidal Obstruction Syndrome (SOS)
    8. Known positivity for HIV, active HBV, HCV or hepatitis A infection (active hepatitis B defined by HBs Ag positivity, active hepatitis C defined by positive virus load)
    9. Uncontrolled active infection
    10. Evidence or history of severe non-leukemia associated bleeding diathesis or coagulopathy
    11. within 100 days after allo-HCT
    12. clinically relevant Graft-versus-Host-Disease (GvHD) requiring initiation of treatment or treatment escalation within 21 days prior to screening
    13. Any one of the following ongoing or in the previous 6 months: congenital long QT syndrome, Torsades de pointes, arrhythmias (including sustained ventricular tachyarrhythmia), right or left bundle branch block and bifascicular block, unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; as well as bradycardia defined as <50 bpms
    14. QTc interval >450 msec using the Fredericia correction (QTcF).
    15. Patients known to be refractory to platelet or packed red cell transfusions as per institutional guidelines, or who are known to refuse or who are likely to refuse blood product support.
    16. Severe neurologic or psychiatric disorder interfering with ability of giving informed consent
    17. Known or suspected active alcohol or drug abuse
    18. No consent for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician about study participation.
    19. Pregnancy and lactation
    20. History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product
    21. Prior treatment with quizartinib

    1) These patients should be treated with hydroxyurea according to routine practice and are only allowed to enter into the study when leukocyte counts of 30,000/µl or below are reached. If hydroxyurea is not sufficient to control hyperleukocytosis, i.v. application of 100mg cytarabine continuously over 24 hours may be discussed with the Principle Investigator or the Medical Coordinator.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint: CR/CRi
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of Study
    E.5.2Secondary end point(s)
    Secondary Endpoints: EFS, RFS, OS, CIR, CID, PRO
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of Study
    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 No
    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. 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 Yes
    E.8.1.1Randomised Yes
    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 Yes
    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 Yes
    E. description
    no treatment with IMP
    E.8.2.4Number of treatment arms in the trial2
    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 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 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: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state80
    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)
    Treatment ends after the 12th months/cycle maintenance therapy (EOT).
    Afterwards the subjects are followed during an observational follow-up, which consist of 3-monthly visits until EOS.
    After EOS patients are followed and may be treated according to local standard routine care.
    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 Decision2019-12-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2022-09-12
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