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    EudraCT Number:2019-000136-26
    Sponsor's Protocol Code Number:MAURITIUS
    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:2019-10-28
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2019-000136-26
    A.3Full title of the trial
    Midostaurin in MRD positive acute myeloid leukemia after allogeneic stem cell transplantation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Midostaurin in acute myeloid leukemia after allogeneic stem cell transplantation
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberMAURITIUS
    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 SponsorFriedrich-Schiller-Universität Jena
    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 supportNovartis Pharma GmbH
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationStudy Department
    B.5.2Functional name of contact pointStudy Department
    B.5.3 Address:
    B.5.3.1Street AddressAm Klinikum 1
    B.5.3.2Town/ cityJena
    B.5.3.3Post code07747
    B.5.4Telephone number+4936419396670
    B.5.5Fax number+4936419399985
    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. name Rydapt
    D. of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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/3/04/214
    D.3 Description of the IMP
    D.3.1Product nameMidostaurin
    D.3.2Product code Rydapt
    D.3.4Pharmaceutical form Capsule, soft
    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 INNMidostaurin
    D.3.9.1CAS number 120685-11-2
    D.3.9.3Other descriptive nameMIDOSTAURIN
    D.3.9.4EV Substance CodeSUB21040
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    Acute Myeloid Leukemia
    E.1.1.1Medical condition in easily understood language
    Acute Myeloid Leukemia
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10066764
    E.1.2Term Acute myeloid leukaemia progression
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the Leukemia-free survival (LFS) of patients with molecular relapse or persistent molecular positivity on midostaurin treatment after allogeneic stem cell transplantation
    E.2.2Secondary objectives of the trial
    - To explore molecular response to midostaurin treatment in AML patients with MRD positivity after allogeneic SCT
    - To assess the development of graft-versus-host disease (GvHD)
    - To evaluate safety and tolerability of midostaurin after allogeneic SCT
    - To explore mechanisms of primary or secondary resistance to midostaurin by molecular analysis
    - To evaluate quality of life on midostaurin therapy in AML
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Patients with molecular relapse or persistent molecular positivity of AML after allogeneic SCT
    • Detection of FLT3-ITD or FLT3-TKD at primary diagnosis or at antecedent relapse of AML prior to allogeneic SCT
    • Sensitive MRD assessment based on qPCR (i.e. low PCR “cut off” for each applied MRD marker of at least 0.1% - e.g. NPM1mut/ABL1)
    • ANC > 1,0 Gpt/L and Platelets > 50 Gpt/L
    • ECOG performance status 0-2
    • GFR > 30 ml/min and serum bilirubin < 1.5 x ULN
    • Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 3.0 × ULN;
    Serum levels of potassium (3.3-4.5 mmol/L), magnesium (0.77-1.03 mmol/L), total calcium (2.2- 2.65 mmol/L) or within the normal limits (≥LLN [lower limit of normal] and ≤ULN [upper limit of normal]) of the hospital or local laboratory. Correction of electrolytes levels with supplements to fulfil inclusion criteria is allowed.
    • All female patients with reproductive potential and all male patients must agree to use effective methods to prevent pregnancy. Female patients of childbearing potential must agree to use dual methods of contraception (i.e. with progesterone contraceptive implants, intrauterine device with progesterone, pills containing estrogen and progestin, as well as three-month injection with depot progestin) for the duration of the study. Male patients and male partners of female patients must agree to use a barrier method of contraception for the duration of the study if sexually active with a female of childbearing potential. It is required that sexually active men use condom during intercourse while taking the drug and for 2 weeks after stopping treatment and not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Female partners of male patients must be advised to use a highly effective method of contraception. Contraception and a hold on sperm donation for male patients are to be continued for at least 2 weeks after the last dose of midostaurin for safety reasons.
    • All women of child-bearing potential have to complete a serum pregnancy test at screening visit. After screening, monthly serum pregnancy tests must be performed by all enrolled women of child-bearing potential from start of midostaurin until stop of midostaurin. If a test result indicates a pregnancy, the patient must stop treatment with midostaurin immediately. Pregnancy testing is not required for women who are determined to be post-menopausal.
    • Written informed consent prior to any study procedures being performed
    • Age ≥ 18 years
    E.4Principal exclusion criteria
    • Acute promyelocytic leukemia (APL)
    • Hematological relapse of AML (bone marrow blasts ≥5% or reappearance of blasts in the blood or development of extramedullary disease)
    • Lack of a suitable MRD marker (no detectable MRD marker at diagnosis or low sensitivity of an available MRD marker, e.g. sensitivity > 0.1% MRD transcript/ABL1)
    • Impaired left ventricular ejection fraction (LVEF) < 45%
    • Patients with midostaurin treatment after allogeneic SCT or with ongoing TKI therapy < 4 weeks prior to inclusion
    • Treatment with an investigational drug within 5 half-lives preceding the first dose of study medication
    • History of acute or chronic pancreatitis
    • Active and uncontrolled infections
    • History of severe lung disease and/or relevant functional impairment
    • Positive PCR for Human Immunodeficiency Virus (HIV) or Hepatitis B or C
    • Patients unable to swallow medication
    • Known hypersensitivity reaction to midostaurin or any excipient of midostaurin
    • Concomitant medications with known induction of CYP3A4 isoenzyme unless they can be discontinued or replaced prior to enrollment
    • Patients who have undergone major surgery ≤ 2 weeks prior to enrolment or who have not recovered from side effects of such therapy
    • Patients with resting QTcF ≥450 msec prior to enrolment or inability to determine the QTcF interval. Other clinically significant heart disease (e.g. unstable angina, congestive heart failure) Other concurrent uncontrolled medical conditions (e.g., active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol
    • Substance abuse, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
    E.5 End points
    E.5.1Primary end point(s)
    - Leukemia-free survival (LFS) – i.e. the proportion of patients without AML relapse
    E.5.1.1Timepoint(s) of evaluation of this end point
    at 12 months after detection of MRD positivity and initiation of midostaurin
    E.5.2Secondary end point(s)
    - Achievement of “low MRD” at 3 months
    - Incidence and severity of acute or chronic GvHD
    - Incidence of adverse events
    - Next-generation sequencing analyses of FLT3 and other genes
    - Quality of life
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Achievement of “low MRD” at 3 months
    - Incidence and severity of acute or chronic GvHD: end of study
    - Incidence of adverse events: end of study
    - Next-generation sequencing analyses of FLT3 and other genes: per Study Visit
    - Quality of life: end of study
    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 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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 concerned16
    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
    Every patient will be observed for 12 months starting on day of inclusion to the study and initiation of midostaurin treatment or until relapse (whichever occurs first) within the Mauritius trial. The end of study (EOS) is defined as the last assessment and documentation of remission and survival status and treatment change 12 months after inclusion of the last patient.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    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: 29
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 57
    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 state86
    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)
    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 SAL-Study Group
    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 Decision2020-02-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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