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    EudraCT Number:2010-018539-16
    Sponsor's Protocol Code Number:KKS-134
    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:2010-07-21
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2010-018539-16
    A.3Full title of the trial
    A double-blind, placebo-controlled, randomized, multi-center
    phase II trial to assess the efficacy of Sorafenib-maintenance therapy in Flt3-ITD positive AML in complete hematological remission after allogenic stem cell transplantation
    Doppel-blinde, placebo-kontrollierte, randomisierte, Multi-Center, Phase II Studie, um die Wirksamkeit einer Sorafinib-Erhaltungstherapie bei Flt3-ITD positiver AML in kompletter hämatologischer Remission nach allogener Stammzelltransplantation zu testen.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study, to investigate, if Sorafinib can prevent a relapse in AML patients after stem cell transplantation
    Studie, um herauszufinden, wie wirksam Sorafinb die Wiedererkrankung von AML Patienten nach Stammzeltransplantation verhindern kann.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberKKS-134
    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 SponsorPhilipps-Universität Marburg
    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 supportBayer
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKooridinierungszentrum für Klinische Studien Marburg
    B.5.2Functional name of contact pointSusanne Harnisch
    B.5.3 Address:
    B.5.3.1Street AddressKarl-von-Frisch-Strasse 4
    B.5.3.2Town/ cityMarburg
    B.5.3.3Post code35043
    B.5.4Telephone number+4964212866553
    B.5.5Fax number+4964212866517
    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 Nexavar
    D. of the Marketing Authorisation holderBayer Schering Pharma AG 13342 Berlin Deutschland
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSorafenib
    D.3.4Pharmaceutical form 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 INNSORAFENIB
    D.3.9.1CAS number 284461-73-0
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Yes
    D. medicinal product typemulti kinase inhibitor
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Flt3-ITD positive AML
    FLT3-ITD-positive AML
    E.1.1.1Medical condition in easily understood language
    specific kind of AML
    eine spezielle Form der AML
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective:
    Relapse free survival (RFS) of Flt3-ITD+ AML patients in complete hematological remission after allo-SCT receiving Sorafenib maintenance therapy versus placebo
    Ereignisfreie Überlebenszeit (RFS) von Flt3-ITD positiven AML Patienten in kompletter hämatologischer Remission nach allo-SCT, die mit Sorafenib oder Placebo als Erhaltungstherapie behandelt werden.
    E.2.2Secondary objectives of the trial
    Secondary objective:
    1. To compare the median overall survival (OS) of Flt3-ITD+AML patients in CHR after allo-SCT receiving Sorafenib maintenance treatment versus placebo
    2. To compare the median RFS and OS of Flt3-ITD+ AML patients with and without NPM mutations receiving Sorafenib versus placebo
    3. To compare the median RFS and OS of Flt3-ITD+AML patients in CHR after allo-SCT receiving Sorafenib maintenance treatment versus placebo depending on the baseline expression level of Flt3-ITD at diagnosis
    4. To compare the toxicity of Sorafenib maintenance versus placebo
    5. To longitudinally evaluate biomarkers associated with Sorafenib treatment response and Sorafenib resistance
    and correlation with RFS and OS
    6. To assess safety with type, severity graded by NCI CTC criteria version 4.02.
    1. Vergleich der medianen Gesamtüberlebenszeit (OS) von Flt3-ITD positiven AML Patienten in CHR nach allo-SCT, wenn sie entweder Sorafenib oder Placebo als Erhaltungstherapie erhalten
    2. Vergleich des mittleren RFS und OS von Flt3-ITD-positiven AML Patienten unter Sorafenib bzw. Placebo in Abhängigkeit vom NPM1 Mutationsstatus
    3. Vergleich des mittleren RFS und OS von Flt3-ITD-positiven AML Patienten unter Sorafenib bzw. Placebo in Abhängigkeit vom Baseline-Flt3-ITD-Expressionslevel
    4. Vergleich der Toxizität von Sorafenib und Placebo in der Erhaltungstherapie
    5. Longitudinale Untersuchung von Biomarkern, die mit einem Ansprechen oder Resistenz auf Sorafenib assoziiert sind und deren Korrelation in Bezug auf RFS und OS
    6. Analyse der Therapiesicherheit von Sorafenib in Bezug auf Art und Schwere (nach NCI CTC Kriterien, Version 4.02).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Written informed consent
    • Age 18 y.
    • ECOG performance ≤ 1
    • FLT3-ITD-positive AML
    • Complete hematological remission (CHR) after allo-SCT
    CHR must be confirmed by bone marrow analysis within 14 days before randomization (CHR criteria are: ≤ 5% marrow blasts, no peripheral blasts, blood platelet count > 100/nl, WBC count > 3 G/L, ANC > 1000 G/l).
    • Allo-SCT with a HLA-identical allo-family donor (FAM) or a matched unrelated donor (MUD) with up to 1 antigen mismatch acceptable (9/10)
    • Time point of study treatment start of patients in CHR: between d+60 up to d+100 after allo-SCT
    • Adequate organ function:
    Serum creatinine  1.5 x upper normal value
    ALT, AST, AP  2.5 x upper normal value
    Total bilirubin  1.5 x upper limit of normal
    PT-INR/PTT  1.5 x upper limit of normal
    • Patients who are being therapeutically anticoagulated with an agent such as Coumadin or Heparin will be allowed to participate in the trial provided that the medical need for anticoagulation is evidence-based (level I evidence) and PT-INR and PTT values are closely monitored to maintain the therapeutic window.
    • Negative serum pregnancy test within seven days prior to first dose in women of child-bearing potential (WOCBP)
    • WOCBP must use a double barrier method of contraception during the study and for 3 months following the last dose of study drug. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or surgical sterilization or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months).
    • Male subjects whose sexual partners are WOCBP must use a double barrier method of contraception, one of which includes a condom, during the study and for 3 months after the end of treatment.
    Schriftliche Einverständniserklärung
    • Alter  18 Jahre.
    • ECOG ≤ 1
    • FLT3-ITD positive AML
    • Komplette hämatologische Remission(CHR) nach allo-SCT;
    CHR muss durch eine Knochenmarkanalyse bis spätestens 14 Tage vor Studienbeginn festgestellt werden (CHR Kriterien: ≤ 5% Blasten im Knochenmark, keine peripheren Blasten, Plättchen > 100/nl, Leukozyten > 3 G/L, ANC > 1 G/l).
    • Allo-SCT mit HLA-identischem Familienspender (FAM) or passendem unverwandtem Spender (MUD) mit bis zu einem zulässigen Antigen Mismatch (9/10)
    • Zeitpunkt Studienbehandlungsstart von Patienten in CHR : zwischen d+60 bis zu d+100 nach allo-SCT
    • Adäquate Organfunktionen:
    Crea 1.5 x über Normalwert
    Bilirubin gesamt 1.5 x über Normalwert
    ALT, AST, AP  2.5 x über Normalwert
    PT-INR/PTT  1.5 x über Normalwert
    • Patienten, die therapeutisch mit Medikamenten wie Heparin oder Coumadin behandelt werden dürfen teilnehmen, wenn die medizinische Notwendigkeit dieser Antikoagulation evidenz-basiert ist (Level-1-Evidenz) und die PT-INR- und PTT-Werte eng monitoriert werden, um das therapeutische Fenster zu erhalten
    • Negativer Serum-Schwangerschaftstest innerhalb von 7 Tagen vor der ersten Gabe der Studienmedikation bei gebärfähigen Frauen
    • Gebärfähige Frauen müssen zur Verhütung einen doppelten Barriereschutz während der Studie bis einschließlich 3 Monate nach der letzten Medikamentengabe anwenden. Gebärfähige Frauen werden definiert als sexuell reife Frauen, die keine Hysterektomie oder Sterilisation hatten oder sich nicht seit mind. 12 Monaten fortlaufend in der Menopause befinden
    • Die Männer gebärfähiger Frauen müssen ebenfalls während der Studie und bis 3 Monate nach Gabe der letzten Studienmedikation bei der Verhütung auf einen doppelten Barriereschutz achten, wobei einer der Verhütungsmethoden ein Kondom sein muss
    E.4Principal exclusion criteria
    • Any severe concomitant conditions which make it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol (such as substance abuse, uncontrolled infection, known HIV, HBV, HCV infection
    • Psychiatric disorder that interferes with ability to understand the study and give informed consent, and/or impacts study participation or follow-up.
    • Cardiac disease: heart failure NYHA III/IV, unstable coronary artery disease (MI more than 6 months prior to study entry is permitted), serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted)
    • Resting blood pressure consistently higher than systolic 150 mmHg and/or diastolic 90 mmHg despite antihypertensive therapy
    • Patients undergoing renal dialysis
    • Evidence or history of severe non-leukemia associated bleeding diathesis or coagulopathy
    • Patients with uncontrolled seizure disorder despite medication
    • History of organ allograft (except for allogenic SCTX)
    • Patients with major surgery, open biopsy, or significant traumatic injury within 4 weeks prior to start of first dose of study drug
    • Serious non-healing wound, ulcer or bone fracture
    • Known Flt3-kinase inhibitor resistance
    • Previous Sorafenib therapy
    • Active (uncontrolled) graft versus host disease GvHD (> grade I) at time of randomization despite the use of adequate therapeutic measures
    • Investigational drug therapy outside of this trial during or within 4 weeks of study entry
    • Pregnancy or breast feeding
    • Allergy to study medication or compositions of excipients in study medication
    • Secondary allo-SCT
    • Previous or concurrent cancer curatively treated ≤ 3 years prior to study entry

    • Jede schwerwiegende Begleiterscheinung, die es dem Patienten verleidet an der Studie teilzunehmen oder die Durchführbarkeit des Studienprotokolls beeinträchtigen könnte (Drogensucht, unkontrollierte Infektion, bekannte HIV, HBV, HCV Infektion)
    • Psychiatrische Erkrankungen, die
    das Verständnis der Studientherapie / -ziele und somit den Einwilligungsprozess und/oder die Teilnahme an der Studie/ Follow-Up-Phase an sich beeinträchtigen.
    • Herzerkrankungen: Herzinsuffizienz (NYHA III/IV), KHK instabil (außer MI > 6 Monate zurückliegend), hochgradige Herzrhythmusstörungen unter anti-arhythmischer Therapie außer Beta-Blocker oder Digoxin.
    • Arterielle Hypertonie (konsistent über 150mmgHg systolisch oder 90mmHg diastolisch) trotz anti-hypertensiver Therapie
    • Dialysepflichtige Niereninsuffizienz
    • Blutungsdiathese
    • Unkontrolliertes Krampfleiden trotz antikonvulsiver Therapie
    • Zustand nach Organtransplantation (außer allogene SCTX)
    • Zustand nach großem chirurgischem Eingriff, offene Biopsy, oder Trauma innerhalb von 4 Wochen vor Gabe der ersten Studienmedikation
    • Schwerwiegende nicht-heilende Wunden, Geschwüre oder Knochenbrüche
    • Bekannte Flt3-Kinaseinhibitorresistenz
    • Vorausgegangene Sorafenibtherapie
    • Aktive Graft versus Host Erkrankung >Grad I oder mehr bei Randomisierung trotz adäquater Therapie
    • Teilnahme an einer Arzneimittelstudie bis 4 Wochen vor Studieneintritt
    • Schwangerschaft, Stillzeit
    • Allergie zur Studienmedikation oder dessen Bestandteile
    • Zweite allo-SCT
    • Vorherige oder konkurrierende kurative Krebsbehandlung  3 Jahre vor Studieneintritt
    E.5 End points
    E.5.1Primary end point(s)
    Relapse free survival (RFS), 50 events (relapse)
    RFS is defined as time interval from randomization until relapse of AML or death from any cause, which ever occurs first. Relapse is defined as any blast appearance in the peripheral blood, in the bone marrow (> 5%) or extramedullary blasts (chloroma). For a patient with no relapse before the end of study follow-up, observation of RFS will be censored at the date of his or her last follow-up examination.
    Rezidivfreie Überlebenszeit (RFS), 50 Ereignisse (Rezidive)
    RFS wird definiert als Zeitintervall von Randomisierung bis zum Auftreten eines Rezidivs oder bis zum Tod, je nachdem welches Ereignis früher eintritt. Ein Rezidiv besteht bei Nachweis von Blasten im peripheren Blut, Blasten >5% im Knochenmark oder extramedulläre Blasten im Sinne von Chloromen. Für Patienten ohne diese Ereignisse vor Beendigung der Nachbeobachtungsphase wird RFS zum Zeitpunkt der letzten Follow-Up-Visite ermittelt.
    E.5.1.1Timepoint(s) of evaluation of this end point
    50 events (relapse) or end of study
    50 Ereignisse (Rezidive) oder Studienende
    E.5.2Secondary end point(s)
    Overall survival
    Overall survival is defined as time from randomization to the day of death. For a patient who is not known to have died by the end of follow-up, observation of OS will be censored on the date the patient was last known to be alive.
    Gesamtüberlebenszeit (OS)
    OS wird als Zeitintervall von Randomisierung bis zum Tod definiert. Für Patienten, die bei Beendigung der Nachbeobachtungsphase nicht gestorben sind, wird OS zum Zeitpunkt ermittelt, zu dem der Patient nach letztem Erkenntnisstand noch lebte.
    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 Yes
    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 Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other No
    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 concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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 Information not present in EudraCT
    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
    the study ends with last vist of the last patient and databasclosure
    Studienende ist defniert als letzter Patient, letzte Visite und Datenbankschluss
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    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 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.1.3Elderly (>=65 years) Yes
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2010-07-21. Yes
    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 state200
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 200
    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)
    After the treatment phase(24 months) and post treatment follow up of 6 months, further follow up is planned until month 42 for evaluation of RFS and OS only.
    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 Decision2010-09-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-09-28
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-10-31
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