A Study of Gilteritinib Versus Midostaurin in Combination With Induction and Consolidation Therapy Followed by One-year Maintenance in Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndromes With Excess Blasts-2 With FLT3 Mutations Eligible for Intensive Chemotherapy
NCT ID: NCT04027309
Last Updated: 2024-12-17
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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ACTIVE_NOT_RECRUITING
PHASE3
777 participants
INTERVENTIONAL
2019-12-20
2033-06-30
Brief Summary
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Detailed Description
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FLT3 can be inhibited by the drug midostaurin. Adding midostaurin to chemotherapy leads to better treatment results in patients with AML. Therefore, the standard treatment for AML or MDS-EB2 with a FLT3 mutation (FLT3-AML) is a combination of chemotherapy and midostaurin.
Gilteritinib is also a drug that inhibits FLT3. In laboratory studies, gilteritinib was found to be significantly more specific and potent than midostaurin in inhibiting FLT3.
Gilteritinib has subsequently been studied in patients with AML, who relapsed after previous treatment with chemotherapy. This resulted in a much larger number of complete remissions than previously seen when comparable patients were treated with midostaurin.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Arm A (Midostaurin)
Midostaurin (50 mg BID PO) - Cycle 1 (day 8-21), Cycle 2 (day 8-21), Consolidation (only during chemo consolidation (day 8-21 - with max of 3 cycles), Maintenance (day 1-365)
Midostaurin
Patients with a FLT3 mutation w ill be randomized to receive either the investigational drug gilteritinib or midostaurin given sequentially to standard induction and consolidation chemotherapy. After completing induction and consolidation treatment, patients who achieve CR/CRi/MLFS will receive maintenance therapy with gilteritinib or midostaurin
Arm B (Gilteritinib)
Gilteritinib (120 mg QD PO) - Cycle 1 (day 8-21), Cycle 2 (day 8-21), Consolidation (only during chemo consolidation (day 8-21 - with max of 3 cycles), Maintenance (day 1-365)
Gilteritinib
Patients with a FLT3 mutation w ill be randomized to receive either the investigational drug gilteritinib or midostaurin given sequentially to standard induction and consolidation chemotherapy. After completing induction and consolidation treatment, patients who achieve CR/CRi/MLFS will receive maintenance therapy with gilteritinib or midostaurin
Interventions
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Gilteritinib
Patients with a FLT3 mutation w ill be randomized to receive either the investigational drug gilteritinib or midostaurin given sequentially to standard induction and consolidation chemotherapy. After completing induction and consolidation treatment, patients who achieve CR/CRi/MLFS will receive maintenance therapy with gilteritinib or midostaurin
Midostaurin
Patients with a FLT3 mutation w ill be randomized to receive either the investigational drug gilteritinib or midostaurin given sequentially to standard induction and consolidation chemotherapy. After completing induction and consolidation treatment, patients who achieve CR/CRi/MLFS will receive maintenance therapy with gilteritinib or midostaurin
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Newly diagnosed AML or MDS with excess of blasts-2 (EB2) defined according to WHO criteria (appendix A), with centrally documented FLT3 gene mutation (either TKD or ITD or both). AML may be secondary to prior hematological disorders, including MDS, and/or therapy-related. Patients may have had previous treatment with erythropoiesis stimulating agents (ESA) or hypomethylating agents (HMAs) for an antecedent phase of MDS. ESA and HMAs have to be stopped at least four weeks before registration.
* FLT3 mutation as assessed by DNA fragment analysis PCR for FLT3-ITD and FLT3-TKD mutation. Positivity is defined as a FLT3-ITD or FLT3-TKD / FLT3-WT ratio of ≥ 0.05 (5%).
* Considered to be eligible for intensive chemotherapy
* Patient is suitable for oral administration of study drug
* WHO/ECOG performance status ≤ 2
* Adequate hepatic function as evidenced by
* Serum total bilirubin ≤ 2.5 × upper limit of normal (ULN) unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
* Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
* Adequate renal function as defined by creatinine clearance \> 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR)
* Written informed consent
* Patient is capable of giving informed consent
* Female patient must either:
* Be of nonchildbearing potential:
* Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
* Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening)
* Or, if of childbearing potential,
* Agree not to try to become pregnant during the study and for 6 months after the final study drug administration
* And have a negative urine or serum pregnancy test at screening
* And, if heterosexually active, agree to consistently use highly effective\* contraception per locally accepted standards in addition to a barrier method starting at screening and throughout the study period and for 6 months after the final study drug administration.
* Highly effective forms of birth control include:
* Consistent and correct usage of established hormonal contraceptives that inhibit ovulation,
* Established intrauterine device (IUD) or intrauterine system (IUS),
* Bilateral tubal occlusion,
* Vasectomy (A vasectomy is a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.)
* Male is sterile due to a bilateral orchiectomy.
* Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
* (\*)List is not all inclusive. Prior to enrollment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control per the requirements of the CTFG Guidance document 'Recommendations related to contraception and pregnancy testing in clinical trials', September 2014 (and any updates thereof) during the protocol defined period.
* Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration.
* Female patient must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
* Male patient and their female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and continue throughout the study period and for 4 months and 1 week after the final study drug administration.
* Male patient must not donate sperm starting at screening and throughout the study period and for 4 months and 1 week after the final study drug administration.
* Patient agrees not to participate in another interventional study while on treatment
Exclusion Criteria
* Acute promyelocytic leukemia (APL) with PML-RARA or one of the other pathognomonic variant fusion genes/chromosome translocations
* Blast crisis after CML
* Known or suspected hypersensitivity to midostaurin or gilteritinib and/or any excipients
* Patient requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A
* Breast feeding at start of study treatment
* Active infection, including hepatitis B or C or HIV infection that is uncontrolled at randomization. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed.
* Patients with a currently active second malignancy. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
* Basal or squamous cell carcinoma of the skin;
* Carcinoma in situ of the cervix;
* Carcinoma in situ of the breast;
* Incidental histologic finding of prostate cancer
* Significant active cardiac disease within 6 months prior to the start of study treatment, including:
* New York Heart Association (NYHA) Class III or IV congestive heart failure;
* Myocardial infarction;
* Unstable angina and/or stroke;
* Left ventricular ejection fraction (LVEF) \< 40% by ECHO or MUGA scan obtained within 28 days prior to the start of study treatment
* QTc interval using Fridericia's formula (QTcF) ≥ 450 msec (average of triplicate determinations) or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, family history of long QT interval syndrome). Prolonged QTc interval associated with bundle branch block or pacemaking is permitted with written approval of the (co) Principal Investigator.
* Patient with hypokalemia and/or hypomagnesemia before registration (defined as values below LLN) Note: electrolyte suppletion is allowed to correct LLN values before registration.
* Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs
* Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening
* Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation
* Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to give informed consent or participate in the study
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
18 Years
ALL
No
Sponsors
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Deutsch-Österreichische Studiengruppe Akute Myeloische Leukämie (AMLSG)
UNKNOWN
Astellas Pharma Global Development, Inc.
INDUSTRY
Stichting Hemato-Oncologie voor Volwassenen Nederland
OTHER
Responsible Party
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Principal Investigators
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M. Raaijmakers, Prof. Dr.
Role: PRINCIPAL_INVESTIGATOR
Erasmus MC / HOVON
Locations
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AU-Adelaide-FLINDERS
Adelaide, , Australia
AU-Adelaide-RAH
Adelaide, , Australia
AU-Brisbane-PAH
Brisbane, , Australia
AU-Brisbane-RBWH
Brisbane, , Australia
AU-Camperdown-RPA
Camperdown, , Australia
AU-Douglas-TOWNSVILLE
Douglas, , Australia
AU-Geelong VIC-BARWONHEALTH
Geelong, , Australia
AU-Gosford NSW-GOSFORDHOSPITAL
Gosford, , Australia
AU-Hobart TAS-RHOBART
Hobart, , Australia
AU-Melbourne-ALFRED
Melbourne, , Australia
AU-Melbourne-AUSTIN
Melbourne, , Australia
AU-Melbourne-BOXHILL
Melbourne, , Australia
AU-Melbourne-MONASH
Melbourne, , Australia
AU-Melbourne-RMELBOURNE
Melbourne, , Australia
AU-Melbourne-SVHM
Melbourne, , Australia
AU-Perth-FSH
Perth, , Australia
AU-Perth-RPH
Perth, , Australia
AU-Perth-SCGH
Perth, , Australia
AU-Sydney-CONCORD
Sydney, , Australia
AU-Sydney-NEPEAN
Sydney, , Australia
AU-Sydney-RNSH
Sydney, , Australia
AU-Sydney-WSAH
Sydney, , Australia
St George Hospital
Sydney, , Australia
AU-Waratah-CALVARYMATER
Waratah, , Australia
AT-Graz-MEDUNIGRAZ
Graz, , Austria
AT-Innsbruck-IMED
Innsbruck, , Austria
AT-Linz-KEPLER
Linz, , Austria
AT-Linz-ORDENSKLINIKUM
Linz, , Austria
AT-Salzburg-SALK
Salzburg, , Austria
AT-Vienna-HANUSCH
Vienna, , Austria
BE-Antwerpen-ZNASTUIVENBERG
Antwerp, , Belgium
BE-Brugge-AZBRUGGE
Bruges, , Belgium
BE-Brussel-BORDET
Brussels, , Belgium
BE-Bruxelles-STLUC
Brussels, , Belgium
BE-Gent-UZGENT
Ghent, , Belgium
BE-Haine-Saint-Paul-JOLIMONT
Haine-Saint-Paul, , Belgium
BE-Hasselt-VIRGAJESSE
Hasselt, , Belgium
BE-Leuven-UZLEUVEN
Leuven, , Belgium
BE-Liege-CHRCITADELLE
Liège, , Belgium
BE-Liege-CHULIEGE
Liège, , Belgium
BE-Mons-AMBROISE
Mons, , Belgium
BE-Roeselare-AZDELTA
Roeselare, , Belgium
BE-Yvoir-MONTGODINNE
Yvoir, , Belgium
FI-Helsinki-HUS
Helsinki, , Finland
FI-Tampere-TAYS
Tampere, , Finland
FR-Amiens-CHUAMIENS
Amiens, , France
FR-Angers-CHUANGERS
Angers, , France
FR-Argenteuil-CHARGENTEUIL
Argenteuil, , France
FR-Bayonne-CHCOTEBASQUE
Bayonne, , France
FR-Besançon Cedex-JEANMINJOZ
Besançon, , France
FR-Bobigny-AVICENNE
Bobigny, , France
FR-Le Chesnay cedex-CHVERSAILLES
Chesnay, , France
FR-Clamart-HIAPERCY
Clamart, , France
FR-Clermont-Ferrand-ESTAING
Clermont-Ferrand, , France
FR-Grenoble cedex 9-CHUGRENOBLE
Grenoble, , France
FR-Lille-CHULILLE
Lille, , France
FR-Limoges-CHULIMOGES
Limoges, , France
FR-Lyon Pierre Benite cedex-LYONSUD
Lyon, , France
FR-Lyon-LEONBERARD
Lyon, , France
FR-Marseille-IPC
Marseille, , France
FR-Montpellier-STELOI
Montpellier, , France
FR-Nantes-CHUNANTES
Nantes, , France
FR-Nice-CAL
Nice, , France
FR-Nice-LARCHET
Nice, , France
FR-Paris cedex 10-SAINTLOUIS
Paris, , France
FR-Paris cedex 15-NECKER
Paris, , France
FR-Pessac Cedex-CHUBORDEAUX
Pessac, , France
FR-Poitiers-CHUPOITERS
Poitiers, , France
FR-Reims-CHREIMS
Reims, , France
FR-Rennes cedex 9-CHURENNES
Rennes, , France
FR-Rouen cedex-BECQUEREL
Rouen, , France
FR-Saint-Priest-en-Jarez-ICLOIRE
Saint-Priest-en-Jarez, , France
FR-Strasbourg cedex-HAUTEPIERRE
Strasbourg, , France
FR-Toulouse-CHUTOULOUSE
Toulouse, , France
FR-Tours cedex-BRETONNEAU
Tours, , France
FR-Vandoeuvre Les Nancy-CHRUNANCY
Vandœuvre-lès-Nancy, , France
FR-Villejuif-GUSTAVEROUSSY
Villejuif, , France
DE-Aschaffenburg-KLINIKUMAB
Aschaffenburg, , Germany
DE-Bad Saarow-HELIOSBADSAAROW
Bad Saarow, , Germany
DE-Berlin-CAMPUSBENFRANKLIN
Berlin, , Germany
DE-Berlin-CAMPUSMITTE
Berlin, , Germany
DE-Berlin-CAMPUSVIRCHOW
Berlin, , Germany
DE-Berlin-VIVANTESNEUKOLLN
Berlin, , Germany
DE-Berlin-VIVANTESURBAN
Berlin, , Germany
DE-Bochum-RUB
Bochum, , Germany
DE-Bonn-UNIBONN
Bonn, , Germany
DE-Braunschweig-KLINIKUMBRAUNSCHWEIG
Braunschweig, , Germany
DE-Bremen-KBM
Bremen, , Germany
DE-Darmstadt-KLINIKUMDARMSTADT
Darmstadt, , Germany
DE-Dortmund-JOHODORTMUND
Dortmund, , Germany
DE-Düsseldorf-MEDUNIDUESSELDORF
Düsseldorf, , Germany
DE-Essen-KEM
Essen, , Germany
DE-Esslingen-KLINIKUMESSLINGEN
Esslingen am Neckar, , Germany
DE-Flensburg-MALTESER
Flensburg, , Germany
DE-Frankfurt-KLINIKUMFRANKFURT
Frankfurt, , Germany
DE-Giessen-UKGM
Giessen, , Germany
DE-Goch-KKLE
Goch, , Germany
DE-Greifswald-UNIGREIFSWALD
Greifswald, , Germany
DE-Hamburg-ASKLEPIOSSTGEORG
Hamburg, , Germany
DE-Hamburg-ASKLEPIOS
Hamburg, , Germany
DE-Hamburg-UKE
Hamburg, , Germany
DE-Hamm-EVKHAMM
Hamm, , Germany
DE-Hanau-KLINIKUMHANAU
Hanau, , Germany
DE-Hannover-MHHANNOVER
Hanover, , Germany
DE-Hannover-SILOAHKRH
Hanover, , Germany
DE-Heilbronn-SLK
Heilbronn, , Germany
DE-Herne-MARIENHOSPITALHERNE
Herne, , Germany
DE-Homburg-UNIKLINIKSAARLAND
Homburg, , Germany
DE-Kaiserslautern-WESTPFALZ
Kaiserslautern, , Germany
DE-Karlsruhe-KLINIKUMKARLSRUHE
Karlsruhe, , Germany
DE-Lemgo-KLINIKUMLIPPE
Lemgo, , Germany
DE-Ludwigshafen-KLILU
Ludwigshafen, , Germany
DE-Lübeck-UKSHLUBECK
Lübeck, , Germany
DE-Luedenscheid-KLINIKUMLUEDENSCHEID
Lüdenscheid, , Germany
DE-Magdeburg-OVGU
Magdeburg, , Germany
DE-Mainz-UNIMEDIZINMAINZ
Mainz, , Germany
DE-Meschede-HOCHSAUERLAND
Meschede, , Germany
DE-Minden-MUEHLENKREISKLINKEN
Minden, , Germany
DE-München-IRZTUM
München, , Germany
DE-Offenburg-ORTENAUKLINIKUM
Offenburg, , Germany
DE-Oldenburg-KLINIKUMOLDENBURG
Oldenburg, , Germany
DE-Passau-KLINIKUMPASSAU
Passau, , Germany
DE-Regensburg-UKR
Regensburg, , Germany
DE-Saarbrücken-CARITASKLINIKUM
Saarbrücken, , Germany
DE-Stuttgart-DIAKSTUTTGART
Stuttgart, , Germany
DE-Stuttgart-KLINIKUMSTUTTGART
Stuttgart, , Germany
DE-Trier-MUTTERHAUS
Trier, , Germany
DE-Tübingen-MEDUNITUEBINGEN
Tübingen, , Germany
DE-Ulm-UNIKLINKULM
Ulm, , Germany
DE-Villingen-Schwenningen-SBKVS
Villingen-Schwenningen, , Germany
DE-Wuppertal-HELIOSGESUNDHEIT
Wuppertal, , Germany
IE-Cork-CUH
Cork, , Ireland
IE-Dublin 24-TUH
Dublin, , Ireland
IE-Dublin 4-SVUH
Dublin, , Ireland
IE-Dublin 7-MATER
Dublin, , Ireland
IE-Dublin 8-STJAMES
Dublin, , Ireland
IE-Dublin 9-BEAUMONT
Dublin, , Ireland
IE-Galway-UHGALWAY
Galway, , Ireland
IE-Co. Limerick-UHL
Limerick, , Ireland
LT-Vilnius-SANTA
Vilnius, , Lithuania
NL-Den Bosch-JBZ
's-Hertogenbosch, , Netherlands
NL-Amersfoort-MEANDERMC
Amersfoort, , Netherlands
NL-Amsterdam-AMC
Amsterdam, , Netherlands
NL-Amsterdam-OLVG
Amsterdam, , Netherlands
NL-Amsterdam-VUMC
Amsterdam, , Netherlands
NL-Arnhem-RIJNSTATE
Arnhem, , Netherlands
NL-Breda-AMPHIA
Breda, , Netherlands
NL-Delft-RDGG
Delft, , Netherlands
NL-Dordrecht-ASZ
Dordrecht, , Netherlands
NL-Eindhoven-MAXIMAMC
Eindhoven, , Netherlands
NL-Enschede-MST
Enschede, , Netherlands
NL-Groningen-UMCG
Groningen, , Netherlands
NL-Leeuwarden-MCL
Leeuwarden, , Netherlands
NL-Leiden-LUMC
Leiden, , Netherlands
NL-Maastricht-MUMC
Maastricht, , Netherlands
NL-Nieuwegein-ANTONIUS
Nieuwegein, , Netherlands
NL-Nijmegen-RADBOUDUMC
Nijmegen, , Netherlands
NL-Rotterdam-ERASMUSMC
Rotterdam, , Netherlands
NL-Den Haag-HAGA
The Hague, , Netherlands
NL-Utrecht-UMCUTRECHT
Utrecht, , Netherlands
NL-Zwolle-ISALA
Zwolle, , Netherlands
NO-Bergen-HELSEBERGEN
Bergen, , Norway
NO-Oslo-OSLOUH
Oslo, , Norway
NO-Stavanger-HELSESTAVANGER
Stavanger, , Norway
NO-Tromsø-NORTHNOORWEGEN
Tromsø, , Norway
NO-Trondheim-STOLAV
Trondheim, , Norway
ES-Barcelona-CLINICUB
Barcelona, , Spain
ES-Barcelona-GERMANTRIALS
Barcelona, , Spain
ES-Barcelona-ICODURANREYNALS
Barcelona, , Spain
ES-Barcelona-MUTUATERRASSA
Barcelona, , Spain
ES-Barcelona-PARCDESALUTMAR
Barcelona, , Spain
ES-Barcelona-SANTPAU
Barcelona, , Spain
ES-Barcelona-VHEBRON
Barcelona, , Spain
ES-Girona-ICSTRUETA
Girona, , Spain
ES-Lleida-ICSVILANOVA
Lleida, , Spain
ES-Madrid-CSGREGORIOMARANON
Madrid, , Spain
ES-Palma-HSLL
Palma, , Spain
ES-Palma-SSIB
Palma, , Spain
ES-Tarragona-JOAN
Tarragona, , Spain
ES-Valencia-MALVARROSA
Valencia, , Spain
SE-Lund-SUH
Lund, , Sweden
SE-Stockholm-KAROLINSKAHUDDINGE
Stockholm, , Sweden
SE-Uppsala-UPPSALAUH
Uppsala, , Sweden
CH-Aarau-KSA
Aarau, , Switzerland
CH-Basel-USB
Basel, , Switzerland
CH-Bellinzona-IOSI
Bellinzona, , Switzerland
CH-Bern-INSEL
Bern, , Switzerland
CH-Fribourg-HFR
Fribourg, , Switzerland
CH-Geneve (14)-HCUGE
Geneva, , Switzerland
CH-Lausanne-CHUV
Lausanne, , Switzerland
CH-Luzern-LUKS
Lucerne, , Switzerland
CH-St. Gallen-KSSG
Sankt Gallen, , Switzerland
CH-Zürich-USZ
Zurich, , Switzerland
Countries
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Related Links
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HOVON trial website
Other Identifiers
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2018-000624-33
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
AMLSG 28-18
Identifier Type: OTHER
Identifier Source: secondary_id
Pasha
Identifier Type: OTHER
Identifier Source: secondary_id
HO156
Identifier Type: -
Identifier Source: org_study_id