Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Patients With Newly Diagnosed AML or MDS-EB-2
NCT ID: NCT04628026
Last Updated: 2026-01-22
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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RECRUITING
PHASE3
650 participants
INTERVENTIONAL
2022-09-13
2032-02-29
Brief Summary
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Detailed Description
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After the feasibility run-in phase, eligible patients will be randomized to intensive chemotherapy with venetoclax or placebo. Patients will receive two cycles of induction chemotherapy; patients achieving CR or CRi after two cycles will continue with consolidation treatment according to initial randomization, and according to Cooperative Group-specific consolidation regimens or investigator choice. Patients achieving morphologic leukemia-free state (MLFS) only, may also continue consolidation treatment on protocol. Assignment to either allogeneic hematopoietic cell transplantation (HCT), conventional chemotherapy or autologous HCT will be done according to institutional standards, and based on (prognostic) disease characteristics, individual patient assessment, and established comorbidity risk scores (e.g., HCT-CI score).
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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1
standard chemotherapy in combination with venetoclax
Venetoclax
Venetoclax will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy
Standard chemotherapy
Induction cycle 1: Patients will receive cytarabine 200 mg/m2 continuous IV (days 1-7) and daunorubicin 60 mg/m2 IV (days 1-3). Induction cycle 2: Patients ≤ 60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-4, and daunorubicin 60 mg/m2 IV (days 1-3). Patients \>60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-4 without daunorubicin.
Consolidation chemotherapy with intermediate doses of cytarabine. Patients ≤60 yrs will receive up to 3 cycles of IDAC (single dose 1500 mg/m2 every 12 hours, days 1-3). Patients who are \>60 yrs will receive up to 3 cycles of IDAC with single doses of 1000 mg/m2, every 12 hours, days 1-3. In patients \>60 yrs less than 3 cycles of IDAC or dose-reduced IDAC (500 mg/m2 per single dose) may be given based on an individual risk assessment.
Allogeneic stem cell transplantation
Generally, patients will proceed to allogeneic HCT upon completion of remission induction chemotherapy. It is however allowed, as per investigator's discretion, for a patient to receive 'bridging' consolidation chemotherapy in exceptional cases of delay towards transplantation. At baseline, HLA-compatible donor search must be initiated as soon as possible, first among siblings and second in the world donor bank for unrelated donors or cord blood. In order to avoid inappropriate delay in cases where no suitable sibling is present, high-resolution HLA typing should be performed immediately after registration, enabling a more rapid matched-unrelated donor search. In case no sibling or unrelated donor can be identified, haploidentical allogeneic HCT is allowed. Conditioning and GVHD prophylaxis will take place according to institutional guidelines. Patients who undergo allogeneic HCT will not receive venetoclax during conditioning, engraftment or after hematologic recovery.
2
standard chemotherapy in combination with placebo
Placebo
Placebo will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy
Standard chemotherapy
Induction cycle 1: Patients will receive cytarabine 200 mg/m2 continuous IV (days 1-7) and daunorubicin 60 mg/m2 IV (days 1-3). Induction cycle 2: Patients ≤ 60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-4, and daunorubicin 60 mg/m2 IV (days 1-3). Patients \>60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-4 without daunorubicin.
Consolidation chemotherapy with intermediate doses of cytarabine. Patients ≤60 yrs will receive up to 3 cycles of IDAC (single dose 1500 mg/m2 every 12 hours, days 1-3). Patients who are \>60 yrs will receive up to 3 cycles of IDAC with single doses of 1000 mg/m2, every 12 hours, days 1-3. In patients \>60 yrs less than 3 cycles of IDAC or dose-reduced IDAC (500 mg/m2 per single dose) may be given based on an individual risk assessment.
Allogeneic stem cell transplantation
Generally, patients will proceed to allogeneic HCT upon completion of remission induction chemotherapy. It is however allowed, as per investigator's discretion, for a patient to receive 'bridging' consolidation chemotherapy in exceptional cases of delay towards transplantation. At baseline, HLA-compatible donor search must be initiated as soon as possible, first among siblings and second in the world donor bank for unrelated donors or cord blood. In order to avoid inappropriate delay in cases where no suitable sibling is present, high-resolution HLA typing should be performed immediately after registration, enabling a more rapid matched-unrelated donor search. In case no sibling or unrelated donor can be identified, haploidentical allogeneic HCT is allowed. Conditioning and GVHD prophylaxis will take place according to institutional guidelines. Patients who undergo allogeneic HCT will not receive venetoclax during conditioning, engraftment or after hematologic recovery.
Interventions
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Venetoclax
Venetoclax will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy
Placebo
Placebo will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy
Standard chemotherapy
Induction cycle 1: Patients will receive cytarabine 200 mg/m2 continuous IV (days 1-7) and daunorubicin 60 mg/m2 IV (days 1-3). Induction cycle 2: Patients ≤ 60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-4, and daunorubicin 60 mg/m2 IV (days 1-3). Patients \>60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-4 without daunorubicin.
Consolidation chemotherapy with intermediate doses of cytarabine. Patients ≤60 yrs will receive up to 3 cycles of IDAC (single dose 1500 mg/m2 every 12 hours, days 1-3). Patients who are \>60 yrs will receive up to 3 cycles of IDAC with single doses of 1000 mg/m2, every 12 hours, days 1-3. In patients \>60 yrs less than 3 cycles of IDAC or dose-reduced IDAC (500 mg/m2 per single dose) may be given based on an individual risk assessment.
Allogeneic stem cell transplantation
Generally, patients will proceed to allogeneic HCT upon completion of remission induction chemotherapy. It is however allowed, as per investigator's discretion, for a patient to receive 'bridging' consolidation chemotherapy in exceptional cases of delay towards transplantation. At baseline, HLA-compatible donor search must be initiated as soon as possible, first among siblings and second in the world donor bank for unrelated donors or cord blood. In order to avoid inappropriate delay in cases where no suitable sibling is present, high-resolution HLA typing should be performed immediately after registration, enabling a more rapid matched-unrelated donor search. In case no sibling or unrelated donor can be identified, haploidentical allogeneic HCT is allowed. Conditioning and GVHD prophylaxis will take place according to institutional guidelines. Patients who undergo allogeneic HCT will not receive venetoclax during conditioning, engraftment or after hematologic recovery.
Eligibility Criteria
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Inclusion Criteria
2. Age ≥ 18 and ≤ 75 years.
3. Patients considered eligible for intensive chemotherapy.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
5. Molecular analysis centrally performed in AMLSG and HOVON laboratories.
6. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of norm (ULN) or creatinine clearance \>40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR).
7. Adequate hepatic function as evidenced by:
* Serum total bilirubin ≤ 2.5 × ULN unless considered due to Gilbert's disease, or leukemic involvement following approval by the Principal Investigators or Trial Coordinators of the study
* Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following approval by the Principal Investigators or Trial Coordinators.
8. No prior chemotherapy for AML, except hydroxyurea for up to 14 days during the diagnostic screening phase for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell \[WBC\] counts \> 25x109/L); patients may have had previous treatment with erythroid 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 start of study treatment.
9. Patients must not have received a known strong or moderate CYP3A inducer 7 days before start of study treatment. Patients must have no known medical conditions requiring chronic therapy with moderate or strong CYP3A inducers.
10. Female patient must either:
* Be of nonchildbearing potential:
* Postmenopausal (defined as at least 1 year without any menses)
* Documented surgically sterile (e.g. documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy or congenital sterile) or status post hysterectomy (at least 1 month prior to screening)
* Or, if of childbearing potential (not surgically sterile and not postmenopausal)
* Not planning 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 apply one highly effective\* method of birth control in combination to a barrier method for the duration of the study and for 27 weeks after the final study drug administration
\*Highly effective forms of birth control include
* Consistent and correct usage of established hormonal contraceptives that inhibit ovulation for at least 1 month prior to taking study drug. (hormonal contraception is only a highly effective method of birth control, if a combined \[estrogen and progestogen containing\] hormonal contraception or a progestogen-only hormonal contraception - both associated with inhibition of ovulation - is used.
* Established intrauterine device (IUD) or intrauterine system (IUS)
* Bilateral tubal occlusion
* Vasectomy - a vasectomy is 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 enrolment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination with a barrier method according to locally accepted standards 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 27 weeks after the final study drug administration.
11. 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 (while on therapy and for 27 weeks after the final study drug administration). In addition, their female partners of childbearing potential have to use a highly effective method of birth control.
12. Male patient must not donate sperm starting at screening and throughout the study period and for 27 weeks after the final study drug administration.
13. Able to understand and willing to sign an informed consent form (ICF).
18 Years
75 Years
ALL
No
Sponsors
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Stichting Hemato-Oncologie voor Volwassenen Nederland
OTHER
University of Ulm
OTHER
Responsible Party
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Prof. Dr. Hartmut Doehner
Prof. Dr.
Principal Investigators
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Hartmut Doehner, MD
Role: PRINCIPAL_INVESTIGATOR
University of Ulm
Locations
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Tirol Kliniken GmbH
Innsbruck, , Austria
Kepler Universitaetsklinikum GmbH
Linz, , Austria
Ordensklinikum Linz GmbH
Linz, , Austria
Landeskrankenhaus (LKH) Rankweil, Interne E am Landeskrankenhaus Rankweil
Rankweil, , Austria
Gemeinnuetzige Salzburger Landeskliniken Betriebsgesellschaft mbH
Salzburg, , Austria
Hanusch Krankenhaus Der Wiener Gebietskrankenkasse
Vienna, , Austria
Ziekenhuis Aan De Stroom
Antwerp, , Belgium
Az St-Jan Brugge-Oostende A.V.
Bruges, , Belgium
Universitair Ziekenhuis Brussel
Brussels, , Belgium
Katholieke Universiteit te Leuven
Leuven, , Belgium
Algemeen Ziekenhuis Delta
Roeselare, , Belgium
CHU UCL NAMUR - Mont Godinne
Yvoir, , Belgium
North Estonia Medical Centre Foundation
Tallinn, , Estonia
Tartu University Hospital
Tartu, , Estonia
Helsinki University Central Hospital Meilahden Kolmiosairaala
Helsinki, , Finland
Tampere University Hospital
Tampere, , Finland
Klinikum Aschaffenburg-Alzenau gGmbH
Aschaffenburg, , Germany
HELIOS Klinikum Bad Saarow GmbH
Bad Saarow, , Germany
Charité Berlin - Campus Mitte
Berlin, , Germany
Charité Berlin - Campus Benjamin Franklin
Berlin, , Germany
Charité Berlin - Campus Virchow Klinikum
Berlin, , Germany
Vivantes am Urban
Berlin, , Germany
Vivantes Neukölln
Berlin, , Germany
Vivantes Spandau
Berlin, , Germany
Knappschaftskrankenhaus Bochum-Langendreer
Bochum, , Germany
Uniklinikum Bonn
Bonn, , Germany
Staedtisches Klinikum Braunschweig
Braunschweig, , Germany
Gesundheit Nord gGmbH Klinikverbund Bremen
Bremen, , Germany
Klinikum Darmstadt GmbH
Darmstadt, , Germany
St. Johannes Hospital Dortmund
Dortmund, , Germany
Marien Hospital Duesseldorf GmbH
Düsseldorf, , Germany
Klinikum Frankfurt Hoechst GmbH
Frankfurt, , Germany
Justus-Liebig-Universitaet Giessen
Giessen, , Germany
Wilhelm-Anton-Hospital Goch
Goch, , Germany
Universitätsmedizin Greifswald
Greifswald, , Germany
Univeritätsklinikum
Halle, , Germany
Universitätsklinikum Hamburg-Eppendorf
Hamburg, , Germany
Asklepios Klinik Altona
Hamburg, , Germany
Asklepios Klinik St Georg
Hamburg, , Germany
Medizinische Hochschule Hannover
Hanover, , Germany
KRH Klinikum Siloah
Hanover, , Germany
SLK-Kliniken Heilbronn GmbH
Heilbronn, , Germany
Marien Hospital Herne
Herne, , Germany
Universitaetsklinikum des Saarlandes AöR
Homburg, , Germany
Wespfalz-Klinikum
Kaiserslautern, , Germany
Städtisches Klinikum Karlsruhe
Karlsruhe, , Germany
Staedtisches Klinikum Karlsruhe gGmbH
Karlsruhe, , Germany
Klinikum der Stadt Ludwigshafen am Rhein gGmbH
Ludwigshafen, , Germany
UNIVERSITÄTSKLINIKUM Schleswig-Holstein
Lübeck, , Germany
Otto Von Guericke Universitaet Magdeburg
Magdeburg, , Germany
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
Mainz, , Germany
Klinikum Hochsauerland GmbH
Meschede, , Germany
Muhlenkreiskliniken AöR
Minden, , Germany
Klinikum rechts der Isar der TU Muenchen AöR
München, , Germany
Ortenauklinikum
Offenburg, , Germany
Klinikum Oldenburg AöR
Oldenburg, , Germany
Universitaetsklinikum Regensburg AöR
Regensburg, , Germany
Universitaetsklinikum
Rostock, , Germany
Diakonie Klinikum Stuttgart
Stuttgart, , Germany
Klinikum Traunstein
Traunstein, , Germany
Barmherzige Brueder Trier gGmbH
Trier, , Germany
Klinikum Mutterhaus der Borromaerinnen
Trier, , Germany
Uniklinikum Tübingen
Tübingen, , Germany
University Hospital Ulm
Ulm, , Germany
Schwarzwald-Baar Klinikum Villingen-Schwenningen GmbH
Villingen-Schwenningen, , Germany
Helios Universitaetsklinikum Wuppertal
Wuppertal, , Germany
Vilnius University Hospital Santaros Klinik
Vilnius, , Lithuania
Jeroen Bosch ziekenhuis
's-Hertogenbosch, , Netherlands
Meander Medisch Centrum
Amersfoort, , Netherlands
Amsterdam UMC Stichting
Amsterdam, , Netherlands
OLVG
Amsterdam, , Netherlands
Rijnstate Ziekenhuis Stichting
Arnhem, , Netherlands
Amphia Hospital
Breda, , Netherlands
Reinier de Graaf Gasthuis
Delft, , Netherlands
Albert Schweitzer Ziekenhuis
Dordrecht, , Netherlands
Maxima Medisch Centrum
Eindhoven, , Netherlands
Medisch Spectrum Twente
Enschede, , Netherlands
UMCG
Groningen, , Netherlands
Medisch Centrum Leeuwarden B.V.
Leeuwarden, , Netherlands
Leids Universitair Medisch Centrum (LUMC)
Leiden, , Netherlands
Maastricht University Medical Center+ (MUMC+)
Maastricht, , Netherlands
Sint Antonius Ziekenhuis Stichting
Nieuwegein, , Netherlands
Radboudumc
Nijmegen, , Netherlands
Erasmus MC - Daniel
Rotterdam, , Netherlands
Hagaziekenhuis, locatie Leyweg
The Hague, , Netherlands
UMCU
Utrecht, , Netherlands
Isala Klinieken Stichting
Zwolle, , Netherlands
Haukeland University Hospital
Bergen, , Norway
Stavanger Univ. Hosp.-Rogaland Hosp.
Oslo, , Norway
University Hospital of North Norway
Tromsø, , Norway
St. Olavs Hospital
Trondheim, , Norway
Countries
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Central Contacts
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Facility Contacts
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David Nachbaur
Role: primary
Clemens Schmitt
Role: primary
Sigrid Machherndl-Spandl
Role: primary
Bernd Hartmann
Role: primary
Lisa Pleyer
Role: primary
Elisabeth Koller
Role: primary
D. Breems
Role: primary
T. Lodewyck
Role: primary
A. de Becker
Role: primary
J. Maertens
Role: primary
D. Deeren
Role: primary
E. Collinge
Role: primary
K. Palk
Role: primary
A. Kaare
Role: primary
M. Kontro
Role: primary
J. Rimpilainen
Role: primary
Manfred Welslau
Role: primary
Daniel Schoendube
Role: primary
Marie-Luise Huetter-Kroenke, Prof.
Role: primary
Marie-Luise Hütter-Kroenke
Role: primary
Marie-Luise Huetter-Kroenke, Prof.
Role: primary
Hannes Kroenlein
Role: primary
Maike de Wit
Role: primary
Roland Schroers, Prof.
Role: primary
Lino Teichmann, Dr.
Role: primary
Jürgen Krauter, Prof.
Role: primary
Maher Hanoun
Role: primary
Helga Bernhard
Role: primary
Eva Schulte
Role: primary
Felicitas Scholten
Role: primary
Tobias Arnold
Role: primary
Volker Runde
Role: primary
Jan Kroenke
Role: primary
Michael Heuser
Role: primary
Franziska Westendorf
Role: primary
Hans Salwender
Role: primary
Ahmet Elmaagacli
Role: primary
Michael Heuser, Prof.
Role: primary
Kim Marienhagen
Role: primary
Markus Lindauer
Role: primary
Dirk Strumberg
Role: primary
Thomas Bittenbring
Role: primary
Gerhard Held
Role: primary
Mark Ringhoffer, Prof.
Role: primary
Mark
Role: primary
Peter Paschka
Role: primary
Friederike Wortmann
Role: primary
Mirjeta Berisha
Role: primary
Michael Kuehn
Role: primary
Mohammad Wattad
Role: primary
Kai Wille
Role: primary
Katharina Götze
Role: primary
Carsten Schwaenen
Role: primary
Andreas Voss
Role: primary
Hendrik Poeck
Role: primary
Frauke Theis
Role: primary
Jochen Greiner, Prof
Role: primary
Florian Zettl
Role: primary
Iordanis Deligiannis
Role: primary
Frank Ruecker
Role: primary
Claudia Lengerke, Prof. Dr.
Role: primary
Hartmut Döhner, Prof. Dr.
Role: primary
Gaidzik Verena, PD Dr.
Role: backup
Paul La Rosee
Role: primary
Silke Schostok
Role: primary
A. Zucenka
Role: primary
A. Herbers
Role: primary
M. Corsten
Role: primary
D. de Leeuw
Role: primary
A. Gerrits
Role: primary
M. Cuijpers
Role: primary
R. Fiets
Role: primary
R. Brouwer
Role: primary
P. Westerweel
Role: primary
L. Tick
Role: primary
T. Snijders
Role: primary
S. K. Klein
Role: primary
B. Franken
Role: primary
H. Veelken
Role: primary
J. van Elssen
Role: primary
M. Söhne
Role: primary
J. Janssen
Role: primary
M. Jongen-Lavrenic
Role: primary
D. Lammeren, van-Venema
Role: primary
A. van Rhenen
Role: primary
G. van Sluis
Role: primary
O. Sefland
Role: primary
A. Lenartova
Role: primary
N. Leknes
Role: primary
A. von Krogh
Role: primary
Other Identifiers
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AMLSG31-19/HO501/AbbVieB18-982
Identifier Type: -
Identifier Source: org_study_id
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