Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Patients With Newly Diagnosed AML or MDS-EB-2

A Randomized, Placebo-Controlled Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome With Excess Blasts-2

A Randomized, Placebo-Controlled Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome With Excess Blasts-2

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Other: Allogeneic stem cell transplantation; Drug: Venetoclax; Drug: Placebo; Combination product: Standard chemotherapy

Detailed Description

Prospective, multicenter, double-blind, randomized, placebo-controlled phase 3 clinical study. The randomized phase of the study will be preceded by a feasibility run-in dose-escalation phase in patients with AML in which the venetoclax dose for the phase 3 part will be established.

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).

• Study Type: Interventional
• Enrollment (Estimated): 650
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Hartmut Doehner, MD; Phone Number: 004973150045501; Email: harmut.doehner@uniklinik-ulm.de

Study Locations

• Austria
  • Innsbruck, Austria
    • Not yet recruiting
    • Tirol Kliniken GmbH
    • Contact: David Nachbaur
  • Linz, Austria
    • Not yet recruiting
    • Ordensklinikum Linz GMBH
    • Contact: Sigrid Machherndl-Spandl
  • Linz, Austria
    • Not yet recruiting
    • Kepler Universitaetsklinikum GmbH
    • Contact: Clemens Schmitt
  • Rankweil, Austria
    • Not yet recruiting
    • Landeskrankenhaus (LKH) Rankweil, Interne E am Landeskrankenhaus Rankweil
    • Contact: Bernd Hartmann
  • Salzburg, Austria
    • Not yet recruiting
    • Gemeinnuetzige Salzburger Landeskliniken Betriebsgesellschaft mbH
    • Contact: Lisa Pleyer
  • Vienna, Austria
    • Not yet recruiting
    • Hanusch Krankenhaus Der Wiener Gebietskrankenkasse
    • Contact: Elisabeth Koller
• Belgium
  • Antwerp, Belgium
    • Not yet recruiting
    • Ziekenhuis Aan De Stroom
    • Contact: D. Breems
  • Bruges, Belgium
    • Not yet recruiting
    • Az St-Jan Brugge-Oostende A.V.
    • Contact: T. Lodewyck
  • Brussels, Belgium
    • Recruiting
    • Universitair Ziekenhuis Brussel
    • Contact: A. de Becker
  • Leuven, Belgium
    • Not yet recruiting
    • Katholieke Universiteit te Leuven
    • Contact: J. Maertens
  • Roeselare, Belgium
    • Recruiting
    • Algemeen Ziekenhuis Delta
    • Contact: D. Deeren
  • Yvoir, Belgium
    • Recruiting
    • CHU UCL NAMUR - Mont Godinne
    • Contact: E. Collinge
• Estonia
  • Tallinn, Estonia
    • Not yet recruiting
    • North Estonia Medical Centre Foundation
    • Contact: K. Palk
  • Tartu, Estonia
    • Recruiting
    • Tartu University Hospital
    • Contact: A. Kaare
• Finland
  • Helsinki, Finland
    • Not yet recruiting
    • Helsinki University Central Hospital Meilahden Kolmiosairaala
    • Contact: M. Kontro
  • Tampere, Finland
    • Not yet recruiting
    • Tampere University Hospital
    • Contact: J. Rimpilainen
• Germany
  • Aschaffenburg, Germany
    • Recruiting
    • Klinikum Aschaffenburg-Alzenau gGmbH
    • Contact: Manfred Welslau
  • Bad Saarow, Germany
    • Recruiting
    • HELIOS Klinikum Bad Saarow GmbH
    • Contact: Daniel Schoendube
  • Berlin, Germany, 12200
    • Recruiting
    • Charité Berlin - Campus Benjamin Franklin
    • Contact: Marie-Luise Hütter-Kroenke
  • Berlin, Germany, 10117
    • Recruiting
    • Charité Berlin - Campus Mitte
    • Contact: Marie-Luise Huetter-Kroenke, Prof.
  • Berlin, Germany
    • Recruiting
    • Charité Berlin - Campus Virchow Klinikum
    • Contact: Marie-Luise Huetter-Kroenke, Prof.
  • Berlin, Germany
    • Not yet recruiting
    • Vivantes am Urban
    • Contact: Hannes Kroenlein
  • Berlin, Germany
    • Not yet recruiting
    • Vivantes Neukölln
    • Contact: Maike de Wit
  • Berlin, Germany
    • Withdrawn
    • Vivantes Spandau
  • Bochum, Germany, 44892
    • Recruiting
    • Knappschaftskrankenhaus Bochum-Langendreer
    • Contact: Roland Schroers, Prof.
  • Bonn, Germany, 53127
    • Recruiting
    • Uniklinikum Bonn
    • Contact: Lino Teichmann, Dr.
  • Braunschweig, Germany, 38114
    • Recruiting
    • Staedtisches Klinikum Braunschweig
    • Contact: Jürgen Krauter, Prof.
  • Bremen, Germany
    • Recruiting
    • Gesundheit Nord gGmbH Klinikverbund Bremen
    • Contact: Maher Hanoun
  • Darmstadt, Germany
    • Not yet recruiting
    • Klinikum Darmstadt GmbH
    • Contact: Helga Bernhard
  • Dortmund, Germany
    • Recruiting
    • St. Johannes Hospital Dortmund
    • Contact: Eva Schulte
  • Düsseldorf, Germany
    • Withdrawn
    • Marien Hospital Duesseldorf GmbH
  • Frankfurt, Germany
    • Recruiting
    • Klinikum Frankfurt Hoechst GmbH
    • Contact: Felicitas Scholten
  • Giessen, Germany
    • Recruiting
    • Justus-Liebig-Universitaet Giessen
    • Contact: Tobias Arnold
  • Goch, Germany
    • Recruiting
    • Wilhelm-Anton-Hospital Goch
    • Contact: Volker Runde
  • Greifswald, Germany
    • Recruiting
    • Universitätsmedizin Greifswald
    • Contact: Jan Kroenke
  • Halle, Germany
    • Recruiting
    • Univeritätsklinikum
    • Contact: Michael Heuser
  • Hamburg, Germany, 20246
    • Recruiting
    • Universitatsklinikum Hamburg-Eppendorf
    • Contact: Franziska Westendorf
  • Hamburg, Germany
    • Recruiting
    • Asklepios Klinik Altona
    • Contact: Hans Salwender
  • Hamburg, Germany
    • Recruiting
    • Asklepios Klinik St Georg
    • Contact: Ahmet Elmaagacli
  • Hanover, Germany, 30625
    • Recruiting
    • Medizinische Hochschule Hannover
    • Contact: Michael Heuser, Prof.
  • Hanover, Germany
    • Recruiting
    • KRH Klinikum Siloah
    • Contact: Kim Marienhagen
  • Heilbronn, Germany
    • Recruiting
    • SLK-Kliniken Heilbronn GmbH
    • Contact: Markus Lindauer
  • Herne, Germany
    • Recruiting
    • Marien Hospital Herne
    • Contact: Dirk Strumberg
  • Homburg, Germany
    • Recruiting
    • Universitaetsklinikum des Saarlandes AöR
    • Contact: Thomas Bittenbring
  • Kaiserslautern, Germany
    • Not yet recruiting
    • Wespfalz-Klinikum
    • Contact: Gerhard Held
  • Karlsruhe, Germany, 76133
    • Recruiting
    • Stadtisches Klinikum Karlsruhe
    • Contact: Mark Ringhoffer, Prof.
  • Karlsruhe, Germany
    • Not yet recruiting
    • Staedtisches Klinikum Karlsruhe gGmbH
    • Contact: Mark; Phone Number: Ringhoffer
  • Ludwigshafen, Germany
    • Recruiting
    • Klinikum der Stadt Ludwigshafen am Rhein gGmbH
    • Contact: Peter Paschka
  • Lübeck, Germany
    • Recruiting
    • Universitätsklinikum Schleswig-Holstein
    • Contact: Friederike Wortmann
  • Magdeburg, Germany
    • Recruiting
    • Otto von Guericke Universitaet Magdeburg
    • Contact: Mirjeta Berisha
  • Mainz, Germany
    • Recruiting
    • Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
    • Contact: Michael Kuehn
  • Meschede, Germany
    • Recruiting
    • Klinikum Hochsauerland GmbH
    • Contact: Mohammad Wattad
  • Minden, Germany
    • Recruiting
    • Mühlenkreiskliniken AöR
    • Contact: Kai Wille
  • München, Germany
    • Recruiting
    • Klinikum rechts der Isar der TU Muenchen AöR
    • Contact: Katharina Götze
  • Offenburg, Germany
    • Not yet recruiting
    • Ortenauklinikum
    • Contact: Carsten Schwaenen
  • Oldenburg, Germany
    • Recruiting
    • Klinikum Oldenburg AöR
    • Contact: Andreas Voss
  • Regensburg, Germany
    • Not yet recruiting
    • Universitaetsklinikum Regensburg AöR
    • Contact: Hendrik Poeck
  • Rostock, Germany
    • Recruiting
    • Universitaetsklinikum
    • Contact: Frauke Theis
  • Stuttgart, Germany, 70176
    • Recruiting
    • Diakonie Klinikum Stuttgart
    • Contact: Jochen Greiner, Prof
  • Traunstein, Germany
    • Recruiting
    • Klinikum Traunstein
    • Contact: Florian Zettl
  • Trier, Germany
    • Recruiting
    • Klinikum Mutterhaus der Borromaerinnen
    • Contact: Frank Ruecker
  • Trier, Germany
    • Not yet recruiting
    • Barmherzige Brueder Trier gGmbH
    • Contact: Iordanis Deligiannis
  • Tübingen, Germany, 72076
    • Recruiting
    • Uniklinikum Tübingen
    • Contact: Claudia Lengerke, Prof. Dr.
  • Ulm, Germany, 89081
    • Recruiting
    • University Hospital Ulm
    • Contact: Hartmut Döhner, Prof. Dr.
    • Contact: Gaidzik Verena, PD Dr.
  • Villingen-Schwenningen, Germany
    • Recruiting
    • Schwarzwald-Baar Klinikum Villingen-Schwenningen GmbH
    • Contact: Paul La Rosee
  • Wuppertal, Germany
    • Recruiting
    • Helios Universitaetsklinikum Wuppertal
    • Contact: Silke Schostok
• Lithuania
  • Vilnius, Lithuania
    • Not yet recruiting
    • Vilnius University Hospital Santaros Klinik
    • Contact: A. Zucenka
• Netherlands
  • 's-Hertogenbosch, Netherlands
    • Recruiting
    • Jeroen Bosch Ziekenhuis
    • Contact: A. Herbers
  • Amersfoort, Netherlands
    • Recruiting
    • Meander Medisch Centrum
    • Contact: M. Corsten
  • Amsterdam, Netherlands
    • Recruiting
    • OLVG
    • Contact: A. Gerrits
  • Amsterdam, Netherlands
    • Recruiting
    • Amsterdam UMC Stichting
    • Contact: D. de Leeuw
  • Arnhem, Netherlands
    • Recruiting
    • Rijnstate Ziekenhuis Stichting
    • Contact: M. Cuijpers
  • Breda, Netherlands
    • Recruiting
    • Amphia Hospital
    • Contact: R. Fiets
  • Delft, Netherlands
    • Recruiting
    • Reinier de Graaf Gasthuis
    • Contact: R. Brouwer
  • Dordrecht, Netherlands
    • Recruiting
    • Albert Schweitzer Ziekenhuis
    • Contact: P. Westerweel
  • Eindhoven, Netherlands
    • Recruiting
    • Maxima Medisch Centrum
    • Contact: L. Tick
  • Enschede, Netherlands
    • Recruiting
    • Medisch Spectrum Twente
    • Contact: T. Snijders
  • Groningen, Netherlands
    • Recruiting
    • UMCG
    • Contact: S. K. Klein
  • Leeuwarden, Netherlands
    • Recruiting
    • Medisch Centrum Leeuwarden B.V.
    • Contact: B. Franken
  • Leiden, Netherlands
    • Recruiting
    • Leids Universitair Medisch Centrum (LUMC)
    • Contact: H. Veelken
  • Maastricht, Netherlands
    • Not yet recruiting
    • Maastricht University Medical Center+ (MUMC+)
    • Contact: J. van Elssen
  • Nieuwegein, Netherlands
    • Recruiting
    • Sint Antonius Ziekenhuis Stichting
    • Contact: M. Söhne
  • Nijmegen, Netherlands
    • Recruiting
    • Radboudumc
    • Contact: J. Janssen
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus MC - Daniel
    • Contact: M. Jongen-Lavrenic
  • The Hague, Netherlands
    • Recruiting
    • Hagaziekenhuis, locatie Leyweg
    • Contact: D. Lammeren, van-Venema
  • Utrecht, Netherlands
    • Recruiting
    • UMCU
    • Contact: A. van Rhenen
  • Zwolle, Netherlands
    • Not yet recruiting
    • Isala Klinieken Stichting
    • Contact: G. van Sluis
• Norway
  • Bergen, Norway
    • Not yet recruiting
    • Haukeland University Hospital
    • Contact: O. Sefland
  • Oslo, Norway
    • Not yet recruiting
    • Stavanger Univ. Hosp.-Rogaland Hosp.
    • Contact: A. Lenartova
  • Tromsø, Norway
    • Not yet recruiting
    • University Hospital of North Norway
    • Contact: N. Leknes
  • Trondheim, Norway
    • Recruiting
    • St. Olavs Hospital
    • Contact: A. von Krogh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with newly diagnosed acute myeloid leukemia (AML) according to the International Consensus Classification (ICC).
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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; standard chemotherapy in combination with venetoclax	Other: 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.; Drug: Venetoclax; Venetoclax will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy; Combination product: 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.
Placebo Comparator: 2; standard chemotherapy in combination with placebo	Other: 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.; Drug: Placebo; Placebo will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy; Combination product: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Free Survival (EFS)	EFS in adult patients with newly diagnosed AML, defined as the time from randomization to treatment failure, death from any cause, or relapse after achieving CR or CRi, or start of new therapy due to confirmed molecular relapse whichever occurs first. Treatment failure is defined as not attaining CR or CRi after induction chemotherapy, and EFS event time for treatment failure is Day 1 of post-randomization	6 months/16 months after inclusion of last patient
Frequency of dose-limiting toxicities (DLTs) during the observation period (Primary safety endpoint during dose-finding phase)	Frequency of dose-limiting toxicities (DLTs) during the observation period (from start of cycle 1 up to a maximum of day 42, or until the start of cycle 2)	after cycle 1 (maximal day 42)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS in patients with newly diagnosed AML	6 months/16 months/28 months after inclusion of last patient
CR/CRi rate	Complete remission (CR/CRi) rate in newly diagnosed AML patients defined as the proportion of AML patients with CR/CRi after induction chemotherapy	2 months
CR rate	Complete remission (CR) rates in newly diagnosed AML patients defined as the proportion of AML patients with CR after induction chemotherapy	2 months
Cumulative incidence of relapse (CIR) in newly diagnosed AML patients	Cumulative incidence of relapse (CIR) in newly diagnosed AML patients	16 months after inclusion of last patient
Cumulative incidence of death (CID)	Cumulative incidence of death (CID) in newly diagnosed AML patients.	16 months after inclusion of last patient
Event Free Survival (EFS) including CRh	EFS in adult patients with newly diagnosed AML, defined as the time from randomization to treatment failure, death from any cause, or relapse after achieving CR, CRh or CRi, or start of new therapy due to confirmed molecular relapse whichever occurs first. Treatment failure is defined as not attaining CR, CRh or CRi by end of induction chemotherapy, i.e. if a patient's best response during or at completion of the induction treatment is less than CR/CRh/CRi	6 months/16 months after inclusion of last patient
Rates of complete remission without measurable residual disease (CRMRD-) after induction therapy	Rates of complete remission without measurable residual disease (CRMRD-) after induction therapy, defined as the proportion of AML patients achieving CR with negativity for a genetic marker by RT-qPCR, and/or with negativity by multi-color flow cytometry, if studied pre-treatment	2 months
Relapse-free survival (RFS) in newly diagnosed AML patients	Relapse-free survival (RFS) in newly diagnosed AML patients, defined as the time from achievement of a remission (CR/CRh/CRi) following curative therapy (induction and consolidation), to relapse, or start of new therapy due to confirmed molecular relapse or death from any cause	16 months after inclusion of last patient
EQ-5D-5L questionnaire of the EuroQoL (EQ) group, among AML patients	Health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated using a 5 level (5L) scale from 1 (minimum) to 5 (maximum). Higher score values mean a worse outcome.	at study entry, 2 months, 3 months, 6 months
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) among AML patients	All sub scales and single items have values from 1 (minimum) to 100 (maximum) points. A higher point value represents a better condition in terms of the functional scales and quality of life. In the symptomal sub scales a higher point value represents a worse condition.	at study entry, 2 months, 3 months, 6 months
Patient Reported Outcome Measurement Information System (PROMIS) Cancer Fatigue short form among AML patients	The 7-item PROMIS Cancer Fatigue Short Form assesses the frequency of fatigue in the past seven days (7). Table 2 presents a list of the items. Items are measured on a five point scale (1 = never; 5 = always) and summed, after reverse scoring item 7, with higher scores indicating greater fatigue (worse condition).	at study entry, 2 months, 3 months, 6 months
CR/CRh rate	Complete remission (CR/CRh) rate in newly diagnosed AML patients defined as the proportion of AML patients with CR/CRh after induction chemotherapy	2 months
Rates of complete remission without measurable residual disease (CR/CRh MRD-) after induction therapy	Rates of complete remission without measurable residual disease (CR/CRh MRD-) after induction therapy, defined as the proportion of AML patients achieving CR/CRh with negativity for a genetic marker by RT-qPCR, and/or with negativity by multi-color flow cytometry, if studied pre-treatment	2 months
Rates of complete remission without measurable residual disease (CR/CRi MRD-) after induction therapy	Rates of complete remission without measurable residual disease (CR/CRi MRD-) after induction therapy, defined as the proportion of AML patients achieving CR/CRi with negativity for a genetic marker by RT-qPCR, and/or with negativity by multi-color flow cytometry, if studied pre-treatment	2 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rates of CR+CRi in newly diagnosed AML patients after induction 1	Rates of CR+CRi in newly diagnosed AML patients defined as proportion of AML patients achieving CR/CRi after first course of induction	1 month
Rates of CR in newly diagnosed AML patients after induction 1	Rates of CR in newly diagnosed AML patients defined as proportion of AML patients achieving CR after first course of induction	1 month
EFS in newly diagnosed AML patients across different patient subgroups	EFS in newly diagnosed AML patients across different groups are defined based on prognostic characteristics including age at randomization , risk category according to ELN 2022 recommendations, as well as specific AML genotypes	6 months/16 months after inclusion of last patient
OS in newly diagnosed AML patients across different patient subgroups	OS in newly diagnosed AML patients across different groups are defined based on prognostic characteristics including age at randomization , risk category according to ELN 2022 recommendations, as well as specific AML genotypes	6 months/16 months/28 months after inclusion of last patient
CR/CRi rates in newly diagnosed AML patients across different patient subgroups	CR/CRi rates in newly diagnosed AML patients across different groups are defined based on prognostic characteristics including age at randomization , risk category according to ELN 2022 recommendations, as well as specific AML genotypes	2 months
CR rates in newly diagnosed AML patients across different patient subgroups	CR rates in newly diagnosed AML patients across different groups are defined based on prognostic characteristics including age at randomization , risk category according to ELN 2022 recommendations, as well as specific AML genotypes	2 months
RFS in newly diagnosed AML patients across different patient subgroups	RFS in newly diagnosed AML patients across different groups are defined based on prognostic characteristics including age at randomization , risk category according to ELN 2022 recommendations, as well as specific AML genotypes	16 months after inclusion of last patient
CIR in newly diagnosed AML patients across different patient subgroups	CIR in newly diagnosed AML patients across different groups are defined based on prognostic characteristics including age at randomization , risk category according to ELN 2022 recommendations, as well as specific AML genotypes	16 months after inclusion of last patient
CID in newly diagnosed AML patients across different patient subgroups	CID in newly diagnosed AML patients across different groups are defined based on prognostic characteristics including age at randomization , risk category according to ELN 2022 recommendations, as well as specific AML genotypes	16 months after inclusion of last patient
Frequency and severity of AE	Frequency and severity of AE according to CTCAE version 5.0 in newly diagnosed AML patients	6 months
Times to hematopoietic recovery	Times to hematopoietic recovery (absolute neutrophil counts ≥0.5 and ≥1.0 x 109/L; platelets ≥50 and ≥100 x 109/L) after each chemotherapy treatment cycle, defined as the time from the start of the cycle until recovery among AML patients	6 months
EFS with modified definition	To evaluate the impact of venetoclax on EFS in newly diagnosed AML patients using modified endpoint definitions: o Modified EFS includes treatment failure defined as not achieving CR by end of induction chemotherapy assessed by investigator. The date of treatment failure is date of randomization. Patients achieving CRh or CRi are counted as events.	6 months/16 months after inclusion of last patient
RFS with modified definition	To evaluate the impact of venetoclax on RFS in newly diagnosed AML patients using modified endpoint definitions: o Modified RFS includes only subjects achieving CR	16 months after inclusion of last patient
Rates of CR/CRh in newly diagnosed AML patients after induction 1	Rates of CR/CRh in newly diagnosed AML patients defined as proportion of AML patients achieving CR/CRh after first course of induction	1 month
CR/CRh rates in newly diagnosed AML patients across different patient subgroups	CR/CRh rates in newly diagnosed AML patients across different groups are defined based on prognostic characteristics including age at randomization , risk category according to ELN 2022 recommendations, as well as specific AML genotypes	2 months

Collaborators and Investigators

• Sponsor: University of Ulm
• Collaborators: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Investigators: Principal Investigator: Hartmut Doehner, MD, University of Ulm

Study record dates

Study Major Dates

• Study Start (Actual): September 13, 2022
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): February 1, 2032

Study Registration Dates

• First Submitted: November 3, 2020
• First Submitted That Met QC Criteria: November 12, 2020
• First Posted (Actual): November 13, 2020

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: adult patients
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Substandard Drugs; Pharmaceutical Preparations; venetoclax
• Other Study ID Numbers: AMLSG31-19/HO501/AbbVieB18-982

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No