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
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
650
Venetoclax will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy
Placebo will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the 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.
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
Time frame: 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)
Time frame: after cycle 1 (maximal day 42)
Overall Survival (OS)
OS in patients with newly diagnosed AML
Time frame: 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
Time frame: 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
Time frame: 2 months
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
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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.
Tirol Kliniken GmbH
Innsbruck, Austria
NOT_YET_RECRUITINGKepler Universitaetsklinikum GmbH
Linz, Austria
NOT_YET_RECRUITINGOrdensklinikum Linz GmbH
Linz, Austria
NOT_YET_RECRUITINGLandeskrankenhaus (LKH) Rankweil, Interne E am Landeskrankenhaus Rankweil
Rankweil, Austria
NOT_YET_RECRUITINGGemeinnuetzige Salzburger Landeskliniken Betriebsgesellschaft mbH
Salzburg, Austria
NOT_YET_RECRUITINGHanusch Krankenhaus Der Wiener Gebietskrankenkasse
Vienna, Austria
NOT_YET_RECRUITINGZiekenhuis Aan De Stroom
Antwerp, Belgium
NOT_YET_RECRUITINGAz St-Jan Brugge-Oostende A.V.
Bruges, Belgium
NOT_YET_RECRUITINGUniversitair Ziekenhuis Brussel
Brussels, Belgium
RECRUITINGKatholieke Universiteit te Leuven
Leuven, Belgium
NOT_YET_RECRUITING...and 81 more locations
Time frame: 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
Time frame: 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
Time frame: 16 months after inclusion of last patient
Cumulative incidence of relapse (CIR) in newly diagnosed AML patients
Cumulative incidence of relapse (CIR) in newly diagnosed AML patients
Time frame: 16 months after inclusion of last patient
Cumulative incidence of death (CID)
Cumulative incidence of death (CID) in newly diagnosed AML patients.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 2 months