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

Phase 3

Recruiting

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: Venetoclax; Drug: Placebo; Combination Product: Standard chemotherapy; Other: Allogeneic stem cell transplantation; Other: Autologous stem cell transplantation

• Registration Number: NCT04628026
• Lead Sponsor: University of Ulm

Brief Summary

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

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 Timeline

• Study First Submitted: 2020-11-03
• Study First Submitted QC: 2020-11-12
• Study First Posted: 2020-11-13
• Study Start: 2022-09-13
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-04
• Last Update Posted: 2025-07-10
• Primary Completion: 2029-03
• Study Completion: 2032-02-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 650

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).

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1	Venetoclax	standard chemotherapy in combination with venetoclax
1	Standard chemotherapy	standard chemotherapy in combination with venetoclax
1	Allogeneic stem cell transplantation	standard chemotherapy in combination with venetoclax
2	Placebo	standard chemotherapy in combination with placebo
2	Standard chemotherapy	standard chemotherapy in combination with placebo
2	Allogeneic stem cell transplantation	standard chemotherapy in combination with placebo
1	Standard chemotherapy	standard chemotherapy in combination with venetoclax
1	Autologous stem cell transplantation	standard chemotherapy in combination with venetoclax
1	Allogeneic stem cell transplantation	standard chemotherapy in combination with venetoclax
2	Placebo	standard chemotherapy in combination with placebo
2	Standard chemotherapy	standard chemotherapy in combination with placebo
2	Autologous stem cell transplantation	standard chemotherapy in combination with placebo
2	Allogeneic stem cell transplantation	standard chemotherapy in combination with placebo
1	Venetoclax	standard chemotherapy in combination with venetoclax

Primary Outcome Measures

Name	Time	Method
Frequency of dose-limiting toxicities (DLTs) during the observation period (Primary safety endpoint during dose-finding phase)	after cycle 1 (maximal day 42)	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)
Event Free Survival (EFS)	6 months/16 months after inclusion of last patient	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

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	6 months/16 months/28 months after inclusion of last patient	OS in patients with newly diagnosed AML
CR/CRi rate	2 months	Complete remission (CR/CRi) rate in newly diagnosed AML patients defined as the proportion of AML patients with CR/CRi after induction chemotherapy
CR rate	2 months	Complete remission (CR) rates in newly diagnosed AML patients defined as the proportion of AML patients with CR after induction chemotherapy
Event Free Survival (EFS) including CRh	6 months/16 months after inclusion of last patient	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
Rates of complete remission without measurable residual disease (CRMRD-) after induction therapy	2 months	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
Relapse-free survival (RFS) in newly diagnosed AML patients	16 months after inclusion of last patient	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
Cumulative incidence of relapse (CIR) in newly diagnosed AML patients	16 months after inclusion of last patient	Cumulative incidence of relapse (CIR) in newly diagnosed AML patients
Cumulative incidence of death (CID)	16 months after inclusion of last patient	Cumulative incidence of death (CID) in newly diagnosed AML patients.
EQ-5D-5L questionnaire of the EuroQoL (EQ) group, among AML patients	at study entry, 2 months, 3 months, 6 months	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.
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) among AML patients	at study entry, 2 months, 3 months, 6 months	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.
Patient Reported Outcome Measurement Information System (PROMIS) Cancer Fatigue short form among AML patients	at study entry, 2 months, 3 months, 6 months	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).
CR/CRh rate	2 months	Complete remission (CR/CRh) rate in newly diagnosed AML patients defined as the proportion of AML patients with CR/CRh after induction chemotherapy
Rates of complete remission without measurable residual disease (CR/CRh MRD-) after induction therapy	2 months	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
Rates of complete remission without measurable residual disease (CR/CRi MRD-) after induction therapy	2 months	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

Trial Locations

Locations (85)

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; 🇧🇪 Antwerpen, Belgium

Az St-Jan Brugge-Oostende A.V.; 🇧🇪 Brugge, Belgium

Universitair Ziekenhuis Brussel; 🇧🇪 Brussels, Belgium

Katholieke Universiteit te Leuven; 🇧🇪 Leuven, Belgium

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