A Multicenter Trial Evaluating Efficacy and Safety of A Reduced Venetoclax Exposure To Seven Days Versus Standard Continuous Venetoclax Exposure Combined With Azacitidine in Treatment Naïve Subjects With Acute Myeloid Leukemia Who Are Ineligible for Intensive Induction

NCT07082452 | Not Yet Recruiting Phase 3

• 2 other identifiers: 2025-521634-29-002025/4132
• Study Type: interventional
• Target: 262
• Locations: 1 country
• Sites: 1

Brief Summary

Combination of azacitidine (AZA) for 7 days every 28 days with a continuous daily exposure to Venetoclax (VEN), an oral bcl-2 inhibitor, is now approved for the treatment of acute myeloid leukemia (AML) in patients ineligible for intensive chemotherapy due to age (\>75 years) or comorbidities. VEN+AZA showed significant overall response rate and survival benefit but combination carries a risk of considerable toxicity (such as profound/prolonged cytopenia and infections) before but also after remission. These toxicities make it difficult to apply the recommended treatment regimen, in particular the continuous daily intake of VEN. Recent reports suggest that reducing VEN duration per cycle seems safe and feasible. We propose to investigate a reduced-intensity VEN regimen (7-day dosing/28) versus the standard continuous VEN therapy (28-day dosing/28), combined with AZA, with the primary goal of maintaining efficacy while reducing associated toxicity.

Conditions

Leukemia, B-Cell, Chronic; Leukemia

Keywords

Acute Myeloid Leukemia, Venetoclax Exposure, Venetoclax, Azacitidine

Outcome Measures

Primary Outcomes (1)

• Proportion of subjects with complete remission or complete remission with incomplete marrow recovery (CR/CRi)

  This proportion will be calculated based on current IWG criteria for AML

  at any time point during the study (at 30 days, 60 days, 3 years)

Secondary Outcomes (10)

• Overall survival (OS)

  at 30 days, 60 days, 1, 2 and 3 years

• Event-Free Survival (EFS)

  at 30 days, 60 days, 1, 2 and 3 years

• Early mortality rate

  At day 60

• Time to first response

  at 30 days, 60 days, 1, 2 and 3 years

• Time to best response

  at 30 days, 60 days, 1, 2 and 3 years

Study Arms (2)

Arm A: Venetoclax (7 days) + Azacitidine

EXPERIMENTAL

Arm A (experimental): Patients will receive venetoclax for a total of seven days. * Azacitidine 75 m Subcutaneous (SC) or intravenous (IV) Daily with a continuous 7-day scheme or on a 5-on/2-off \[weekend\]/2-on schedule (5-0-2) in 28-day cycle * Venetoclax 400 mg orally once Daily on Days 1 - 7, in case of AZA treatment with a continuous 7-day scheme OR Venetoclax 400 milligram (mg) Daily on Days 1 - 5 and Day 8-9 in case of AZA treatment with a 5-0-2 scheme.

Drug: Venetoclax; Drug: Azacitidine

Arm B: Venetoclax (28 days) + Azacitidine

ACTIVE COMPARATOR

Arm B (standard): Patients will receive venetoclax for a total of 28 days (before remission), according to VIALE-A protocol. * Azacitidine 75 mg/m2 Subcutaneous (SC) or IV Daily with a continuous 7-day scheme or on a 5-on/2-off \[weekend\]/2-on schedule (5-0-2) in 28-day cycle. * Venetoclax 400 mg orally once Daily on Days 1 - 28.

Drug: Venetoclax; Drug: Azacitidine

Interventions

Venetoclax DRUG

Venetoclax 400 mg orally once Daily

Arm A: Venetoclax (7 days) + Azacitidine; Arm B: Venetoclax (28 days) + Azacitidine

Azacitidine DRUG

75 mg/m2 Subcutaneous (SC) or intravenous (IV) Daily with a continuous 7-day scheme or on a 5-on/2-off \[weekend\]/2-on schedule (5-0-2) in 28-day cycle

Arm A: Venetoclax (7 days) + Azacitidine; Arm B: Venetoclax (28 days) + Azacitidine

Eligibility Criteria

• Age: 70 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• Subject must have confirmation of AML by WHO 2022 criteria and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age or co-morbidities.
• Subject must be ≥ 60 years of age.
• Subject must have a projected life expectancy of at least 12 weeks.
• Subject must be considered ineligible for induction therapy defined by the following:
• years of age OR
• to 74 years of age with at least one of the following co-morbidities:
• ECOG Performance Status of 2 or 3;
• Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina;
• DLCO ≤ 65% or FEV1 ≤ 65%;
• Severe Renal impairment: Creatinine clearance ≥ 30 mL/min to \< 45 ml/min
• Moderate hepatic impairment with total bilirubin \> 1.5 to ≤ 3.0 × ULN
• Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the coordinator before study enrollment
• Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status (Appendix 4):
• to 2 for subject ≥ 75 years of age.
• to 3 for subject ≥ 60 to 74 years of age.

You may not qualify if:

• Subject has received treatment with the following:
• Hypomethylating agent, venetoclax and/or any chemo-therapeutic agent for Myelodysplastic syndrome (MDS).
• Chimeric Antigen Receptor (CAR)-T cell therapy.
• Experimental therapies for MDS or Acute Myeloid Leukemia (AML).
• Current participation in another research or observational study.
• Subject has history of myeloproliferative neoplasm \[MPN\], including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia (CML) with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation.
• Subject has favorable risk cytogenetics such as t(8;21), inv(16), t(16;16) or t(15;17) as per the NCCN Guidelines Version 2, 2016 for Acute Myeloid Leukemia.
• Subject has acute promyelocytic leukemia
• Subject has known active CNS involvement with AML.
• Known human immunodeficiency virus HIV
• Known hepatitis B or C infection with the exception of those with an undetectable viral load within 3 months.
• Subject has a cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
• Subject has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study.
• Subject has a malabsorption syndrome or other condition that precludes enteral route of administration.
• Subject exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial or fungal).

Sponsors & Collaborators

• Gustave Roussy, Cancer Campus, Grand Paris: lead

Study Sites (1)

Gustave Roussy

Villejuif, 94805, France

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia; Leukemia, Myeloid, Acute

Interventions

venetoclax; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Myeloid

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Central Study Contacts

Christophe WILLEKENS, MD

CONTACT

+33 (0)1 42 11 23 79; christophe.willekens@gustaveroussy.fr

Jean-Luc JOANNIC, PhD

CONTACT

+33 (0)1 42 11 47 94; jeanluc.joannic@gustaveroussy.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 23, 2025
• First Posted: July 24, 2025
• Study Start: September 1, 2025
• Primary Completion (Estimated): September 1, 2030
• Study Completion (Estimated): March 1, 2031
• Last Updated: July 24, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)