Comparison of Seven-Day versus Continuous Venetoclax Exposure with Azacitidine in Treatment-Naïve Patients with Ineligible-for-Intensive Acute Myeloid Leukemia
- Trial ID
- 2025-521634-29-00
- Protocol
- CSET 2025/4132
- Sponsor
- Institut Gustave Roussy
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the non-inferiority of a reduced venetoclax exposure, administered for 7 days every 28-day cycle, compared to conventional continuous 28-day exposure in combination with azacitidine. This evaluation is performed in treatment-naïve patients with acute myeloid leukemia who are ineligible for intensive induction, focusing on the composite complete remission rate, which includes complete remission and complete remission with incomplete marrow recovery, during the first 6 cycles. 5
Secondary objectives include the assessment of:
- Overall survival and event-free survival.
- Early mortality at Day 60.
- Time to first response, time to best response, and duration of response.
- Quality of life using EQ5D-5L and QLQ-ELD14 questionnaires.
- Dosing schedule modifications, delays, or discontinuation in patients achieving complete remission or complete remission with incomplete marrow recovery.
- Toxicity of special interest and healthcare consumption.
- Cost-minimization analysis and cost-effectiveness analysis.
Participants
The sponsor did not provide information regarding the total number of participants. The study population consists of male and female patients with acute myeloid leukemia who are treatment naïve. Eligible individuals must be 60 years of age or older and deemed ineligible for standard cytarabine and anthracycline induction regimens due to age or co-morbidities. Inclusion requires a life expectancy of at least 12 weeks and specific Eastern Cooperative Oncology Group performance status levels. Participants must demonstrate adequate renal function and hepatic function. Female subjects must be postmenopausal or surgically sterile, while non-sterile male subjects are required to utilize contraceptive methods. The population is selected based on a confirmed diagnosis according to WHO 2022 criteria and eligibility for azacitidine and venetoclax therapy.
Plans and Procedures
This Phase 5, randomized, open-label, multicenter trial is designed to evaluate the efficacy and safety of a reduced venetoclax exposure for seven days compared to standard continuous exposure when combined with azacitidine in treatment-naïve subjects with acute myeloid leukemia who are ineligible for intensive induction. The primary objective is to demonstrate the non-inferiority of the reduced exposure regimen regarding the composite complete remission rate, including complete remission with incomplete marrow recovery, during the first six cycles. The study involves an initial screening visit to confirm the diagnosis and assess eligibility based on specific age, performance status, and organ function criteria. Following screening, participants will undergo treatment cycles which include bone marrow aspiration for diagnosis and follow-up. Secondary endpoints include overall survival, event-free survival, and health-related quality of life. Participation continues through the completion of the treatment cycles and subsequent follow-up assessments. Study involvement is subject to protocol adherence, and conditions such as unauthorized treatment modifications or specific safety concerns may lead to early termination. The total trial period is estimated to conclude by February 2031.
Treatment
The experimental treatment involves the administration of azacitidine, provided as a suspension for injection. The dosage is 75 mg/m² administered via intravenous, subcutaneous, or intramuscular routes every 28 days.
The trial also utilizes venetoclax in the form of film-coated tablets. The dosage is 400 mg administered via the oral route. The study evaluates different exposure schedules for this substance in subjects with acute myeloid leukemia.
Efficacy
The primary efficacy endpoint is the proportion of subjects achieving complete remission or complete remission with incomplete marrow recovery (CR/CRi). This assessment is conducted according to the International Working Group (IWG) criteria for acute myeloid leukemia. The evaluation occurs at any time point during the first six cycles.
Secondary efficacy parameters include:
- Overall survival (OS) and event-free survival (EFS).
- Early mortality rate at Day 60.
- Time to first response and time to best response.
- Duration of response (DoR).
- Health-related quality of life (HRQoL), which is measured using the EORTC QLQ-ELD14 and EuroQol EQ-5D-5L questionnaires.
- Scheme modification, defined as the proportion of CR/CRi patients experiencing unauthorized venetoclax schedule modifications, including changes in dose or duration, delays greater than two days from the initial day of a subsequent cycle, or temporary or definitive venetoclax discontinuation.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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:≥ 75 years of age OR ≥ 60 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 impairement: 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): • 0 to 2 for subject ≥ 75 years of age. • 0 to 3 for subject ≥ 60 to 74 years of age.
- Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula.
- Subject must have adequate liver function as demonstrated by: • Aspartate aminotransferase (AST) ≤ 3.0 × ULN* • alanine aminotransferase (ALT) ≤ 3.0 × ULN* • bilirubin ≤ 1.5 × ULN* * Unless considered to be due to leukemic organ involvement. Subjects who are < 75 years of age may have a bilirubin of ≤ 3.0 × ULN
- Female subjects must be either postmenopausal (amenorrhea for at least 12 months with no alternative medical reasons) or surgically sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
- Non-sterile male subjects must use contraceptive methods with partner(s) prior to beginning study drug administration and continuing up to 90 days after the last dose of study drug. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug.
- Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.
- Patients must be affiliated to a social security system or beneficiary of the same (only for France)
- Patients shall be eligible to undergo Azacitidine and Venetoclax treatment and BM aspiration. Patients who do not consent to a BM aspiration will not be eligible (diagnosis and follow –up)
Exclusion Criteria
- 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 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).
- Subject has a history of other malignancies prior to study entry, with the exception of: • Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;• Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent and considered in remission for 3 years.
- Subject has a white blood cell count > 25 × 109/L. (Hydroxyurea is permitted to meet this criterion.)
- Subject has hypersensitivity to the active substances of any of the excipients
- Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.
- 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.
- NB: patients with IDH1-mutant AML will not be formally excluded from the study. However, investigators are strongly encouraged to prefer treatment combining Azacitidine and Ivosidenib (AGILE phase III trial).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 31 Jan 2026 | 131 |
 Spain | Recruiting | 31 Jan 2026 | 131 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Vidaza 25 mg/ml powder for suspension for injection | Test | POWDER FOR SUSPENSION FOR INJECTION | INTRAVENOUS/SUBCUTANEOUS/INTRAMUSCULAR | 75 | 42 | PRD9244549 |
Venclyxto 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 400 | 168 | PRD11643495 |