A Randomized, Open-labelled, 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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Patients

Age range

65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Immune System Diseases [C20]

Trial duration

2 Mar 2026 → ongoing

Decision date (initial)

2026-02-11

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacoeconomic, Safety, Efficacy

To demonstrate the non-inferiority of a reduced VEN exposure to 7 days of AZA every 28 days cycle from the first cycle in terms of composite complete remission rate (complete remission + complete remission with incomplete marrow recovery CR/CRi) at any time point during the first 6 cycles compared to conventional continuous 28-day exposure in treatment naïve AML patients.

Secondary objectives 8

1. To evaluate OS and EFS (7-day VEN dosing and conventional 28-day dosing).
2. To evaluate early mortality at Day 60 (7-day VEN dosing vs conventional 28-day dosing)
3. To evaluate time to first response and time to best response (7-day VEN dosing and conventional 28-day dosing).
4. To evaluate DoR (7-day VEN dosing and conventional 28-day dosing).
5. To evaluate quality-of-life (according to EQ5D-5L and QLQ-ELD14 questionnaires).
6. To evaluate, in patients who reached CR/CRi, dosing schedule modification, delays (>2 days) or discontinuation (7-day VEN dosing and conventional 28-day dosing).
7. To evaluate toxicity of special interest and healthcare consumption especially in patients who reached CR/CRi (7-day VEN dosing and conventional 28-day dosing).
8. Health economic analysis: cost-minimization analysis and cost-effectiveness analysis (only for included patients treated in France)

Conditions and MedDRA coding

Acute Myeloid Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 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.
2. Subject must be ≥ 60 years of age.
3. Subject must have a projected life expectancy of at least 12 weeks.
4. 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
5. 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.
6. Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula.
7. 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
8. 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).
9. 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.
10. 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.
11. Patients must be affiliated to a social security system or beneficiary of the same (only for France)
12. 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 16

1. 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
2. Subject has a malabsorption syndrome or other condition that precludes enteral route of administration.
3. Subject exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial or fungal).
4. 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.
5. Subject has a white blood cell count > 25 × 109/L. (Hydroxyurea is permitted to meet this criterion.)
6. Subject has hypersensitivity to the active substances of any of the excipients
7. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.
8. 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.
9. 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.
10. Subject has acute promyelocytic leukemia
11. Subject has known active CNS involvement with AML.
12. Known human immunodeficiency virus HIV
13. Known hepatitis B or C infection with the exception of those with an undetectable viral load within 3 months.
14. 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.
15. 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.
16. 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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The proportion of subjects with complete remission or complete remission with incomplete marrow recovery (CR/CRi) will be calculated based on current IWG criteria for AML (Cheson et al J Clin Oncol 2003)

Secondary endpoints 8

1. Overall survival (OS). Event-Free Survival (EFS).
2. Early mortality rate at Day 60.
3. Time to first response. Time to best response.
4. Duration of response (DoR).
5. Health-Related Quality of Life (HRQoL) assessed by the EORTC QLQ-ELD14 and EuroQol EQ-5D-5L questionnaires
6. Scheme modification will be defined as the proportion of CR/CRi patients that presented treatment modification not authorized by protocol as VEN schedule modification (dose, duration), delay >2 days from the initial Day of the subsequent cycle and/or temporary/definitive VEN discontinuation.
7. Toxicity evaluated by platelet transfusion, febrile neutropenia or severe infection episodes, hospitalization requirement and hospitalization length stay
8. Incremental costs and QALY and ICER (€/QALY) (only for included patients treated in France)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Dr. WILLEKENS Christophe

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Dr. WILLEKENS Christophe

Locations

2 EU/EEA countries · 22 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 28 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications