Azacitidine Combined With Venetoclax in Patients With Higher-risk Chronic Myelomonocytic Leukemia (AVENHIR)

NCT ID: NCT05768711

Last Updated: 2025-12-08

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 44 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-04
• Study Completion Date: 2028-10-31

Brief Summary

Open-label phase II, single arm, multicenter study with safety run-in to evaluate the efficacy and safety of Azacitidine combined with Venetoclax in patients with higher-risk chronic myelomonocytic leukemia

Detailed Description

AVENHIR trial is an open-label phase II, single arm, multicenter study with safety run-in to evaluate the efficacy and safety of the combination of Azacitidine and Venetoclax in, hypomethylating agent-naïve, higher-risk chronic myelomonocytic leukemia patients

Conditions

Chronic Myeloid Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Azacidine+Venetoclax

Azacitidine will be administered subcutaneously at the standard dose of 75 mg/m²/d either on days 1-7 or using a 5-2-2 schedule of the 28 day-cycles.

Patiens will be exposed to Venetoclax during the first 7 or 14 days of the 28 day-cycles (number of days of Venetoclax determined during the safety run-in phase).

At cycle 1, Venetoclax will be given orally with 3-day ramp-up, at 100 mg on day 1, 200 mg on day 2 and 400 mg on days 3 to 7 or 14 of the cycle.

At all subsequent cycles, Venetoclax will be given orally at 400 mg on days 1 to 7 or 14 of the cycle.

Treatment duration will be 24 months.

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Combination of Azacitidine and Venetoclax

Interventions

Venetoclax

Combination of Azacitidine and Venetoclax

Intervention Type: DRUG

Other Intervention Names

ABT-199

Eligibility Criteria

Inclusion Criteria

1. Age 18 and older.

2. CMML diagnosis according to ICC 2022 criteria.

3. Intermediate-2 or high risk according to the molecular CMML Prognostic Scoring System (CPSS-mol) at study entry. In patients treated with HY at screening, the white blood count (WBC) prior to introduction of HY will be used to compute CPSS-mol. In patients with failed or missing cytogenetics or genetics at screening, cytogenetics and genetics at CMML diagnosis will be used to compute CPSS-mol.

4. No prior treatment with hypomethylaing agents, including Azacitidine, decitabine, SGI-110, AST7227 or CC-486 for CMML or any antecedent condition, including antecedent MDS or auto-immune disease. Prior treatment with Erythropoiesis Stimulating Agents (ESA) is allowed with a > 15 days washout from ESAs. Prior treatment with hydroxyurea (HY) is acceptable. No washout is necessary for those patients but pre-HY WBC will be taken in consideration for CPSS-mol computation.

5. Performance status 0-2 on the Eastern Cooperative Oncology Group (ECOG) Scale.

6. Adequate organ function including the following:

• total bilirubin < 2 times upper limit of normal (ULN) (except moderate unconjugated hyperbilirubinemia due to intra medullary hemolysis or due to Gilbert syndrome),
• alanine transaminase (ALT) and aspartate transaminase (AST) < 3 times ULN,
• Creatinine clearance > 30 mL/min as estimated by the CKD-EPI equation.

7. Signed Informed Consent Form (ICF).

8. Negative pregnancy and adequate contraception (including in male patients) if relevant.

A FCBP (female of childbearing potential) for this study is defined as a sexually mature woman who: (1) has not undergone a hysterectomy or bilateral oophorectomy; or (2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).

A FCBP participating in the study must:

• Have had 2 negative pregnancy tests as verified by the investigator prior to starting investigational medicinal product (IMP) (unless the screening pregnancy test was done within 72 hours of Cycle 1 Day 1). She must have had agreed to ongoing pregnancy testing during the course of the study and after end of treatment.
• If sexually active, agree to use, and be able to comply with, highly effective contraception** without interruption, 5 weeks prior to starting IMP, during treatment with IMP (including dose interruptions), and for 3 months after the last dose of IMP.

• Highly effective contraception is defined in this protocol as the following (information also appears in the ICF): Hormonal contraception (eg, birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation (tying your tubes), or a partner with a vasectomy.

Male subjects must have agreed to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (eg, polyurethane), during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions, and for at least 3 months after the last dose of IMP, even if he had undergone a successful vasectomy.

9. Affiliation to a health insurance system.

Exclusion Criteria

1. Myeloproliferative / myelodysplastic syndrome other than CMML.

2. Bone marrow or peripheral blood blasts (including promonocytes) ≥ 20%. If both local and central review are available and discrepant, the central review will be used.

3. CMML with t(5;12) or PDGFRbeta rearrangement that may be treated with imatinib.

4. Unavailable CPSS-mol at inclusion (WBC prior to HY used to compute CPSS-mol at inclusion in HY-exposed patients) or with a CPSS-mol low or intermediate-1 at study entry.

5. Pregnant or breastfeeding.

6. Serious concomitant systemic disorder, including auto-immune or auto-inflammatory disease requiring > 20 mg/d prednisone equivalent, active bacterial, fungal or viral infection that in the opinion of the investigator, would compromise the safety of the patient and/or his/her ability to complete the study.

7. Medical condition requiring therapies with CYP3A strong or moderate inducing or inhibiting activity at screening. All strong or moderate CYP3A inducers should be discontinued 7 days prior to the first dose of study drug. All strong or moderate CYP3A inhibitors should be discontinued 3 days prior to the first dose of study drug. A sample list of CYP3A4 inhibitors and inducers is provided in Appendix F.

8. Prior malignancy (except in situ cervix carcinoma, limited basal cell carcinoma, asymptomatic prostatic cancer not requiring treatment, or other tumors if not active during the last 2 years).

9. Known positive test for human immunodeficiency virus (HIV). Note that HIV testing is not required at Screening.

10. Malabsorption syndrome or other condition that precludes an enteral route of administration.

11. Previous therapy with a hypomethylating agent including azacitidine, decitabine, SGI-110, AST7227 or CC-486 for CMML or any antecedent condition, including antecedent MDS or auto-immune disease.

12. Previous therapy with a BH3 mimetic.

13. Antecedent allogeneic stem cell transplantation (HSCT) for CMML or an antecedent of hematological malignancy. Those never transplanted but eligible for HSCT are eligible for the trial.

14. Subjects referred to in Articles L1121-5 to L1121-8-1 and L1122-1-2 of the Public Health Code.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AbbVie

INDUSTRY

Sponsor Role: collaborator

Groupe Francophone des Myelodysplasies

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Raphaël ITZYKSON, MD/PhD

Role: PRINCIPAL_INVESTIGATOR

Hôpital Saint Louis

Pierre FENAUX, MD/PhD

Role: PRINCIPAL_INVESTIGATOR

Hôpital Saint Louis

Locations

CHU d'Amiens

Amiens, , France

CHU d'Angers

Angers, , France

Hôpital Avicenne

Bobigny, , France

Hôpital privé Sévigné

Cesson-Sévigné, , France

CHU de Grenoble

Grenoble, , France

Hôpital Claude Huriez

Lille, , France

CHRU de Limoges

Limoges, , France

Centre Hospitalier de Mont de Marsan

Mont-de-Marsan, , France

CHU de Montpellier - Hôpital Saint Eloi

Montpellier, , France

CHU Hôtel Dieu

Nantes, , France

Hôpital privé du Confluent SAS

Nantes, , France

Hôpital Archet 1

Nice, , France

Hôpital Saint Louis

Paris, , France

Hôpital Cochin

Paris, , France

CHU de Bordeaux - Hôpital Haut-Lévêque

Pessac, , France

Centre hospitalier Lyon sud

Pierre-Bénite, , France

CHU de Poitiers

Poitiers, , France

Hôpital NOVO

Pontoise, , France

Centre Hospitalier Annecy Genevois - Site d'Annecy

Pringy, , France

Hôpital Pontchaillou

Rennes, , France

Centre Henri Becquerel

Rouen, , France

IUCT oncopole

Toulouse, , France

CHU de Tours - Hôpital Bretonneau

Tours, , France

Institut Gustave Roussy

Villejuif, , France

Countries

France

Other Identifiers

2024-514878-53-00

Identifier Type: CTIS

Identifier Source: secondary_id

2021-002007-35

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

AVENHIR

Identifier Type: -

Identifier Source: org_study_id