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

NCT05768711 | Active Not Recruiting Phase 2 DMC

• 3 other identifiers: AVENHIR2024-514878-53-002021-002007-35
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 24

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

Conditions

Chronic Myeloid Leukemia

Keywords

CMML; Azacitidine; Venetoclax

Outcome Measures

Primary Outcomes (2)

• Safety run-in

  Determination of dose-limiting toxicities within the first two cycles of treatment

  after 2 cycles of treatment of the safety run-in phase patients (each cycle is 28 days)

• Overall response rate

  Overall response encompasses complete remission, partial remission, marrow response and clinical benefit according to protocol-defined criteria modified from MDS/MPN IWG criteria after 3 and 6 cycles of treatment

  after 3 and 6 cycles of treatment of the phase II patients (each cycle is 28 days)

Secondary Outcomes (15)

• Complete remission rate

  after 3 and 6 cycles of treatment (each cycle is 28 days)

• Overall response rate at best response

  through study completion, an average of 5 years

• Overall response rate after 3 and 6 cycles of treatment

  after 3 and 6 cycles of treatment (each cycle is 28 days)

• Duration of response

  through study completion, an average of 5 years

• Identification and grading of adverse events

  through study completion, an average of 5 years

Other Outcomes (2)

• Patient reported outcomes

  through study completion, an average of 5 years

• Exploratory endpoints

  through study completion, an average of 5 years

Study Arms (1)

Azacidine+Venetoclax

EXPERIMENTAL

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.

Drug: Venetoclax

Interventions

Venetoclax DRUG

Combination of Azacitidine and Venetoclax

Also known as: ABT-199

Azacidine+Venetoclax

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 and older.
• CMML diagnosis according to ICC 2022 criteria.
• 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.
• 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.
• Performance status 0-2 on the Eastern Cooperative Oncology Group (ECOG) Scale.
• 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.
• Signed Informed Consent Form (ICF).
• 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.

You may not qualify if:

• Myeloproliferative / myelodysplastic syndrome other than CMML.
• 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.
• CMML with t(5;12) or PDGFRbeta rearrangement that may be treated with imatinib.
• Pregnant or breastfeeding.
• 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.
• 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.
• 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).
• Known positive test for human immunodeficiency virus (HIV). Note that HIV testing is not required at Screening.
• Malabsorption syndrome or other condition that precludes an enteral route of administration.
• 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.
• Previous therapy with a BH3 mimetic.
• 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.
• Subjects referred to in Articles L1121-5 to L1121-8-1 and L1122-1-2 of the Public Health Code.

Sponsors & Collaborators

• Groupe Francophone des Myelodysplasies: lead
• AbbVie: collaborator

Study Sites (24)

CHU d'Amiens

Amiens, 80054, France

Location

CHU d'Angers

Angers, 49033, France

Location

Hôpital Avicenne

Bobigny, 93009, France

Location

Hôpital privé Sévigné

Cesson-Sévigné, 35510, France

Location

CHU de Grenoble

Grenoble, 38043, France

Location

Hôpital Claude Huriez

Lille, 59037, France

Location

CHRU de Limoges

Limoges, 87046, France

Location

Centre Hospitalier de Mont de Marsan

Mont-de-Marsan, 40000, France

Location

CHU de Montpellier - Hôpital Saint Eloi

Montpellier, 34295, France

Location

CHU Hôtel Dieu

Nantes, 44093, France

Location

Hôpital privé du Confluent SAS

Nantes, 44277, France

Location

Hôpital Archet 1

Nice, 06200, France

Location

Hôpital Saint Louis

Paris, 75010, France

Location

Hôpital Cochin

Paris, 75014, France

Location

CHU de Bordeaux - Hôpital Haut-Lévêque

Pessac, 33604, France

Location

Centre hospitalier Lyon sud

Pierre-Bénite, 69495, France

Location

CHU de Poitiers

Poitiers, 86021, France

Location

Hôpital NOVO

Pontoise, 95300, France

Location

Centre Hospitalier Annecy Genevois - Site d'Annecy

Pringy, 74374, France

Location

Hôpital Pontchaillou

Rennes, 35033, France

Location

Centre Henri Becquerel

Rouen, 76038, France

Location

IUCT oncopole

Toulouse, 31059, France

Location

CHU de Tours - Hôpital Bretonneau

Tours, 37000, France

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Interventions

venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Raphaël ITZYKSON, MD/PhD

  Hôpital Saint Louis

  PRINCIPAL INVESTIGATOR

• Pierre FENAUX, MD/PhD

  Hôpital Saint Louis

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 23, 2023
• First Posted: March 14, 2023
• Study Start: October 4, 2023
• Primary Completion: May 1, 2026
• Study Completion (Estimated): October 1, 2028
• Last Updated: March 5, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

FR (24)