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

Phase II Study With Safety run-in of Azacitidine (AZA) Combined With Venetoclax (VEN) in Patients With Higher-risk Chronic Myelomonocytic Leukemia (CMML)

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

Study Overview

• Status: Recruiting
• Conditions: Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: Venetoclax

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 newly diagnosed, hypomethylating agent-naïve, higher-risk chronic myelomonocytic leukemia patients

• Study Type: Interventional
• Enrollment (Estimated): 44
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Fatiha CHERMAT; Phone Number: +33 1 71 20 70 59; Email: fatiha.chermat-ext@aphp.fr

Study Locations

• France
  • Amiens, France, 80054
    • Not yet recruiting
    • CHU d'AMIENS
    • Contact: Delphine LEBON, MD; Phone Number: +33 3 22 45 59 14; Email: lebon.delphine@chu-amiens.fr
    • Principal Investigator: Delphine LEBON, MD
  • Angers, France, 49033
    • Not yet recruiting
    • CHU d'Angers
    • Contact: Sylvain THEPOT, MD; Phone Number: +33 2 41 35 44 75; Email: sylvain.thepot@chu-angers.fr
    • Principal Investigator: Sylvain THEPOT, MD
  • Bobigny, France, 93009
    • Not yet recruiting
    • Hôpital Avicenne
    • Contact: Thorsten BRAUN, MD/PhD; Phone Number: +33 1 48 95 70 72; Email: thorsten.braun@aphp.fr
    • Principal Investigator: Thorsten BRAUN, MD/PhD
  • Grenoble, France, 38043
    • Not yet recruiting
    • CHU de Grenoble
    • Contact: Sophie PARK, MD/PhD; Phone Number: +33 4 76 76 62 77; Email: spark@chu-grenoble.fr
    • Principal Investigator: Sophie PARK, MD/PhD
  • Limoges, France, 87046
    • Not yet recruiting
    • CHRU de Limoges
    • Contact: Marie-Pierre GOURIN, MD; Phone Number: +33 5 55 05 66 42; Email: marie-pierre.gourin@chu-limoges.fr
    • Principal Investigator: Marie-Pierre GOURIN, MD
  • Marseille, France, 13273
    • Not yet recruiting
    • Institut Paoli Calmettes
    • Contact: Norbert VEY, MD/PhD; Phone Number: +33 4 91 22 36 95; Email: veyn@ipc.unicancer.fr
    • Principal Investigator: Norbert VEY, MD/PhD
  • Montpellier, France, 34295
    • Not yet recruiting
    • CHU DE MONTPELLIER - Hopital Saint Eloi
    • Contact: Franciane PAUL, MD; Phone Number: +33 4 67 33 22 54; Email: f-paul@chu-montpellier.fr
    • Principal Investigator: Franciane PAUL, MD
  • Nantes, France, 44093
    • Not yet recruiting
    • CHU Hôtel Dieu
    • Contact: Alice GARNIER, MD; Phone Number: +33 2 40 08 32 71; Email: alice.garnier@chu-nantes.fr
    • Principal Investigator: Alice GARNIER, MD
  • Nantes, France, 44277
    • Not yet recruiting
    • Hôpital privé du Confluent SAS
    • Contact: Jacques DELAUNAY, MD; Phone Number: +33 2 28 27 21 16; Email: Jacques.delaunay@groupeconfluent.fr
    • Principal Investigator: Jacques DELAUNAY, MD
  • Nice, France, 06200
    • Not yet recruiting
    • Hôpital Archet 1
    • Contact: Thomas CLUZEAU, MD/PhD; Phone Number: +33 4 92 03 58 39; Email: cluzeau.t@chu-nice.fr
    • Principal Investigator: Thomas CLUZEAU, MD/PhD
  • Paris, France, 75010
    • Recruiting
    • Hopital Saint Louis
    • Contact: Raphaël ITZYKSON, MD/PhD; Phone Number: +33 1 42 38 51 27; Email: raphael.itzykson@aphp.fr
    • Principal Investigator: Raphaël ITZYKSON, MD/PhD
  • Paris, France, 75014
    • Not yet recruiting
    • Hôpital COCHIN
    • Contact: Rudy BIRSEN, MD; Phone Number: +33 1 58 41 21 20; Email: rudy.birsen@aphp.fr
    • Principal Investigator: Rudy BIRSEN, MD
  • Pierre-Bénite, France, 69495
    • Not yet recruiting
    • Centre Hospitalier Lyon Sud
    • Contact: Maël HEIBLIG, MD; Phone Number: +33 4 78 86 22 34; Email: mael.heiblig@chu-lyon.fr
    • Principal Investigator: Maël HEIBLIG, MD
  • Poitiers, France, 86021
    • Not yet recruiting
    • CHU de Poitiers
    • Principal Investigator: Jose Miguel TORREGROSA DIAZ, MD
    • Contact: Jose Miguel TORREGROSA DIAZ, MD; Phone Number: +33 5 48 44 44 44; Email: jose-miguel.torregrosa-diaz@chu-poitiers.fr
  • Rennes, France, 35033
    • Not yet recruiting
    • Hôpital Pontchaillou
    • Principal Investigator: Stanislas NIMUBONA, MD
    • Contact: Stanislas NIMUBONA, MD; Phone Number: +33 2 99 28 95 21; Email: stanislas.nimubona@chu-rennes.fr
  • Rouen, France, 76038
    • Recruiting
    • Centre Henri Becquerel
    • Contact: Aspasia STAMATOULLAS, MD; Phone Number: +33 2 32 08 22 88; Email: aspasia.stamatoullas@chb.unicancer.fr
    • Principal Investigator: Aspasia STAMATOULLAS, MD
  • Toulouse, France, 31059
    • Not yet recruiting
    • IUCT Oncopole
    • Contact: Thibault COMONT, MD; Phone Number: +33 5 31 15 62 66; Email: comont.thibault@iuct-oncopole.fr
    • Principal Investigator: Thibault COMONT, MD
  • Tours, France, 37000
    • Not yet recruiting
    • CHU de Tours - Hôpital Bretonneau
    • Contact: Emmanuel GYAN, MD/PhD; Phone Number: +33 2 47 25 87 78; Email: emmanuel.gyan@univ-tours.fr
    • Principal Investigator: Emmanuel GYAN, MD/PhD
  • Villejuif, France, 94800
    • Not yet recruiting
    • Institut Gustave Roussy
    • Contact: Christophe WILLEKENS, MD; Phone Number: +33 1 42 11 23 79; Email: christophe.willekens@gustaveroussy.fr
    • Principal Investigator: Christophe WILLEKENS, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18 and older.
2. CMML diagnosis according to WHO 2016 criteria.
3. Intermediate-2 or high risk according to the CMML Prognostic Scoring System (CPSS) 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. In patients with failed or missing cytogenetics at screening, cytogenetics at CMML diagnosis will be used to compute CPSS.
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) for < 6 weeks is acceptable. No washout is necessary for those patients but pre-HY WBC will be taken in consideration for CPSS 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 at inclusion (WBC prior to HY used to compute CPSS at inclusion in HY-exposed patients) or with a CPSS 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: Venetoclax; Combination of Azacitidine and Venetoclax; Other Names: ABT-199

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete remission rate	Complete remission 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 (each cycle is 28 days)
Overall response rate at best response	Overall response (complete remission, partial remission, marrow response, clinical benefit) according to protocol-defined criteria modified from MDS/MPN IWG criteria at best response	through study completion, an average of 5 years
Overall response rate after 3 and 6 cycles of treatment	Overall response (complete remission, partial remission, marrow response, clinical benefit) according to the DACOTA trial response criteria after 3 and 6 cycles of treatment	after 3 and 6 cycles of treatment (each cycle is 28 days)
Duration of response	Duration of response defined as the time interval between the first date of achievement of any response according to MDS/MPN IWG criteria to progressive disease	through study completion, an average of 5 years
Identification and grading of adverse events	Safety profile, both hematological and non-hematological of treatment (Venetoclax combined with Azacitidine) including identification and grading of adverse events based on NCI CTCAE version 5.0	through study completion, an average of 5 years
Overall survival	Overall survival defined as the time from inclusion until death or end of follow-up	through study completion, an average of 5 years
Acute Myeloid Leukemia (AML)-free survival	AML-free survival defined as the time from inclusion to transformation to AML according to WHO 2016 criteria, death or end of follow-up, whichever occurs first	through study completion, an average of 5 years
Progression-free survival	Progression-free survival defined as the time from inclusion to progressive disease according to MDS/MPN IWG criteria, transformation to AML, death or end of follow-up, whichever occurs first	through study completion, an average of 5 years
Event-free survival	Event-free survival defined as the time from inclusion to failure to achieve any response according to MDS/MPN IWG criteria at the 6-cycle evaluation, occurence of progressive disease according to MDS/MPN IWG criteria, transformaion to AML, or death, whichever occurs first	through study completion, an average of 5 years
Cumulative incidence of AML and cumulative risk of death without AML	Cumulative incidence of AML and cumulative risk of death without AML, considering death and transformation to AML as competing risk	through study completion, an average of 5 years
Cumulative incidence of progressive disease or transformation to AML and cumulative risk of death without progression or AML	Cumulative incidence of progressive disease or transformation to AML and cumulative risk of death without progression or AML	through study completion, an average of 5 years
Rate of Hematopoietic Stem Cell Transplantation (HSCT)	Rate of Hematopoietic Stem Cell Transplantation (HSCT) and post-HSCT ovrall survival and AML-free survival	through study completion, an average of 5 years
Survival censoring at Hematopoietic Stem Cell Transplantation (HSCT)	Overall survival, AML-free survival and progressive-free survival censoring at Hematopoietic Stem Cell Transplantation (HSCT)	through study completion, an average of 5 years
Subsequent therapy	Rate and description of subsequent therapy	through study completion, an average of 5 years
Survival censoring to subsequent therapy	Overall survival, AML-free survival and progressive-free survival censoring at subsequent therapy	through study completion, an average of 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient reported outcomes	Patient reported outcomes according to the Myeloproliferative Neoplasm Safety Assessment Form Total Symptom Score which is a 10-item instrument designed to monitor clinically relevant symptoms among patients with myeloproliferative neoplasm. The score has possible range of 0 to 100.	through study completion, an average of 5 years
Exploratory endpoints	Biomarkers including somatic mutations by targeted sequencing and BH3 profiling CD34+ cells and monocytes	through study completion, an average of 5 years

Collaborators and Investigators

• Sponsor: Groupe Francophone des Myelodysplasies
• Collaborators: AbbVie
• Investigators: Principal Investigator: Raphaël ITZYKSON, MD/PhD, Hopital Saint Louis; Principal Investigator: Pierre FENAUX, MD/PhD, Hopital Saint Louis

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2023
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: February 23, 2023
• First Submitted That Met QC Criteria: March 3, 2023
• First Posted (Actual): March 14, 2023

Study Record Updates

• Last Update Posted (Actual): January 3, 2024
• Last Update Submitted That Met QC Criteria: January 2, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Venetoclax; Azacitidine; CMML
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid; Chronic Disease; Leukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: AVENHIR; 2021-002007-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No