Venetoclax + Azacitidine in Patients With Acute Myeloid Leukemia (VERDI)

Preemptive Treatment With Venetoclax Plus Azacitidine in Patients Diagnosed With Acute Myeloid Leukemia (AML) With Persistence or Reappearance of Measurable Residual Disease (MRD) After Frontline Chemotherapy and High-level MRD Prior to Allogeneic Hematopoietic Cell Transplantation (alloHCT)

The VERDI study is an investigator-initiated, multicenter, multicohort, phase II trial with combination of venetoclax + azacitidine for patients treated for AML under according to an intensive chemotherapy protocol (CETLAM-20) failing to achieve or maintain MRD negativity at pre-established time-points: at chemotherapy completion for ELN favorable subtypes, and prior to alloHCT for non-favorable European LeukemiaNet (ELN) AML patients.

The primary objective is to determine Ven/Aza treatment activity in MRD clearance in patients diagnosed with AML with persistent MRD or MRD reappearance after frontline chemotherapy, or prior to alloHCT.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Azacitidine (AZA); Drug: Venetoclax

Detailed Description

The trial will enroll competitively between 25 and 29 patients.

Patients will be recruited in two independent cohorts depending on the pre-established time point for the intervention and ELN risk subtype:

Cohort 1: Patients diagnosed with a favorable ELN subtype AML, not intended for alloHCT in first complete remission (CR1), but who present an MRD failure by after frontline intensive chemotherapy, as defined in the 2021 update on MRD guidelines elaborated by the European LeukemiaNet MRD Working Party (Heuser et al. 2023):

In patients with persistent low-level MRD (<2%) after consolidation chemotherapy, an increase of MRD ≥1log10 between 2 positive samples Confirmed MRD conversion of MRD negativity to MRD positivity AML during subsequent follow-up (up to 3 years after chemotherapy completion

Cohort 2: Patients diagnosed with a non-favorable ELN AML subtype, intended to undergo alloHCT, in first complete morphological remission but harboring detectable MRD at time of alloHCT (>0.1%).

• Study Type: Interventional
• Enrollment (Estimated): 29
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: A Responsible Person Designated by the sponsor; Phone Number: 0034934344412; Email: investigacio@mfar.net

Study Locations

• Spain
  • Balearic Islands
    • Palma de Mallorca, Balearic Islands, Spain, 07198
      • Recruiting
      • Hospital Son Llàtzer
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Antonia Cladera, M.D.; Ph.D.
    • Palma de Mallorca, Balearic Islands, Spain, 07120
      • Recruiting
      • University Hospital Son Espases
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Antonia Sampol, M.D.; Ph.D.
  • Catalonia
    • Badalona, Catalonia, Spain, 08916
      • Recruiting
      • Institut Catala d Oncologia Badalona
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Susana Vives, M.D.; Ph.D.
    • Barcelona, Catalonia, Spain, 08025
      • Recruiting
      • Hospital de la Santa Creu i Sant Pau
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Ana Garrido, M.D.; Ph.D.
    • Barcelona, Catalonia, Spain, 08036
      • Recruiting
      • Hospital Clínic de Barcelona
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Jordi Esteve, M.D.; Ph.D.
    • Barcelona, Catalonia, Spain, 08003
      • Recruiting
      • Hospital del Mar
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Sara García, M.D.; Ph.D.
    • Barcelona, Catalonia, Spain, 08035
      • Recruiting
      • Hospital Universitari Vall d Hebron
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Olga Salamero, M.D.; Ph.D.
    • Girona, Catalonia, Spain, 17007
      • Recruiting
      • Institut Catala D oncologia Girona
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Rosa Coll Jorda, M.D.; Ph.D.
    • L'Hospitalet de Llobregat, Catalonia, Spain, 08908
      • Recruiting
      • Institut Catala d Oncologia Hospitalet
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Montserrat Arnan, M.D.; Ph.D.
    • Lleida, Catalonia, Spain, 25196
      • Recruiting
      • Hospital Universitari Arnau De Vilanova De La Gerencia Territorial De Lleida
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Antonio García, M.D.; Ph.D.
    • Tarragona, Catalonia, Spain, 43005
      • Recruiting
      • Hospital Universitari Joan XXIII de Tarragona
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Luiz Andre Aguilar, M.D.; Ph.D.
    • Terrassa, Catalonia, Spain, 08221
      • Recruiting
      • Fundacio Assistencial De Mutua De Terrassa
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Ferran Vall-Llovera, M.D.; Ph.D.
  • Madrid
    • Madrid, Madrid, Spain, 28009
      • Recruiting
      • Hospital General Universitario Gregorio Marañon
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Mi Kwon, M.D.; Ph.D.
  • Valencia
    • Valencia, Valencia, Spain, 46010
      • Recruiting
      • Hospital Clínico Universitario de Valencia
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: Mar Tormo, M.D.; Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must have confirmation of with acute myeloid leukemia (AML) with persistent measurable residual disease (MRD) or MRD reappearance after frontline intensive chemotherapy (including at least one cycle of cytarabine and anthracycline), and prior to allogeneic hematopoietic cell transplantation (allo-HCT).

   1. In patients with NPM1 mutation, qRT-PCR of NPM1 will be the method used to establish a molecular failure, defined as failure to achieve molecular response after consolidation therapy (NPM1mut/ABL1·100 > 0.1) or MRD reappearance after molecular response. All cases of molecular failure must be confirmed with a second MRD assessment in 2 to 4 weeks.
   2. In patients with core-binding factor AML, qRT-BCR of RUNX1-RUNX1T1 and CBFb-MYH11 transcripts will be used. Patients failing to achieve a major MRD reduction after consolidation therapy (i.e., RUNX1-RUNX1T1/ABL1·100>0.1 or CBFb-MYH11/ABL1·100>0.1), a log increase in MRD between two positive samples or confirmed MRD reappearance after molecular response will be considered as molecular failures and could be included in the trial.
   3. In the remaining cases, an appropriate leukemia-associated immunophenotype (LAIP) measured by multiparameter flow cytometry will be used for MRD surveillance. A cutoff of 0.1% will be used to define MRD positivity.
2. Age ≥18 years.
3. Without clinical signs of active central nervous system disease.
4. Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance status of ≤2 or Karnofsky performance status (KPS) equivalent.
5. Patients must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula.

6. Patients must have adequate liver function as demonstrated by:

   1. aspartate aminotransferase (AST) ≤ 3.0 × upper limit normal (ULN)
   2. alanine aminotransferase (ALT) ≤ 3.0 × ULN
   3. bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome
7. Non-sterile male patients must use contraceptive methods with partner(s) prior to beginning study drug administration and continuing up to 3 months after the last dose of study drug. Male patients must agree to refrain from sperm donation from initial study drug administration until 3 months after the last dose of study drug.
8. WOCBP must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting therapy; 2) throughout the entire duration of treatment; 3) during dose interruptions; and 4) for at least 6 months after discontinuation of therapy (last dose of study drug).
9. Patients must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any research directed screening procedures.

Exclusion Criteria:

1. Patient has received other prior rescue treatment for MRD.

2. Patient is known to be positive for Human immunodeficiency virus (HIV) infection with the exception of those with an undetectable viral load under correct virological control throughout the study.

   Note: HIV testing is not required.

3. Patient is known to be positive for hepatitis B (HBV) or C (HCV) infection with the exception of those with an undetectable viral load.

   Note: Hepatitis B or C testing is not required and patients with serologic evidence of prior vaccination to HBV (i.e., HBsAg-, anti-HBs+ and anti-HBc-) may participate.

4. Patient has known active central nervous system (CNS) involvement from AML.
5. Patient has received within 7 days prior to the first dose of study drug: steroid therapy ≥ 20 mg/day (prednisone or equivalent) for antineoplastic intent; strong and moderate CYP3A inhibitors; strong and moderate CYP3A inducers.
6. Patient has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment.

7. Patient has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to:

   1. New York Heart Association heart failure > class 2.
   2. Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia.
8. Patient has a malabsorption syndrome or other condition that precludes the enteral route of administration.
9. Patient exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal).

10. Patient has a history of other malignancies within the prior year to study entry, except for:

    1. Adequately treated in situ carcinoma of the breast or cervix uteri.
    2. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin.
    3. Prostate cancer with no plans for therapy of any kind.
    4. Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
11. Pregnant and breastfeeding females.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Patients diagnosed with a favorable ELN subtype AML, not intended for alloHCT in CR1, but who present an MRD failure by after frontline intensive chemotherapy, as defined in the 2021 update on MRD guidelines elaborated by the European LeukemiaNet MRD Working Party (Heuser et al. 2021)	Drug: Azacitidine (AZA); Dosing is 75 mg/m2 x 7 days (Q28days) After 2 courses, a first decision-making for allo-HCT based on bone marrow MRD assessment will be performed. After 4th course, a new MRD assessment will be performed. For cohort 1 treatment may continue up to cycle 12 (prioritized over allo-HCT). For cohort 2 treatment may continue up to cycle 24 (prioritizing allo-HCT); Drug: Venetoclax; Dosing: 400 mg daily After 2 courses, a first decision-making for allo-HCT based on bone marrow MRD assessment will be performed. After 4th course, a new MRD assessment will be performed. For cohort 1 treatment may continue up to cycle 12 (prioritized over allo-HCT). For cohort 2 treatment may continue up to cycle 24 (prioritizing allo-HCT)
Experimental: Cohort 2; Patients diagnosed with a non-favorable ELN AML subtype, intended to undergo alloHCT, in first complete morphological remission but harboring detectable MRD at time of alloHCT (>0.1%)	Drug: Azacitidine (AZA); Dosing is 75 mg/m2 x 7 days (Q28days) After 2 courses, a first decision-making for allo-HCT based on bone marrow MRD assessment will be performed. After 4th course, a new MRD assessment will be performed. For cohort 1 treatment may continue up to cycle 12 (prioritized over allo-HCT). For cohort 2 treatment may continue up to cycle 24 (prioritizing allo-HCT); Drug: Venetoclax; Dosing: 400 mg daily After 2 courses, a first decision-making for allo-HCT based on bone marrow MRD assessment will be performed. After 4th course, a new MRD assessment will be performed. For cohort 1 treatment may continue up to cycle 12 (prioritized over allo-HCT). For cohort 2 treatment may continue up to cycle 24 (prioritizing allo-HCT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of MRD conversion after 2 to 4 courses of study treatment	Defined as the percentage of patients who achieve MRD clearance after 2-4 courses of study treatment. Failure to achieve MRD negativity after 4 courses will be considered a treatment failure.	After the administration of 2 and 4 cycles (i.e. approximately 2 and 4 months after. Throughout the study period (up to 3 years) the initiation of study treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of MRD response	Defined as the time elapsed from the first obtention of MRD clearance until MRD progression. Confirmed MRD conversion from MRD negativity to MRD positivity will be performed during subsequent follow-up.	Throughout the study period, up to 3 years after chemotherapy completion. Throughout the study period (up to 3 years)
Relapse risk after intervention	Defined as the time elapsed from the intervention for AML until confirmed hematological relapse.	Throughout the study period, up to 3 years after chemotherapy completion. Throughout the study period (up to 3 years)
Safety profile	Incidence of Treatment-Emergent Adverse Events Percentage of patients experiencing treatment-related adverse events (AEs).	Throughout the study period, up to 3 years after chemotherapy completion. Throughout the study period (up to 3 years)
Treatment Compliance	Percentage of patients experiencing AEs that lead to dose modifications, including treatment interruption, delays and dose reductions.	Throughout the study period, up to 3 years after chemotherapy completion. Throughout the study period (up to 3 years)

Collaborators and Investigators

• Sponsor: Grupo Cooperativo de Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias
• Investigators: Study Chair: Jordi Esteve, M.D.; Ph.D., Hematology department Institute Clínic of Hematological and Oncological diseases (ICMHO) Hospital Clínic of Barcelona

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2024
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: October 29, 2024
• First Submitted That Met QC Criteria: October 30, 2024
• First Posted (Actual): October 31, 2024

Study Record Updates

• Last Update Posted (Estimated): September 19, 2025
• Last Update Submitted That Met QC Criteria: September 15, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: venetoclax; azacitidine; measurable residual disease (MRD); allogeneic hematopoietic cell transplantation (alloHCT)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Neoplastic Processes; Leukemia, Myeloid; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Neoplasm, Residual; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; venetoclax
• Other Study ID Numbers: CETLAM-LMA-AC-2024-01; 2024-510648-29-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: To protect confidentiality of patients the IPD will be restricted and only shared upon reasonable request if the purposes of this request complies with the conditions agreed with patients consent.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No