Venetoclax + Azacitidine in Patients with Acute Myeloid Leukemia

Phase 2

Not yet recruiting

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: Azacitidine (AZA); Drug: Venetoclax

• Registration Number: NCT06668558
• Lead Sponsor: Grupo Cooperativo de Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias

Brief Summary

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, ...

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:
...

Basic Information
|
Recruitment & Eligibility
|
Study & Design
|
Trial Locations

Study Timeline

• Status Verified: 2024-10
• Study Start: 2024-10
• Study First Submitted: 2024-10-29
• Study First Submitted QC: 2024-10-30
• Last Update Submitted: 2024-10-30
• Study First Posted: 2024-10-31
• Last Update Posted: 2024-10-31
• Primary Completion: 2028-06
• Study Completion: 2028-07

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 29

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 > 0.01) 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.

Read More

Exclusion Criteria

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

2. Patient is known to be positive for Human immunodeficiency virus (HIV). 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.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1	Azacitidine (AZA)	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)
Cohort 1	Venetoclax	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)
Cohort 2	Azacitidine (AZA)	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%)
Cohort 2	Venetoclax	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%)

Primary Outcome Measures

Name	Time	Method
Rate of MRD conversion after 2 to 4 courses of study treatment	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)	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.

Secondary Outcome Measures

Name	Time	Method
Duration of MRD response	Throughout the study period, up to 3 years after chemotherapy completion. Throughout the study period (up to 3 years)	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.
Relapse risk after intervention	Throughout the study period, up to 3 years after chemotherapy completion. Throughout the study period (up to 3 years)	Defined as the time elapsed from the intervention for AML until confirmed hematological relapse.
Safety profile	Throughout the study period, up to 3 years after chemotherapy completion. Throughout the study period (up to 3 years)	Incidence of Treatment-Emergent Adverse Events Percentage of patients experiencing treatment-related adverse events (AEs).
Treatment Compliance	Throughout the study period, up to 3 years after chemotherapy completion. Throughout the study period (up to 3 years)	Percentage of patients experiencing AEs that lead to dose modifications, including treatment interruption, delays and dose reductions.

Trial Locations

Locations (14)

University Hospital Son Espases; 🇪🇸 Palma de Mallorca, Baleares, Spain

Hospital Son Llatzer; 🇪🇸 Palma de Mallorca, Baleares, Spain

Institut Catala D oncologia Badalona; 🇪🇸 Badalona, Cataluña, Spain

Hospital Del Mar; 🇪🇸 Barcelona, Cataluña, Spain

Hospital De La Santa Creu I Sant Pau; 🇪🇸 Barcelona, Cataluña, Spain

Hospital Universitari Vall D Hebron; 🇪🇸 Barcelona, Cataluña, Spain

Hospital Clinic De Barcelona; 🇪🇸 Barcelona, Cataluña, Spain

Institut Catala D oncologia Girona; 🇪🇸 Girona, Cataluña, Spain

Institut Catala D oncologia Hospitalet; 🇪🇸 Hospitalet de Llobregat, Cataluña, Spain

Hospital Universitari Arnau De Vilanova De La Gerencia Territorial De Lleida; 🇪🇸 Lleida, Cataluña, Spain

Hospital Universitari Joan XXIII De Tarragona; 🇪🇸 Tarragona, Cataluña, Spain

Fundacio Assistencial De Mutua De Terrassa; 🇪🇸 Terrassa, Cataluña, Spain

Hospital General Universitario Gregorio Maranon; 🇪🇸 Madrid, Comunidad Autónoma de Madrid, Spain

Hospital Clinico Universitario De Valencia; 🇪🇸 Valencia, Comunitat Valenciana, Spain