Combining venetoclax and azacitidine for treating acute myeloid leukemia

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)

This study is testing if combining the drugs venetoclax and azacitidine can help patients with acute myeloid leukemia clear leftover cancer cells after chemotherapy.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 29 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Grupo Cooperativo de Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias (other)
• Drugs / interventions: chemotherapy, prednisone
• Locations: 14 sites (Palma de Mallorca, Balearic Islands and 13 other locations)
• Trial ID: NCT06668558 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the effectiveness of a combination treatment using venetoclax and azacitidine in patients with acute myeloid leukemia (AML) who have measurable residual disease (MRD) after intensive chemotherapy. The trial is divided into two cohorts: one for patients with favorable ELN subtypes not intended for allogeneic hematopoietic cell transplantation (alloHCT) and another for those with non-favorable subtypes preparing for alloHCT. The primary goal is to assess the ability of this treatment to clear MRD in these patients. A total of 25 to 29 patients will be enrolled across multiple centers in Spain.

Who should consider this trial

Good fit: Ideal candidates include AML patients with persistent MRD or MRD reappearance after frontline chemotherapy, specifically those with favorable or non-favorable ELN subtypes.

Not a fit: Patients who have achieved MRD negativity after initial treatment or those with advanced stages of AML may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could improve MRD clearance in AML patients, potentially leading to better outcomes and increased chances of remission.

How similar studies have performed: While this approach is innovative, similar studies have shown promise in targeting MRD in AML, indicating potential for success.

Eligibility criteria

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.

Where this trial is running

Palma de Mallorca, Balearic Islands and 13 other locations

• University Hospital Son Espases — Palma de Mallorca, Balearic Islands, Spain (RECRUITING)
• Hospital Son Llatzer — Palma de Mallorca, Balearic Islands, Spain (RECRUITING)
• Institut Catala D oncologia Badalona — Badalona, Catalonia, Spain (RECRUITING)
• Hospital Del Mar — Barcelona, Catalonia, Spain (RECRUITING)
• Hospital De La Santa Creu I Sant Pau — Barcelona, Catalonia, Spain (RECRUITING)
• Hospital Universitari Vall D Hebron — Barcelona, Catalonia, Spain (RECRUITING)
• Hospital Clinic De Barcelona — Barcelona, Catalonia, Spain (RECRUITING)
• Institut Catala D oncologia Girona — Girona, Catalonia, Spain (RECRUITING)
• Institut Catala D oncologia Hospitalet — L'Hospitalet de Llobregat, Catalonia, Spain (RECRUITING)
• Hospital Universitari Arnau De Vilanova De La Gerencia Territorial De Lleida — Lleida, Catalonia, Spain (RECRUITING)
• Hospital Universitari Joan XXIII De Tarragona — Tarragona, Catalonia, Spain (RECRUITING)
• Fundacio Assistencial De Mutua De Terrassa — Terrassa, Catalonia, Spain (RECRUITING)
• Hospital General Universitario Gregorio Maranon — Madrid, Madrid, Spain (RECRUITING)
• Hospital Clinico Universitario De Valencia — Valencia, Valencia, Spain (RECRUITING)

Study contacts

• Study coordinator: A responsible person Designated by the sponsor

Conditions: Acute Myeloid Leukemia, venetoclax, azacitidine, measurable residual disease, allogeneic hematopoietic cell transplantation