Venetoclax plus azacitidine versus standard intensive chemotherapy for patients with newly diagnosed acute myeloid leukemia (AML) and NPM1 mutations eligible for intensive treatment (VINCENT)

Prior treatment

• Inability to swallow oral medications
• Cardiovascular disability status of New York Heart Association (NYHA) Class ≥ 2, unstable coronary artery disease (MI more than 6 months prior to study entry is permitted); serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy (Note: Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain).
• AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment
• Previous treatment with HMA or venetoclax
• Previous treatment for AML except hydroxyurea
• Cumulative previous exposure to anthracyclines of > 200 mg/m2 doxorubicin equivalents

Other illness

• Any malabsorption condition
• Prior history of malignancy, other than MDS, unless the subject has been free of the disease for equal to or greater than 1 year prior to start of study treatment (exceptions are basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or of the breast, incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis clinical staging system))
• CNS involvement or extramedullary disease only
• Known hypersensitivity to excipients of the preparation or any agent given in association with this study including venetoclax, azacitidine, cytarabine, daunorubicin, gemtuzumab-ozogamicin, or mitoxantrone

Lab values

• Known positivity for human immunodeficiency virus (HIV), and history of active or chronic infectious hepatitis unless serology demonstrates clearance of infection (i.e. PCR undetectable viral load for hepatitis).

Other

• Activating FLT3 mutation
• Relapsed or refractory AML

• Signed informed consent
• Newly diagnosed CD33-positive AML with NPM1 mutation according to WHO criteria
• Age 18-70 years
• Fit for intensive chemotherapy, defined by: 1. ECOG 0-2 2. Adequate hepatic function: ALAT/ASAT/Bilirubin ≤ 2.5 x ULN unless considered due to leukemic organ involvement (Note: Subjects with Gilbert's Syndrome may have a bilirubin > 2.5 × ULN per discussion between the investigator and Coordinating investigator.) 3. Adequate renal function assessed by serum creatinine ≤ 1.5x ULN OR creatinine clearance (by Cockcroft Gault formula) ≥ 50 mL/min
• WBC < 25 x 109/L (<25,000/µL) (Note: Prior hydroxyurea is permitted to meet this criterion.)
• Ability to understand and the willingness to sign a written informed consent.
• Male subjects must agree to refrain from unprotected sex and sperm donation from time point of signing the informed consent until 7 months after the last dose of study drug.
• Women of childbearing potential must have a negative serum pregnancy test performed within 72 hours before first dose of study drug.