A study to compare Venetoclax Azacitidine and Quizartinib Vs Venetoclax and Azacitidine in newly diagnosed acute myeloid leukemia patient´s ineligible for standard induction chemotherapy

Prior treatment

• Prior treatment with any investigational drug or device within 14 days prior to Randomization (within 2 weeks for investigational or approved immunotherapy) or currently participating in other investigational interventional procedures.
• Prior therapy for AML (except hydroxiurea, or maximum 1 gram/sqm per 2 days of cytarabine allowed to control hyperleukocytosis during the screening period).
• Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade-containing Seville oranges), or star fruit within 3 days before anticipated first dose of Venetoclax and must consent not to consume through the last dose of Venetoclax.
• Subject has received prior treatment with hypomethylating agent, FLT3 or BCL2 inhibitors.
• Treated (excluding surgery or hormone-therapy) for another malignancy within 6 months before randomization or previously diagnosed with another malignancy and have any evidence of disease which may compromise the administration of investigational treatment schedule.

Other illness

• Contraindications for Azacitidine, Quizartinib or Venetoclax (such as history of hypersensitivity to any excipients in Azacitidine, Quizartinib, or Venetoclax).
• Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy at physician discretion.
• Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C)
• Known history of human immunodeficiency virus (HIV).
• Presence of any severe psychiatric disease or physical condition that, according to the physician´s criteria, contraindicates the inclusion of the patient into the clinical trial.

Lab values

• Known uncontrolled or significant cardiovascular disease, including any of the following: a) Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker; b) QTcF interval >450 msec in males, >470 in female patients; c) Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome); d) Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg; e) History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes); f) History of second (Mobitz II) or third degree heart block (subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker); g) History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening; h) History of New York Heart Association Class 3 or 4 heart failure; i) Known history of LVEF ≤45%; j) Complete left bundle branch block; k) Severe aortic stenosis
• Confirmed diagnosis of prior myelodysplastic syndrome (MDS) or a myeloproliferative neoplasm (MPN) or MDS/MPNs including CMML, aCML, JMML and others. This exclusion criterion will not be applicable to patients with with FLT3 (allelic ratio >0.03) or NPM1 mutations (as per technical sensitivity threshold of local and/or central laboratory), who can be enrolled.
• Serum creatinine ≥ 2.5 mg/dL or creatinine clearance < 30 mL/min (unless it is attributable to AML activity).
• Bilirubin >1.5 times, SGPT or SGOT > 3 times the upper normal limit (unless it is attributable to AML activity).
• WBC >25 x 109/L before randomization.

Age

• Age <18 years old at screening.

Other

• Known central nervous system (CNS) active leukemia, including cerebrospinal fluid positive for AML blasts.
• Uncorrected Grade 3 or 4 hypokalemia, hypomagnesemia or hypocalcemia (Subjects with Grade 1 or 2 electrolyte abnormalities can be enrolled while electrolytes are being corrected).
• Uncontrolled hypothyroidism.
• Genetic diagnosis of acute promyelocytic leukemia.

• The subject must have confirmation of AML by 2022 WHO criteria, previously untreated and be ineligible for treatment with a standard cytarabine and anthracycline based induction regimen due to age and/or comorbidities.
• Patients must be considered ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age or co-morbidities defined by the following criteria: - ≥ 75 years of age; - or ≥ 18 to 75 years of age with at least one of the following co-morbidities: • ECOG Performance Status of 2 or 3; • Cardiac history of cardiac heart failure (CHF) requiring treatment or left ventricular ejection fraction (LVEF) >45% and ≤ 55% or chronic stable angina. • DLCO ≤ 65% or FEV1 ≤ 65% and/or significant history of chronic pulmonary obstructive; • Creatinine clearance ≥ 30 mL/min to < 50 ml/min (see Appendix 7); • Moderate hepatic impairment with total bilirubin, SGPT or SGOT > 1.5 to ≤ 3.0 × ULN; • Non active/controlled prior neoplastic disease; • Any other patient´s comorbidity or disease condition that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Clinical Trial Coordinator before study enrollment (e.g, prior neoplastic disease, high-risk cytogenetics). All patients aged less than 60 years old must be reviewed and approved by Clinical Trial Coordinator before study enrollment.
• ECOG performance status ≤2 for patients >75 years, ≤3 for patients ≥ 60 to 75 years of age.
• Male subjects who are sexually active, must agree, from Study Day 1 through at least 120 days after the last dose of study drug, to practice the protocol specified contraception (see Section 7.9).
• Female subjects must be either postmenopausal for at least 1 year before screening OR permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) or Women of Childbearing Potential (WOCBP) must agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 7 months after the last dose of study drug (female and male condoms should not be used together), or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception). Female subjects of childbearing potential must have negative results for pregnancy test performed and must not be lactating and breastfeeding.
• Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.