Clinical Trial to Assess the Safety and Tolerability of the Combination of Low-dose Cytarabine or Azacitidine Plus Venetoclax and Quizartinib in Newly Diagnosed AML Patients Aged Equal or More Than 60 Years Old

Inclusion Criteria:

1. Newly diagnosed AML.
2. Morphological diagnosis of AML (WHO criteria 2008).
3. Patient must be considered be ineligible for treatment with a standard cytarabine andanthracycline induction regimen due to age or co-morbidities defined by the followingcriteria: 3.1. ≥ 71 years of age; 3.2. ≥ 60 to 70 years of age with at least one ofthe following co-morbidities:

• ECOG Performance Status of 2 or 3;
• Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 55% or chronicstable angina;
• DLCO ≤ 65% or FEV1 ≤ 65% or significant history of chronic pulmonary obstructive;
• Creatinine clearance ≥ 30 mL/min to < 50 ml/min
• 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 tobe incompatible with intensive chemotherapy must be reviewed and approved by theTrial Coordinators before study enrollment (e.g, prior MDS or MPS, high-riskcytogenetics)

4. ECOG performance status ≤ 3.
5. 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 specifiedcontraception (see Section 0).
6. Female subjects must be either postmenopausal for at least 1 year before screening ORpermanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy orhysterectomy) OR Women of Childbearing Potential (WOCBP) must agree to practice 1highly effective method and 1 additional effective (barrier) method of contraception,at the same time, from the time of signing the informed consent through 4 months afterthe last dose of study drug (female and male condoms should not be used together), orAgree to practice true abstinence, when this is in line with the preferred and usuallifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,symptothermal, postovulation methods] withdrawal, spermicides only, and lactationalamenorrhea are not acceptable methods of contraception). Female subjects ofchildbearing potential must have negative results for pregnancy test performed andmust not be lactating and breastfeeding.
7. Subject must voluntarily sign and date an informed consent, approved by an IndependentEthics Committee (IEC) prior to the initiation of any screening or study specificprocedures, with the understanding that consent may be withdrawn by the patient at anytime without prejudice to future medical care.

Exclusion Criteria:

1. Age <60 years.
2. Genetic diagnosis of acute promyelocytic leukemia.
3. Treated (excluding surgery or hormone-therapy) for another malignancy within 6 monthsbefore randomization or previously diagnosed with another malignancy and have anyevidence of disease which may compromise the administration of investigationaltreatment schedule.
4. Presence of any severe psychiatric disease or physical condition that, according tothe physician´s criteria, contraindicates the inclusion of the patient into theclinical trial.
5. Serum creatinine ≥ 2.5 mg/dL or creatinine clearance < 30 mL/min (unless it isattributable to AML activity).
6. Bilirubin, SGPT or SGOT > 3 times the upper normal limit (unless it is attributable toAML activity).
7. WBC> 50 x 109/L. Subject should have white blood cell count <50 × 109/L beforestarting therapy. Patients who are cytoreduced with leukapheresis or with hydroxyureamay be enrolled if they meet the eligibility criteria before starting therapy.
8. Contraindications for Quizartinib or Venetoclax.
9. History of known CNS leukemia, including cerebrospinal fluid positive for AML blasts.
10. Prior treatment with any investigational drug or device within 30 days prior toRandomization (within 2 weeks for investigational or approved immunotherapy) orcurrently participating in other investigational procedures
11. Prior treatment with other FLT3-ITD or BCL-2 inhibitors.
12. Known uncontrolled or significant cardiovascular disease, including any of thefollowing:
13. Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker;
14. QTcF interval >450 msec;
15. Diagnosis of or suspicion of long QT syndrome (including family history of longQT syndrome);
16. Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg;
17. History of clinically relevant ventricular arrhythmias (eg, ventriculartachycardia, ventricular fibrillation, or Torsade de Pointes);
18. History of second (Mobitz II) or third degree heart block (subjects withpacemakers are eligible if they have no history of fainting or clinicallyrelevant arrhythmias while using the pacemaker);
19. History of uncontrolled angina pectoris or myocardial infarction within 6 monthsprior to Screening;
20. History of New York Heart Association Class 3 or 4 heart failure;
21. Known history of left ventricular ejection fraction (LVEF) ≤45% or less than theinstitutional lower limit of normal;
22. Complete left bundle branch block;
23. Prior therapy for AML (except hydroxiurea).
24. Subject enrolling into a dose-escalation cohort must not have received a known strongor moderate inducer or inhibitor of cytochrome P450 (CYP) 3A within 7 days before thefirst Quizartinib or Venetoclax dose. Subject enrolling into a safety expansion cohortmust not have received a known strong or moderate inducer or strong inhibitor of CYP3Awithin 7 days before the first Quizartinib or Venetoclax dose.
25. Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade-containing Seville oranges), or star fruit within 3 days beforeanticipated first dose of Venetoclax and must consent not to consume through the lastdose of Venetoclax.
26. Active acute or chronic systemic fungal, bacterial, or viral infection not wellcontrolled by antifungal, antibacterial or antiviral therapy at physician discretion;
27. Known active clinically relevant liver disease (eg, active hepatitis B, or activehepatitis C)
28. Known history of human immunodeficiency virus (HIV).
29. History of hypersensitivity to any excipients in the Quizartinib, Venetoclax or otherstudy medication.
30. Non mutated FLT3-ITD subjects will be considered ineligible during the randomizedPhase II after 48 non mutated FLT3-ITD subjects have been randomized.