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

A phase I-II trial based on the combination of three drugs regimen LDAC or Azacitidine + Venetoclax + Quizartinib that in this population could be well tolerated by a sequential type administration. The first objective is to achieve rapid control of the disease, using two different schemes, one based in Azacitidine and the other in LDAC, by dose escalation in phase I of the trial. The second goal is to prevent relapse through a maintenance schedule. Phase II will study the efficacy and safety of the recommended dose for Phase II

The prognosis of AML in elderly patients remain very poor and without significant advances in last decades. AML is a heterogeneous disease in which many altered molecular pathways could contribute to the disease. Thus, curative approaches have been based on highly eradicating regimens using high-dose chemotherapy. However, the low rate of CRs and the high rate of deaths due to toxicity and relapses in elderly patients should stimulate the development of new regimens that overcome these therapeutic obstacles. In recent years, there are a series of new drugs under development that allow the design of sequential combination therapies in this vulnerable population. These drugs have an acceptable toxicity profile and are apparently effective in monotherapy or even in combination, being able to improve the CR rate in this population. The investigators hypothesize that the combination of two targeted drugs that have different mechanisms of action could be capable of breaking the viability of leukemic cells as well as their proliferative qualities, and therefore prolong survival. In this way, the combined action of a pro-apoptotic agent (Venetoclax) and an antiproliferative agent (Quizartinib) could produce a powerful antileukemic effect, preventing the adaptive escape mechanisms of leukemic cells. The investigators have designed a phase I-II trial based on the combination of three drugs regimen LDAC or Azacitidine + Venetoclax + Quizartinib that in this population could be well tolerated by a sequential type administration. The first objective is to achieve rapid control of the disease, using two different schemes, one based in Azacitidine and the other in LDAC, by dose escalation in phase I of the trial. The second goal is to prevent relapse through a maintenance schedule. Phase II will study the efficacy and safety of the recommended dose for Phase II.

Eligibility Criteria:
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 and anthracycline induction regimen due to age or co-morbidities defined by the following criteria: 3.1. ≥ 71 years of age; 3.2. ≥ 60 to 70 years of age with at least one of the following co-morbidities:

   * ECOG Performance Status of 2 or 3;
   * Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 55% or chronic stable 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 to be incompatible with intensive chemotherapy must be reviewed and approved by the Trial Coordinators before study enrollment (e.g, prior MDS or MPS, high-risk cytogenetics)
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 specified contraception (see Section 0).
6. 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 4 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.
7. Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC) 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.

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 months before randomization or previously diagnosed with another malignancy and have any evidence of disease which may compromise the administration of investigational treatment schedule.
4. 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.
5. Serum creatinine ≥ 2.5 mg/dL or creatinine clearance \< 30 mL/min (unless it is attributable to AML activity).
6. Bilirubin, SGPT or SGOT \> 3 times the upper normal limit (unless it is attributable to AML activity).
7. WBC\> 50 x 109/L. Subject should have white blood cell count \<50 × 109/L before starting therapy. Patients who are cytoreduced with leukapheresis or with hydroxyurea may 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 to Randomization (within 2 weeks for investigational or approved immunotherapy) or currently 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 the following:

    1. Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker;
    2. QTcF interval \>450 msec;
    3. Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome);
    4. Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg;
    5. History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes);
    6. 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);
    7. History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening;
    8. History of New York Heart Association Class 3 or 4 heart failure;
    9. Known history of left ventricular ejection fraction (LVEF) ≤45% or less than the institutional lower limit of normal;
    10. Complete left bundle branch block;
13. Prior therapy for AML (except hydroxiurea).
14. Subject enrolling into a dose-escalation cohort must not have received a known strong or moderate inducer or inhibitor of cytochrome P450 (CYP) 3A within 7 days before the first Quizartinib or Venetoclax dose. Subject enrolling into a safety expansion cohort must not have received a known strong or moderate inducer or strong inhibitor of CYP3A within 7 days before the first Quizartinib or Venetoclax dose.
15. 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.
16. Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy at physician discretion;
17. Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C)
18. Known history of human immunodeficiency virus (HIV).
19. History of hypersensitivity to any excipients in the Quizartinib, Venetoclax or other study medication.
20. Non mutated FLT3-ITD subjects will be considered ineligible during the randomized Phase II after 48 non mutated FLT3-ITD subjects have been randomized.