Randomized phase II trial to compare the efficacy and safety of standard chemotherapy plus quizartinib versus standard chemotherapy plus placebo in adult patients with newly diagnosed FLT3 wild-type Acute Myeloid Leukemia

Multicenter, prospective, randomized, placebo-controlled, double-blinded phase II trial to assess the efficacy and safety of an oral quizartinib vs. placebo containing front-line chemotherapy-based schedule in FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) wild-type Acute Myeloid Leukemia patients.

The trial will be conducted in two phases:

An open-label safety run-in phase: Cytarabine 200 mg/m2 (days 1-7), Idarubicin 12 mg/m2 (days 1-3) Quizartinib 60 mg/d x 14 days (30mg with strong Cytochrome P450 Family 3 Subfamily A (CYP3A) inhibitor) in a total of 9 patients, being observed during 1 cycle of induction to define the final dose for the randomized phase.

A randomized double-blinded phase 2:1 quizartinib (at the established dose) vs. placebo.

Experimental Arm: Cytarabine 200 mg/m2 (days 1-7), Idarubicin 12 mg/m2 (days 1-3) Quizartinib 60 mg/d x 14 days (30mg with strong CYP3A inhibitor) Standard Arm: Cytarabine 200 mg/m2 (days 1-7), Idarubicin 12 mg/m2 (days 1-3) Placebo 60 mg/d x 14 days (30mg with strong CYP3A inhibitor)

272 patients will be included in this phase.

Inclusion Criteria:

1. Written informed consent in accordance with national, local, and institutional guidelines. The patient must provide informed consent before the first screening procedure. The patient and the investigator must sign informed consent form.
2. Diagnosis of untreated AML (according to the World Health Organization (WHO) 2008/2016 definition)
3. Age ≥ 18 and ≤70 years old at the time of screening
4. Non-FLT3-ITD (allelic ratio <0.03) at diagnosis
5. Considered eligible to receive intensive chemotherapy as per investigator judgment
6. Eastern Cooperative Oncology Group (ECOG) 0-2
7. No contraindications for quizartinib
8. The subject is receiving standard "7+3" induction chemotherapy regimen as specified in the protocol
9. No severe organ function abnormalities
10. Not included in other first-line trials
11. Cardiac ejection fraction ≥ 45% assessed by echocardiography or multiple-gated acquisition (MUGA).
12. Female patients of child-bearing potential must have a negative serum pregnancy test at screening and agree to use reliable methods of contraception upon enrollment, during the treatment period and for 3 months following the last dose of investigational drug or cytarabine, whichever is later
13. Male patients must use a reliable method of contraception (if sexually active with a female of child-bearing potential) upon enrollment, during the treatment period, and for 3 months following the last dose of investigational drug or cytarabine, whichever is later
14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

1. Patients with a genetic diagnosis of acute promyelocytic leukemia

2. Age <18 years or >70 years

3. ECOG performance status of 3 or 4

4. Prior treatment for AML, except for the following allowances:

   c) Leukapheresis d) Treatment for hyperleukocytosis with hydroxyurea

5. Blastic phase of bcr/abl chronic myeloid leukemia.

6. Presence of an associated active and/or uncontrolled malignancy:

   - Patients with another neoplastic disease, for whom the Investigator has a clinical suspicion of active disease at the time of enrollment. Note: Patients with adequately treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia are eligible for this study. Hormonal or adjuvant therapies will be allowed for breast cancer or prostate cancer as long as they are on a stable dose for at least 2 weeks before the first dose.

7. Known active and not controlled hepatitis B or hepatitis C infection. In the event of a positive viral load, please consult with the Sponsor

8. Known human immunodeficiency virus (HIV) infection (HIV testing is not required as part of this study)

9. 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

10. Serum creatinine ≥ 250 μmol/l (≥ 2.5 mg/dL) (unless it is attributable to AML activity)

11. Bilirubin, alkaline phosphatase, or Serum glutamic oxaloacetic transaminase (SGOT) > 3 times the normal upper limit (unless it is attributable to AML activity)

12. Uncontrolled or significant cardiovascular disease, including any of the following:

    1. Symptomatic bradycardia of fewer than 50 beats per minute, unless the subject has a pacemaker;
    2. QT Comparison of Fridericia's (QTcF) >450 msec at Screening. Note: QTcF will be derived from the mean of triplicate readings;
    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 (e.g., ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes)
    6. History of a 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. An ejection fraction <45%
    8. History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening
    9. History of New York Heart Association Class 3 or 4 heart failure
    10. Right bundle branch and left anterior hemiblock (bifascicular block), complete left bundle branch block

13. History of hypersensitivity to any excipients in the quizartinib/placebo tablets

14. Females who are pregnant or breastfeeding

15. Any patients with known significant impairment in gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of quizartinib.

16. Active acute or chronic Graft-Versus-Host-Disease (GVHD) requiring prednisone >10 mg or equivalent corticosteroid daily.

Subjects will be randomized into 1 of the 2 treatment groups (quizartinib or placebo) in a 2:1 ratio. The randomization will be stratified by age (<60 vs. ≥60 years old) at the time of diagnosis of AML. Neither the subjects nor any of the Investigators, Sponsor, or contract research organizations (CROs) will be aware of the treatments received. An independent biostatistician, not otherwise part of the study team, will generate the randomization schedule.