CHIP-AML22/Quizartinib: Quizartinib + Chemotherapy in Newly Diagnosed Pediatric FLT3-ITD+ and NPM1wt AML Patients

Inclusion criteria:

1. Enrollment on CHIP-AML22/Master: Patients must be enrolled on the CHIP-AML22/Master prior to enrollment onCHIP-AML/Quizartinib linked-trial, and may have received a diagnostic work-upaccording to the master protocol. Induction treatment can be started as standard ofcare.
2. FLT3-ITD+ and wild-type NPM1: Presence of FLT3-ITD+ and NPM1 wild type in bone marrow or peripheral blood providedby the local laboratories, as part of standard of care diagnostics. The results ofFLT3-ITD testing must be obtained prior to the first dose of quizartinib (e.g.,Induction course 1, Day 10).
3. Age: Patients must be from 1 month to ≤ 18 years old at initial diagnosis
4. Performance status Karnofsky performance status score of >50% for subjects >16 yearsof age, and a Lansky performance status score of >50% for subjects ≤16 years of age.
5. Organ function criteria: These criteria must be met based on the results before start of any chemotherapy (e.g., MEC) a. Adequate Renal Function Defined as: • Calculated eGFR ≥ 50 mL/min/1.73 m2 using the Schwartz formula. b. Adequate LiverFunction Defined as:

• Total or direct (conjugated) bilirubin < 1.5xULN for age (≤ 5xULN if related toleukemic involvement), AND
• Aspartate transaminase (AST) and alanine transaminase (ALT) <5xULN (<10×ULN ifrelated to leukemic involvement)

6. Life expectancy: > 6 weeks
7. Pregnancy test: Serum/urine pregnancy test (for all girls ≥ age of menarche) negative within 2 weeksprior to enrollment on the quizartinib linked-trial.
8. Taking quizartinib: Patients must be able to reliably swallow or administer quizartinib by NG tube.
9. Informed consent: Written informed consent/assent for the quizartinib linked trial from patients and/orfrom parents or legal guardians for minor patients, according to local law andregulations.

General exclusion criteria:

1. Patients with only extramedullary disease
2. Uncontrolled or significant cardiovascular disease, including -Diagnosed orsuspected congenital long QT syndrome -History of clinically significant ventricular arrhythmias (such as ventriculartachycardia, ventricular fibrillation, or Torsades de Pointes); any history ofarrhythmia will be discussed with sponsor, the national coordinator and C.I.theprior to subject's entry into the study. -QT interval corrected >450 ms: QTc interval corrected with Fridericia's formula (QTcF) for subjects ≥ 6 years of age at the time of enrollment. -Left ventricular systolic dysfunction (LVSD), defined as ejection fraction (EF)below 55% during the screening for the CHIP-AML22/Master protocol. -History of uncontrolled angina pectoris or myocardial infarction within 6months. -History of second (Mobitz II) or third degree heart block (subjects withpacemakers are eligible if they have nohistory of fainting or clinically relevantarrhythmias while using the pacemaker). -Heart rate <50 beats/minute on ECG during the screening for theCHIP-AML22/Master protocol (In case,adolescents with a normal sinusoidal rhythmand no evidence of other cardiac dysfunction will be discussed with sponsor, thenational coordinator and C.I. the prior to subject's entry into the study.) -Uncontrolled hypertension (e.g., systolic blood pressure and /or diastolic bloodpressure that is, on repeated measurement, at or above the 95th percentile forsex, age, and height).

• History of complete left bundle branch block.
• History of New York Heart Association Class 3 or 4 heart failure.

3. Known history of HIV or active clinically relevant liver disease (e.g., activehepatitis B or active hepatitis C)
4. Underlying GI disease that may affect absorption of study drug
5. Use of strong or moderate CYP3A inducers will be prohibited throughout theduration of the study. Strong CYP3A4 inhibitors will be allowed with aconcomitant dose reduction of quizartinib with the exception during the safetyrun-in.
6. History of hypersensitivity to any of the study medications or their excipients.
7. Other serious illnesses or medical conditions, that will likely make itimpossible to complete treatment according to protocol (e.g., patients who shouldnot be given any of the study medications based on the SmPC)
8. Currently participating in other investigational interventional procedures, if itinterferes with any endpoints of the quizartinib trial.

2. Additional exclusion criteria during safety run-in:

1. Patients with CNS3 disease
2. Using strong CYP3A4 inhibitors (If patient can stop using strong CYP3A4 inhibitors,he/she will be allowed to enroll. In such case, no washout is required for the strongCYP3A4 inhibitor)