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

The CHIP-AML22/Quizartinib study is a single-arm, multinational, multicenter, open-label phase II study, with a safety run-in, aiming to assess the safety, efficacy, pharmacokinetics and pharmacodynamics of quizartinib, a FLT3-inhibitor, as IMP added to standard of care chemotherapy in newly diagnosed FLT3-ITD positive and NPM1 wild-type AML pediatric patients.

This study is a linked trial to the CHIP-AML22/Master protocol. Patients will start in the CHIP-AML22/Master study and if they are FLT3-ITD positive and NPM1 wild-type, can be enrolled in the CHIP-AML22/Quizartinib study.

Inclusion criteria

• Enrollment on CHIP-AML22/Master:

Patients must be enrolled on the CHIP-AML22/Master prior to enrollment on CHIP-AML/Quizartinib linked-trial, and may have received a diagnostic work-up according to the master protocol. Induction treatment can be started as standard of care.

• FLT3-ITD+ and wild-type NPM1:

Presence of FLT3-ITD+ and NPM1 wild type in bone marrow or peripheral blood provided by the local laboratories, as part of standard of care diagnostics. The results of FLT3-ITD testing must be obtained prior to the first dose of quizartinib (e.g., Induction course 1, Day 10).

• Age:

Patients must be from 1 month to ≤ 18 years old at initial diagnosis

• Performance status Karnofsky performance status score of >50% for subjects >16 years of age, and a Lansky performance status score of >50% for subjects ≤16 years of age.
• 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 Liver Function Defined as:
• Total or direct (conjugated) bilirubin < 1.5xULN for age (≤ 5xULN if related to leukemic involvement), AND
• Aspartate transaminase (AST) and alanine transaminase (ALT) <5xULN (<10×ULN if related to leukemic involvement)
• Life expectancy: > 6 weeks
• Pregnancy test:

Serum/urine pregnancy test (for all girls ≥ age of menarche) negative within 2 weeks prior to enrollment on the quizartinib linked-trial.

• Taking quizartinib:

Patients must be able to reliably swallow or administer quizartinib by NG tube.

• Informed consent:

Written informed consent/assent for the quizartinib linked trial from patients and/or from parents or legal guardians for minor patients, according to local law and regulations.

General exclusion criteria:

• Patients with only extramedullary disease
• Uncontrolled or significant cardiovascular disease, including -Diagnosed or suspected congenital long QT syndrome

-History of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes); any history of arrhythmia will be discussed with sponsor, the national coordinator and C.I.the prior 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 6 months.

-History of second (Mobitz II) or third degree heart block (subjects with pacemakers are eligible if they have nohistory of fainting or clinically relevant arrhythmias while using the pacemaker).

-Heart rate <50 beats/minute on ECG during the screening for the CHIP-AML22/Master protocol (In case,adolescents with a normal sinusoidal rhythm and no evidence of other cardiac dysfunction will be discussed with sponsor, the national coordinator and C.I. the prior to subject's entry into the study.)

-Uncontrolled hypertension (e.g., systolic blood pressure and /or diastolic blood pressure that is, on repeated measurement, at or above the 95th percentile for sex, age, and height).

• History of complete left bundle branch block.
• History of New York Heart Association Class 3 or 4 heart failure.
• Known history of HIV or active clinically relevant liver disease (e.g., active hepatitis B or active hepatitis C)
• Underlying GI disease that may affect absorption of study drug
• Use of strong or moderate CYP3A inducers will be prohibited throughout the duration of the study. Strong CYP3A4 inhibitors will be allowed with a concomitant dose reduction of quizartinib with the exception during the safety run-in.
• History of hypersensitivity to any of the study medications or their excipients.
• Other serious illnesses or medical conditions, that will likely make it impossible to complete treatment according to protocol (e.g., patients who should not be given any of the study medications based on the SmPC)
• Currently participating in other investigational interventional procedures, if it interferes with any endpoints of the quizartinib trial.

• Additional exclusion criteria during safety run-in:

• Patients with CNS3 disease
• 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 strong CYP3A4 inhibitor)