A phase II, single arm, open label, study on the safety, efficacy, pharmacokinetics and pharmacodynamics of quizartinib in combination with chemotherapy and as single-agent after high dose therapy in newly diagnosed pediatric FLT3-ITD positive and NPM1 wild-type AML patients (A linked-trial of the CHIP-AML22/Master protocol by the NOPHO-DB-SHIP consortium)
ESTADO CLÍNICO
Reclutando
FASE/S DEL ENSAYO
Fase II
PATOLOGÍA
Leucemia mieloide aguda
CENTRO INVESTIGADOR
H.G.U. Gregorio Marañón
INVESTIGADOR PRINCIPAL
Marina García Morin
CENTRO INVESTIGADOR
H.U. La Paz
INVESTIGADOR PRINCIPAL
Berta González
FECHA DE APERTURA
Julio, 2024
FECHA DE CIERRE
,
CRITERIOS DE INCLUSIÓN
Enrollment on CHIP-AML22/Master
FLT3-ITD+ and wild-type NPM1
Age from 1 month to 18 years old at initial diagnosis
Karnofsky Performance status 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: a. Adequate Renal Function Defined as: Calculated eGFR 50 mL/min/1.73 m2 b. Adequate Liver Function Defined as: Total or direct (conjugated) bilirubin <1.5 × ULN 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 negative within 2 weeks prior to enrollment on the quizartinib linked-trial.
Patients must be able to reliably swallow or administer quizartinib by NG tube.
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.
FLT3-ITD+ and wild-type NPM1
Age from 1 month to 18 years old at initial diagnosis
Karnofsky Performance status 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: a. Adequate Renal Function Defined as: Calculated eGFR 50 mL/min/1.73 m2 b. Adequate Liver Function Defined as: Total or direct (conjugated) bilirubin <1.5 × ULN 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 negative within 2 weeks prior to enrollment on the quizartinib linked-trial.
Patients must be able to reliably swallow or administer quizartinib by NG tube.
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.
CRITERIOS DE EXCLUSIÓN
Patients with only extramedullary disease
Uncontrolled or significant cardiovascular disease, including i. Diagnosed or suspected congenital long QT syndrome ii. 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 subjects entry into the study. iii. QT interval corrected >450 ms: - QTc interval corrected with Fridericias formula (QTcF) for subjects 6 years of age at the time of enrollment. iv. Left ventricular systolic dysfunction (LVSD), defined as ejection fraction (EF) below 55% during the screening for the CHIP-AML22/Master protocol. v. History of uncontrolled angina pectoris or myocardial infarction within 6 months. vi. 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). vii. Heart rate <50 beats/minute on ECG during the screening for the CHIPAML22/ 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 subjects entry into the study.) viii. 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). ix. History of complete left bundle branch block. x. 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 a. Patients with CNS3 disease b. 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)
Uncontrolled or significant cardiovascular disease, including i. Diagnosed or suspected congenital long QT syndrome ii. 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 subjects entry into the study. iii. QT interval corrected >450 ms: - QTc interval corrected with Fridericias formula (QTcF) for subjects 6 years of age at the time of enrollment. iv. Left ventricular systolic dysfunction (LVSD), defined as ejection fraction (EF) below 55% during the screening for the CHIP-AML22/Master protocol. v. History of uncontrolled angina pectoris or myocardial infarction within 6 months. vi. 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). vii. Heart rate <50 beats/minute on ECG during the screening for the CHIPAML22/ 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 subjects entry into the study.) viii. 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). ix. History of complete left bundle branch block. x. 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 a. Patients with CNS3 disease b. 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)
DESCRIPCIÓN
Primary Objective (Efficacy): To assess the clinical benefit of quizartinib as measured by the MRD-negativity rate (defined as <0.1% using flow-cytometry) after up to two courses of conventional chemotherapy plus quizartinib, in newly diagnosed pediatric de novo AML with a FLT3-ITD and without a concurrent NPM1 mutation. Primary Objective (Safety): During the safety run-in, the co-primary objective will be to determine the Recommended Phase 2 Dose (RP2D) of quizartinib for newly diagnosed pediatric AML patients with a FLT3-ITD and without a concurrent NPM1 mutation, based on the safety and tolerability profile of quizartinib observed at dose levels.
PALABRAS CLAVE
aml, flt3, npm1
