2023-505000-27-01
招募中
2 期
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)
Prinses Maxima Centrum voor Kinderoncologie B.V.50 个研究点 分布在 12 个国家目标入组 60 人开始时间: 2023年12月27日最近更新:
概览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Prinses Maxima Centrum voor Kinderoncologie B.V.
- 入组人数
- 60
- 试验地点
- 50
- 主要终点
- Efficacy: The percentage of patients with MRD levels <0.1% (MRD negativity) after up to 2 courses of induction chemotherapy plus quizartinib, as measured in the bone marrow using multiparameter flow cytometry (MFCM) before start of consolidation therapy, in the evaluable population for response. o Patients to be evaluated at baseline, end of cycle 1, and end of cycle 2
概览
简要总结
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.
研究设计
- 分配方式
- Not Applicable
- 主要目的
- Quizartinib treatment
- 盲法
- None
入排标准
- 年龄范围
- 0 years 至 64 years（0-17 Years, 18-64 Years）
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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 subject’s entry into the study. iii. QT interval corrected >450 ms: - QTc interval corrected with Fridericia’s 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 subject’s 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)
结局指标
主要结局
Efficacy: The percentage of patients with MRD levels <0.1% (MRD negativity) after up to 2 courses of induction chemotherapy plus quizartinib, as measured in the bone marrow using multiparameter flow cytometry (MFCM) before start of consolidation therapy, in the evaluable population for response. o Patients to be evaluated at baseline, end of cycle 1, and end of cycle 2
Efficacy: The percentage of patients with MRD levels <0.1% (MRD negativity) after up to 2 courses of induction chemotherapy plus quizartinib, as measured in the bone marrow using multiparameter flow cytometry (MFCM) before start of consolidation therapy, in the evaluable population for response. o Patients to be evaluated at baseline, end of cycle 1, and end of cycle 2
Safety: Incidence of Dose-Limiting Toxicities (DLTs) assessed during Induction course 1 and 2 (until day 56 of each course) for the DLTs evaluable patients.
Safety: Incidence of Dose-Limiting Toxicities (DLTs) assessed during Induction course 1 and 2 (until day 56 of each course) for the DLTs evaluable patients.
次要结局
- Efficacy: Other measurements of treatment response: o Proportion of subjects with a complete remission (CR) rate without evidence of MRD after 1 and after 2 induction courses (including CR and remission with incomplete blood count or platelet recovery)
- Efficacy: Other measurements of treatment response: o Bone marrow blast counts by morphology and MFCM after induction course 1 and induction course 2 and before allo-SCT; CRc (CR and CRi) and morphologic leukemia-free state (MLFS) rates after induction course 1 and 2; MRD negativity (<0.1%), after course 1 and 2 and before allo-HSCT; Absolute MRD levels after induction course 1 and 2, and before allo-HSCT;
- Efficacy: Other measurements of treatment response: o Bone marrow blast counts by morphology and MFCM at other timepoints (The disease assessments at other time-points (e.g., After consolidation course 2, 3, before/during continuation treatment)
- Efficacy: Other measurements of treatment response: o Event-free survival (EFS) probability, at least at 1, 2 and 3 years Time from the start of treatment until an event, defined as 1) not achieving CR/CRi because of early death or with refractory disease (ie: treatment failure); 2) morphological relapse; 3) second malignancy; 4) death in complete remission due to any cause.
- Efficacy: Other measurements of treatment response: o Overall survival (OS) probability, at least at 1, 2 and 3 years. o Time from the start of treatment until death, due to any cause.
- Efficacy: Other measurements of treatment response: o Disease free survival (DFS) probability, at least at 1, 2 and 3 years. o Time from CR/CRi until morphological relapse or death due to any cause
- Efficacy: Other measurements of treatment response: o Duration of complete response. o Time from CR until morphological relapse or death due to any cause
- Efficacy: Other measurements of treatment response: o Cumulative incidence of morphological relapse (CIR) probability, at least at 1,2 and 3 years
- Efficacy: Other measurements of treatment response: o Number and percentage of patients proceeding to HSCT
- Efficacy: Other measurements of treatment response: o Number of patients starting and completing continuation treatment post-HSCT
- Safety o Adverse events (AEs), as characterized by type, frequency, severity (as graded using CTCAE, v5.0).
- Safety: o Laboratory abnormalities (including time to recovery of ANC and PLT), electrocardiograms and changes in vital signs as characterized by type, frequency, severity and timing will be tabulated, and reported as AEs when considered clinically significant by the investigator.
- Safety: The cumulative incidence of non-relapse mortality, defined as the cumulative probability of non-relapse mortality, with time calculated between start of study treatment and death due to other causes than relapsed or refractory leukemia, accounting for competing events.
- Pharmacokinetics (PK): Population PK analysis to estimate AUC (tau) and Cmax for quizartinib and AC886, clearance (CL/F) and volume of distribution (Vss/F) for quizartinib.
- Palatability: Patients and/or parents or legal guardians will answer using a Hedonic scale for the taste and ability to swallow the medicine.
研究者
Prof. Dr. Gertjan J.L. Kaspers
Scientific
Prinses Maxima Centrum voor Kinderoncologie B.V.
研究点 (50)
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