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A Multi-Center Seamless Phase II-III Randomized Trial of High-dose Cytarabine in Initial Induction with Evaluation of Flow-cytometry-based Minimal Residual Disease for Children with de Novo Acute Myeloid Leukemia (AML-12)

Basic Information

Recruitment status	Complete: follow-up complete
Health condition(s) or Problem(s) studied	Acute Myeloid Leukemia
Date of first enrollment	2014/03/01
Target sample size	300
Countries of recruitment	Japan
Study type	Interventional
Intervention(s)	<Standard Arm> Induction-1A (ECM): In the Phase II study, patients in the "selected" institutions will be randomly assigned to either high-dose cytarabine (Ara-C) induction (HD-ECM) or standard-dose Ara-C induction (ECM). Patients in the "other" institutions will be non-randomly assigned to the ECM induction. In Phase III study, all the patients will be randomly assigned to either HD-ECM or ECM. Standard arm "Induction-1A (ECM)" consists of standard dose Ara-C, mitoxantrone (MIT), etoposide (VP-16), and triple intrathecal therapy [TIT; Ara-C, methotrexate (MTX), and hydrocortisone (HDC)]. Induction-2 (HCEI): All the patients will receive HCEI consisted of high-dose Ara-C, VP-16, idarubicin (IDA), and TIT. Post-remission therapies: All the patients who achieved CR after 2 course of induction chemotherapy (Induction-1 and Induction-2) will be stratified to either of the three risk groups (SR/CBF, SR/non-CBF, or HR) and undergo risk stratified multiple chemotherapy courses with or without hematopoietic stem cell transplantation (HSCT) in first remission. HSCT is indicated only for the HR group. Chemotherapy is consisted of Ara-C, MIT or IDA, VP-16, and TIT. <Experimental Arm> Induction-1B (HD-ECM): In the Phase II study, patients in the "selected" institutions will be randomly assigned to either high-dose cytarabine (Ara-C) induction (HD-ECM) or standard-dose Ara-C induction (ECM). Patients in the "other" institutions will be non-randomly assigned to the ECM induction. In Phase III study, all the patients will be randomly assigned to either HD-ECM or ECM. Experimental arm "Induction-1B (HD-ECM)" consists of high-dose Ara-C, mitoxantrone (MIT), etoposide (VP-16), and triple intrathecal therapy [TIT; Ara-C, methotrexate (MTX), and hydrocortisone (HDC)]. Induction-2 (HCEI): All the patients will receive HCEI consisted of high-dose Ara-C, VP-16, idarubicin (IDA), and TIT. Post-remission therapies: All the patients who achieved CR after 2 course of induction chemotherapy (Induction-1 and Induction-2) will be stratified to either of the three risk groups (SR/CBF, SR/non-CBF, or HR) and undergo risk stratified multiple chemotherapy courses with or without hematopoietic stem cell transplantation (HSCT) in first remission. HSCT is indicated only for the HR group. Chemotherapy is consisted of Ara-C, MIT or IDA, VP-16, and TIT.

Outcome(s)

Primary Outcome

<Phase II study> Early death rate <Phase III study> 1) 3-year event-free survival (EFS) rate 2) Positive rate of flow-cytometry-based minimal residual disease (FCM-MRD) after initial induction course (TP-1)

Secondary Outcome

1) Overall response (CR+CRi) rate, CR rate, CRi rate, non-CR rate, early death rate, and bone marrow response after Induction-1 2) Rate of severe adverse events (grade 3 or higher) defined by Common Terminology Criteria for Adverse Events (CTCAE) ver4.0 3) Positive rate of FCM-MRD in TP-2 and TP-3 4) 3-year and 5-year EFS and overall survival (OS) rate 5) Relapse rate, non-relapse mortality 6) Comparison of FCM-MRD and MRD measuring WT1 mRNA expression 7) Subgroup analyses on all the endpoints; for the whole study cohort including "other" institutions in the Phase II study (except endpoints regarding MRD analyses) and according to the risk groups, MRD levels on TP-1 and TP-2, and other prognostic factors [age and WBC at diagnosis, WHO classification (ver4.0), cytogenetics (all the risk-stratifying factors, complex karyotype, FLT3-ITD allelic ratio, 11q23/MLL gene abnormalities, CEBPA mutation, NPM1 mutation, KIT mutation, and others] 8) For the high risk (HR) group, 3-year and 5-year post-transplantation EFS and OS for those transplanted in first remission (including subgroup analyses according to the donor type and conditioning regimen received)

Key inclusion & exclusion criteria

Age minimum	Not applicable
Age maximum	18years-old
Gender	Male and Female
Include criteria
Exclude criteria	1) Patients with severe CNS hemorrhage (grade 3 or higher in CTCAE ver4.0) 2) Patients with uncontrollable infection (including those with active tuberculosis or positive HIV antibody) 3) Patients who are pregnant or breast-feeding mother 4) Patients with history of primary or acquired immunodeficiency 5) Patients with uncontrollable heart failure; presence of heart anomaly itself is not an exclusion criteria 6) Patients with any other inappropriate status judged by physician