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Recruitment status No longer recruiting
Unique ID issued by UMIN UMIN000013288
Receipt No. R000015214
Scientific Title 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)
Date of disclosure of the study information 2014/03/01
Last modified on 2018/03/16

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Basic information
Public title 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)
Acronym AML-12
Scientific Title 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)
Scientific Title:Acronym AML-12
Region
Japan

Condition
Condition Acute Myeloid Leukemia
Classification by specialty
Hematology and clinical oncology Pediatrics
Classification by malignancy Malignancy
Genomic information NO

Objectives
Narrative objectives1 To compare an efficacy and safety of initial induction regimen of high-dose cytarabine (HD-ECM) with that of standard-dose cytarabine (ECM) in children less than 18 years old at diagnosis with de novo acute myeloid leukemia
Basic objectives2 Safety,Efficacy
Basic objectives -Others
Trial characteristics_1 Confirmatory
Trial characteristics_2
Developmental phase Phase II,III

Assessment
Primary outcomes <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)
Key secondary outcomes 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)

Base
Study type Interventional

Study design
Basic design Parallel
Randomization Randomized
Randomization unit
Blinding Open -no one is blinded
Control Active
Stratification YES
Dynamic allocation YES
Institution consideration Institution is considered as adjustment factor in dynamic allocation.
Blocking
Concealment

Intervention
No. of arms 2
Purpose of intervention Treatment
Type of intervention
Medicine
Interventions/Control_1 <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.
Interventions/Control_2 <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.
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit
0 years-old <=
Age-upper limit
18 years-old >
Gender Male and Female
Key inclusion criteria 1) AML [excluding APL, AML with Down syndrome (ML-DS), secondary AML, AML developed after MDS, NK/myeloid leukemia, and granulocytic sarcoma]
2) Age 0 year to 18 years old at diagnosis; for neonates aged 30 days or less, patients must be >= 36 weeks gestational age at the time of diagnosis
3) ECOG performance status (PS) score of 0-2; those with PS score 3 is eligible if that is derived from AML
4) newly diagnosed AML without history of previous chemotherapy or radiation therapy; those with history of steroid therapy, ATRA (because of suspicion of APL), or single intrathecal methotrexate therapy (because of suspicion of ALL) are eligible
5) Patients must have sufficient organ function satisfying the laboratory data listed below (should be evaluated within 7 days of study enrollment);
T-Bil: within 3x of the age-dependent normal range
Cre: within 3x of the age-dependent normal range
6) All patients and/or their parents or legal guardians must sign a written informed consent.
Key exclusion 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
Target sample size 300

Research contact person
Name of lead principal investigator
1st name
Middle name
Last name Souichi Adachi, M.D., Ph.D.
Organization Kyoto University
Division name Human Health Sciences
Zip code
Address 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto
TEL 075-751-3297
Email adachiso@kuhp.kyoto-u.ac.jp

Public contact
Name of contact person
1st name
Middle name
Last name Daisuke Tomizawa, M.D., Ph.D.
Organization National Center for Child Health and Development
Division name Division of Leukemia and Lymphoma, Children's Cancer Center
Zip code
Address 2-10-1 Okura, Setagaya-ku, Tokyo
TEL 03-3416-0181
Homepage URL
Email tomizawa-d@ncchd.go.jp

Sponsor
Institute Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)
Institute
Department

Funding Source
Organization Grant for clinical cancer research from the Ministry of Health, Labour and Welfare, Japan
Organization
Division
Category of Funding Organization Japanese Governmental office
Nationality of Funding Organization Japan

Other related organizations
Co-sponsor
Name of secondary funder(s) Grant from the National Center for Child Health and Development

IRB Contact (For public release)
Organization
Address
Tel
Email

Secondary IDs
Secondary IDs NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions

Other administrative information
Date of disclosure of the study information
2014 Year 03 Month 01 Day

Related information
URL releasing protocol
Publication of results Unpublished

Result
URL related to results and publications
Number of participants that the trial has enrolled
Results
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status No longer recruiting
Date of protocol fixation
2014 Year 01 Month 06 Day
Date of IRB
Anticipated trial start date
2014 Year 03 Month 01 Day
Last follow-up date
2023 Year 02 Month 28 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other
Other related information

Management information
Registered date
2014 Year 02 Month 26 Day
Last modified on
2018 Year 03 Month 16 Day


Link to view the page
URL(English) https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000015214

Research Plan
Registered date File name

Research case data specifications
Registered date File name

Research case data
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