UMIN-CTR Clinical Trial

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

Acute Myeloid Leukemia

Classification by specialty

Hematology and clinical oncology

Pediatrics

Classification by malignancy

Malignancy

Genomic information

NO

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

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)

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Cluster

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

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

Age-lower limit

Not applicable

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

Name of lead principal investigator

1st name	Souichi
Middle name
Last name	Adachi

Organization

Kyoto University

Division name

Human Health Sciences

Zip code

606-8507

Address

54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto

TEL

075-751-3297

Email

adachiso@kuhp.kyoto-u.ac.jp

Name of contact person

1st name	Daisuke
Middle name
Last name	Tomizawa

Organization

National Center for Child Health and Development

Division name

Division of Leukemia and Lymphoma, Children's Cancer Center

Zip code

157-8535

Address

2-10-1 Okura, Setagaya-ku, Tokyo

TEL

03-3416-0181

Homepage URL

Email

tomizawa-d@ncchd.go.jp

Institute

Japan Children's Cancer Group (JCCG)

Institute

Department

Personal name

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

Co-sponsor

Name of secondary funder(s)

Grant from the National Center for Child Health and Development

Organization

Clinical Research Review Board, National Hospital Organization Nagoya Medical Center

Address

4-1-1 Sannomaru, Naka-ku, Nagoya

Tel

053-951-1111

Email

311-nmc-rec@mail.hosp.go.jp

Secondary IDs

YES

Study ID_1

jRCTs041180128

Org. issuing International ID_1

Japan Registry of Clinical Trials

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2014

Year

03

Month

01

Day

URL releasing protocol

https://jrct.niph.go.jp/latest-detail/jRCTs041180128

Publication of results

Unpublished

URL related to results and publications

https://jrct.niph.go.jp/latest-detail/jRCTs041180128

Number of participants that the trial has enrolled

387

Results

Primary endpoints of this trial were early mortality rate in the Phase II part and 3-year EFS and rate of patients with positive flow-cytometric MRD at end-of-Induction-1 in the Phase III part.
The main analyses of the Phase III part were performed for the 324 patients (ECM arm, N=168; HD-ECM arm, N=156) defined as FAS.
3-year EFS: ECM 64.3% (95%CI, 56.5-71.0%), HD-ECM 61.2% (95%CI, 53.1-68.4%), p=0.589
Positive FCM-MRD rate at TP1: ECM 21.5% (95%CI, 14.9-29.4%), HD-ECM 25.2% (95%CI, 17.9-33.7%), p=0.517

Results date posted

2023

Year

03

Month

05

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Among the 387 patients registered to the trial, total 324 randomized patients (ECM arm, N=168; HD-ECM arm, N=156) met the definition of full analysis set (FAS). Thus, baseline characteristics of the 324 FAS patients are listed as follows.

Age at diagnosis (years): ECM-8.2 (mean), HD-ECM-8.0 (mean)
Age group:
younger than 1 year old ECM-11.3%, HD-ECM-10.9%
1 - 9 years old ECM-50.0%, HD-ECM-49.4%
10 years old or older ECM-38.7%, HD-ECM-39.8%
Sex:
ECM-Male 53.0%/Female 47.0%, HD-ECM-Male 55.8%/Female 44.2%
WBC count at diagnosis (/microL): ECM-15300 (median), HD-ECM-15300 (median)
Risk group:
CBF SR; ECM-30.4%, HD-ECM-28.2%
Non-CBF SR; ECM-44.6%, HD-ECM-39.1%
HR; ECM-11.9%, HD-ECM-17.9%
Others; ECM-13.1%, HD-ECM-14.7%

Participant flow

This trial is a seamless Phase II-III clinical trial. Phase II part was initiated on March 1, 2014; 189 patients were registered from the selected institutions (eligible for randomized trial) and 37 patients were registered from the other institutions (not eligible for randomized trial). Phase III part was initiated on September 1, 2016; 161 patients were registered (all patients are eligible for randomized trial). Trial registration ended on February 28, 2018, and follow-up was continued until April 30, 2021.

Along with the enactment and enforcement of the Clinical Trials Act in Japan, this trial obtained approval as a specified clinical trial from the certified review board on December 7, 2018, and was released in jRCT on March 26, 2019 (jRCTs041180128).

Adverse events

From March 1, 2014 to March 25, 2019:
Severe adverse events which required immediate report occurred in 7 patients.

Cardiogenic shock, died (during Induction-2)
Bronchospasm, died (before initiating Induction-1)
Sepsis, died (during Induction-1)
Intracranial hemorrhage, died (during Induction-1)
Intracranial hemorrhage, died (during Induction-1)
Sepsis, permanent optic nerve disorder (during Consolidation-2)
Intracranial hemorrhage, died (during Induction-1)

From March 26, 2019 to April 30, 2021 (after jRCT release as a specified clinical trial ):
No severe adverse events requiring immediate report.

Outcome measures

Primary endpoints of this trial were early mortality rate in the Phase II part and 3-year event-free survival rate (EFS) and rate of patients with positive flow-cytometric MRD (FCM-MRD) at end-of-Induction-1 in the Phase III part.

Secondary endpoints included CR rate, early mortality rate, bone marrow remission rate after Induction-1, positive FCM-MRD rate at TP2,overall survival rate (OS), relapse, non-relapse
death, incidence of sever adverse events (grade 3 or higher) during Induction-1 and -2.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2014

Year

01

Month

06

Day

Date of IRB

2014

Year

03

Month

17

Day

Anticipated trial start date

2014

Year

03

Month

01

Day

Last follow-up date

2021

Year

04

Month

30

Day

Date of closure to data entry

2021

Year

06

Month

17

Day

Date trial data considered complete

2022

Year

07

Month

13

Day

Date analysis concluded

2023

Year

02

Month

03

Day

Other related information

Registered date

2014

Year

02

Month

26

Day

Last modified on

2023

Year

03

Month

05

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000015214