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Trial registered on ANZCTR


Registration number
ACTRN12611001233910
Ethics application status
Approved
Date submitted
8/08/2011
Date registered
2/12/2011
Date last updated
17/03/2022
Date data sharing statement initially provided
15/09/2020
Date results information initially provided
15/09/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
An international collaborative (AIEOP-BFM [Associazione Italiana Ematologia Oncologia Pediatrica - Berlin-Franklin-Munster]) treatment protocol for children and adolescents with Acute Lymphoblastic Leukaemia
Scientific title
An international collaborative (AIEOP-BFM [Associazione Italiana Ematologia Oncologia Pediatrica - Berlin-Franklin-Munster]) treatment protocol for children and adolescents with Acute Lymphoblastic Leukaemia
Secondary ID [1] 262718 0
EudraCT Number AIEP-BFM ALL 2009: 2007-004270-43
Universal Trial Number (UTN)
Trial acronym
AIEOP-BFM ALL 2009 - Study 9
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute lymphoblastic leukemia 270426 0
Condition category
Condition code
Cancer 270897 270897 0 0
Leukaemia - Acute leukaemia
Cancer 270899 270899 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
These 'Protocols' are chemotherapy treatment phases which all combined constitute 2 years of chemotherapy. The drugs are administered either orally, intravenously, or via intramuscular injsection.

Patients enrolled on the study will be stratified into 3 treatment groups (standard, medium, and high risk). The stratifications will be determined by certain biologic features of the leukaemia and also by the patients response to treatment. Not all patients will receive every treatment phase - they will receive only those phases tailored to there treatment group. The study also involves 3 randomisations - R1, R2, R-HR. The R1 randomisation is a treatment deintesification for the standard risk group. The R2 and R-HR randomisations will evaluate treatment intensifications for the medium and high risk patient groups.


Protocol IA, IA', and IA-CPM all include the following drugs
- Prednisone (alternatively prednisolone) p.o or i.v
- Vincristine i.v
- Daunorubicin i.v
- Cyclophosphamide i.v with Mesna
- PEG-L-Asparaginase i.v
- Methotrexate intrathecally

Protocol IA-Dexa
- Dexamethasone p.o. or i.v.
- Daunorubicin i.v.

Protocol IB
- Cyclophosphamide i.v give with Mesna
- Cytarabine i.v. or s.c.
- 6-Mercaptoprine p.o.
- Methotrexate intrathecally

Protocol IB-ASP+
This protocol is the same as protocol 1B with the addtion of PEG-L-Asparaginase i.v

Protocol HR-1 (for all patients in the high risk group)
- Dexamethasone p.o. or i.v.
- Vincristine i.v.
- High-dose Methotrexate i.v
- Cyclophosphamide i.v given with Mesna
- High-dose Cytarabine i.v
- PEG-L-Asparaginase i.v
- Methotrexate intrathecally during HD-Methotrexate infusion on day 1
- Granuloctye colony stimulating factor (GCSF) s.c.

Protocol HR-2 (for all patients in the high risk group)
- Dexamethasone p.o. or i.v.
- Vindesine i.v.
- High-dose Methotrexate i.v
- Ifosfamide i.v given with Mesna
- Daunorubicin i.v
- PEG-L-Asparaginase i.v
- Methotrexate intrathecally given during HD-Methotrexate infusion
- Granulocyte colony stimulating factor (GCSF) s.c.

Protocol HR-3 (given after HR-2)
- Dexamethasone p.o. or i.v.
- High-dose Cytarabine i.v
- Etoposide i.v
- PEG-L-Asparaginase i.v
- Methotrexate intrathecally
- Granulocyte colony stimulating factor (GCSF) s.c.

Protocol M
- 6-Mercaptopurine p.o.
- High-Dose Methotrexate i.v
- Methotrexate intrathecally

Protocol IIA
- Dexamethasone p.o. or i.v.
- Vincristine i.v.
- Doxorubicin i.v.
- PEG-L-Asparaginase i.v
- Methotrexate intrathecally

Protocol IIA-ASP+
This protocol is the same as IIA but has the addition of PEG-L-Asparaginase i.v.

Protocol IIB
- Cyclophosphamide i.v.
- Cytarabine i.v. or s.c.
- Thioguanine p.o.
- Methotrexate intrathecally

Protocol IIIA
- Dexamethasone p.o. or i.v.
- Vincristine i.v.
- Doxorubicin i.v.
- PEG-L-Asparaginase i.v.
- Methotrexate intrathecally

Protocol IIIB
- Cyclophosphamide i.v. given with Mesna
- Cytarabine i.v. or s.c.
- Thioguaninie p.o.
- Methotrexate intrathecally

Protocol DNX-FLA (for patients in the high risk group with MRD non-response)
- Fludarabine i.v.
- High-dose Cytarabine i.v.
- Daunoxome i.v.
- Methotrexate intrathecally

Protocol Interim Maintenance (HR)
- 6-Mercaptopurine p.o.
- Methotrexate p.o.
- Cranial Radiotherapy during the 1st interim maintenance phase only for selected subgroups of patients

Protocol - Maintenance
- 6-Mercaptopurine p.o.
- Methotrexate p.o.
- Methotrexate intrathecally
- Cranial radiotherapy

Protocol - Maintenance with PEG-L-ASP
Treatment is the same as the maintenance protocol but has the addition of PEG-L-Asparaginase i.v. for patients randomised into the experimental arm


Prednisone
60 mg/m2/day p.o. or i.v. divided into 3 doses per day, days 1 to 28, Protocol IA, Protocol IA’, Protocol IA-CPM


Cytarabine
Protocol IB;75 mg/m2/dose i.v. or s.c. days
38-41, 45-48, 52-55 and 59-62. Protocol IIB; 75 mg/m2/dose i.v. or s.c. days 38-41, 45-48. HR-3 2mg/m2/dose p.i. (3 h) every 12 hours on days 1 and 2 (4 doses). Protocol IIIB; 75 mg/m2/dose i.v. or s.c. 2 blocks of 4 days each; days17-20, 24-27. DNX-FLA Block; 2 mg/m2/dose p.i. (3 h) every 24 hours on days 1 to 5 (5 doses).


Dexamethasone
Protocol IA; 10 mg/m2/day p.o. or i.v. divided into 3 doses per day, days 8 to 28. Protocol IIA; 10 mg/m2/day p.o. or i.v. divided into 3 doses per day, days 1 to 21. HR-2’; 20 mg/m2/day p.o. or i.v. divided into 3 doses per day, days 1 to 5. HR-3’; 20 mg/m2/day p.o. or i.v. divided into 3 doses per day, days 1 to 5. Protocol IIIA; 10 mg/m2/day p.o. or i.v. divided into 3 doses per
day, days 1 to 14 (14 days).


Doxorubicin
Protocol IIA; 30 mg/m2/dose p.i. (1 h) on days 8, 15, 22 and 29. Protocol IIIA; 30 mg/m2/dose p.i. (1 h) on days 1 and 8.


Methotrexate
Protocol IA, Protocol IA’, Protocol IA-CPM; Methotrexate intrathecally on day 1, 12, 33. In case of initial CNS status CNS 3 or CNS 2 additional intrathecal methotrexate is given on days 19 and 26. Protocol IB; Methotrexate intrathecally on days 45 and 59. Protocol M; Methotrexate intrathecally on days 8, 22, 36 and 50.
Protocol IIA; Methotrexate intrathecally on days 1 and 18 only in patients with initial CNS disease (CNS 3). Protocol IIB; Methotrexate intrathecally on days 38 and 45. Protocol IIIA; Methotrexate intrathecally on day 1 of each Protocol IIIA only in patients with initial CNS disease (CNS 3). Protocol IIIB; Methotrexate intrathecally on days 17 and 24. DNX-FLA; Methotrexate intrathecally on day 1. Age-adjusted dose of intrathecal methotrexate: 1 to < 2 years: 8 mg, 2 to < 3 years: 10 mg, 3 years: 12 mg

HR-1’; Methotrexate intrathecally during HD-MTX infusion on day 1. High-Dose Methotrexate 5g/m2/dose p.i. (24 h) on day 1. HR-2’; High-Dose Methotrexate 5g/m2/dose p.i. (24 h) on day 1. Methotrexate intrathecally during HD-MTX infusion on day 1. Only in case of initial CNS involvement another dose is given on day 5. HR-3’; Methotrexate intrathecally on day 1.

Maintenance; Methotrexate 20 mg/m2/dose p.o. once a
week. Methotrexate intrathecally, beginning at week 6 every 6 weeks up to a total of 6 doses is given to the following subgroups (all CNS status CNS 1 or CNS 2):
- T-ALL with < 2 years of age at start of maintenance,
- T-ALL, non-HR and initial WBC < 100 000/µl
- pB-ALL with PPR and/or FCM-MRD day 15 10 % and/or
PCR-MRD-MR SER as only HR criteria


PEG-asparaginase - Protocol IA, Protocol IA’, Protocol IA-CPM; 2 500 IU/m2/dose p.i. (2 h) on days 12 and 26 (maximal single dose 3 750 IU). Protocol IB-ASP+; 2 500 IU/m2/dose p.i. (2 h) on days 40 , 47, 54, and 61 (maximal single dose 3 750 IU). Protocol IIA; 2 500 IU/m2/dose p.i. (2 h) on day 8 (maximal single dose 3 750 IU). Protocol IIA-ASP+; 2 500 IU/m2/dose p.i. (2 h) (maximal single dose 3 750 IU/) at days 8 and 22. Protocol IIB-ASP+; 2 500 IU/m2/dose p.i. (2 h) on day 36 and 50 (maximal single dose 3 750 IU). HR-1’; 2 500 IU/m2/dose p.i. (2 h) on day 6 (1 dose) (maximal single dose 3 750 IU).
HR-2’; 2 500 IU/m2/dose p.i. (2 h) on day 6 (1 dose) (maximal single dose 3 750 IU). HR-3’; 2 500 IU/dose p.i. (2 h) on day 6 (1 dose).(maximal single dose 3 750 IU)
IIIA; 2 500 IU/m2/dose p.i. (2 h) on day 1 (1 dose) (maximal single dose 3 750 IU). Maintenance; Only for patients randomized into the experimental arm in
randomization R2: 2 500 U/m2/dose p.i. (2 h) every second
week, 10 doses in total, starting in Protocol II-ASP+.


Vincristine
Protocol IA, Protocol IA’, Protocol IA-CPM; Vincristine 1.5 mg/m2/dose i.v. (maximal single dose 2 mg) on days 8, 15, 22, 29. Protocol IIA; Vincristine 1.5 mg/m2/dose i.v. (maximal single dose 2 mg) on days 8, 15, 22, 29.
HR-1’; Vincristine 1.5 mg/m2/dose i.v. (maximal single dose 2 mg) on days 1 and 6. Protocol IIIA; Vincristine 1.5 mg/m2/dose i.v. (maximal single dose 2 mg) on days 1 and 8.


Daunorubicin
Protocol IA, Protocol IA’, Protocol IA-CPM; Daunorubicin 30 mg/m2/dose p.i. (1 h) on days 8, 15, 22 and 29. Only two doses on days 8 and 15 are given to patients randomized into the experimental arm in randomization R1.
Protocol IA-Dexa (IAD); Daunorubicin 30 mg/m2/dose p.i. (1 h) on days 8, 15, 22 and 29.


Cyclophosphamide
Protocol IA-CPM; Cyclophosphamide 1000 mg/m2/dose
p.i. (1 h) on day 10. Protocol IB; Cyclophosphamide 1 000 mg/m2/dose p.i. (1 h) on days 36 and 64. Protocol IIB; Cyclophosphamide 1 000 mg/m2/dose p.i. (1 h) on day 36.
HR-1’; Cyclophosphamide 200 mg/m2/dose p.i. (1 h) every 12 hours on days 2 to 4. Protocol IIIB; Cyclophosphamide 500 mg/m2/dose p.i. (1 h) on day 15.


Mercaptopurine
Protocol IB; 6-Mercaptopurine 60 mg/m2/day p.o., days 36 to 63. Protocol M; 6-Mercaptopurine 25 mg/m2/day p.o., days 1 to 56.


Thioguanine
Protocol IIIB; Thioguanine 60 mg/m2/day p.o., days 15 to 28.


Ifosfamide
HR2; Ifosfamide 800 mg/m2/dose p.i. (1 h) every 12 hours on days 2 to 4 (5 doses).


Etoposide
HR3; Etoposide 100 mg/m2/dose p.i. (1 h) every 12 hours on days 3 to 5 (5 doses).


Fludarabine
DNX-FLA (Applicable to HR patients with “MRD non-response”);Fludarabine 30 mg/m2/dose p.i. (30 min) every 24 hours on days 1 to 5 (5 doses).


Daunoxome
Daunoxome 60 mg/m2/dose p.i. (1 h) on days 1, 3 and 5.


Vindesine
HR-2’; Vindesine 3 mg/m2/dose i.v. (maximal single dose 5 mg) on days 1 and 6.


p.o. = medication administered orally; i.v. medication administered intravenously; s.c = medication administered by subcutaneous injection
Intervention code [1] 267062 0
Treatment: Drugs
Comparator / control treatment
This study is being compared to its historical predecessor study AIEOP-BFM ALL 2000 [PMID: 20154213; PMID: 21719599]. Much of the therapy is identical. Changes include ongoing refinements in ALL risk group stratification, treatment de-intensification for those patients at the lowest risk of relapse, treatment intensification for those patients at a higher risk of relapse, the use of i.v. PEG-L-Asparaginase instead of i.m. PEG-L-Asparaginase.
Control group
Historical

Outcomes
Primary outcome [1] 269314 0
Non-HR pB-ALL pateints with TEL/AML 1-negative ALL or unknown TEL/AML1 status and FCM-MRD in bone marrow on day 15 <0.1% or with TEL/AML1-positive ALL (randomized study question): can the daunorubicin dose in Protocol IA be safely reduced by 50% with a non-inferior EFS and a reduction of toxicity (treatment related mortality and AE/SAE in protocol)?
Timepoint [1] 269314 0
Randomisation R1: 5 year event-free survival from time of randomization
Primary outcome [2] 269315 0
Patients with precursor-B ALL and risk group MR (randomized study question): can the clinical outcome be improved by protracted asparagine depletion achieved through application of intensified pegylated L-asparaginase during reintensification and early maintenance?
Timepoint [2] 269315 0
Randomization R2: 5 year disease-free survival from time of randomization
Primary outcome [3] 269316 0
HR patients (as identified by day 33 - randomized study question): can the clinical outcome be improved by protracted exposure to PEG-L-Aasparaginase during protocol IB?
Timepoint [3] 269316 0
Randomization RHR: rate of MRD highly positive patients (MRD greater than or equal to 10-3) at TP2 (week 12)
Secondary outcome [1] 279359 0
SR patients identified by at least one sensitive marker: Is the clinical outcome comparable to that obtained in SR patients (identified with two sensitive markers) in AIEOP-BFM ALL 2000, or can the outcome even be improved with
the use of PEG-L-asparaginase instead of native E. coli L-asparaginase?
Timepoint [1] 279359 0
5 year DFS for this study compared historically with patients on AIEOP-BFM ALL 2000
Secondary outcome [2] 279360 0
T-ALL non-HR patients: Can the high level of outcome (pEFS) which was obtained for these patients in study AIEOP-BFM ALL 2000 be preserved or even improved with the use of PEG-L-ASP instead of native E.coli L-ASP?
Timepoint [2] 279360 0
5 year EFS for this study compared historically with patients of AIEOP-BFM ALL 2000
Secondary outcome [3] 279361 0
HR patients with persistingly high MRD levels despite the use of the HR blocks in the intensified consolidation phase (so called MRD Non-Responders): Is it possible to improve their outcome and to achieve a further reduction of leukemic cell burden by administration of an innovative treatment schedule (DNX-FLA)? NOTE: if new drugs or therapeutic options become available, the experimental treatment
planned in this patient group may change during the course of the study.
Timepoint [3] 279361 0
For the study question on MRD Non-Responder patients, the main secondary endpoint will be MRD levels after DNX-FLA.
Secondary outcome [4] 279362 0
Patients participating in the randomized asparaginase studies (pB-ALL/MR, HR): Are asparaginase activity and asparaginase antibodies associated with development of allergic reactions, and do they have an effect on the outcome of the patients?

This outcome will be assessed using a pharmacokinetic assay (ie a blood test) and correlating this result to the patients clinical situation.
Timepoint [4] 279362 0
At the time of each asparaginase administration

Eligibility
Key inclusion criteria
Patients meeting all:
- newly diagnosed acute lymphoblastic leukemia
- no Ph+ (BCR/ABL or t(9;22)-positive) ALL
- no evidence of pregnancy or lactation period
- no participation in another study
- patient enrolled in participating centre
- written informed consent
Minimum age
365 Days
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients meeting any of the following will not be eligible and will be analysed seperately:
- pre-treatment with cytostatic drugs
- steroid pre-treatment with >/= 1mg/kg/d for more than two weeks during the last month before diagnosis
- treatment started according to another protocol
- underlying diseases that prohibit treatment according to the protocol
- ALL diagnosed as second malignancy

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
27/09/2011
Actual
20/12/2011
Date of last participant enrolment
Anticipated
Actual
8/12/2016
Date of last data collection
Anticipated
14/07/2028
Actual
Sample size
Target
4750
Accrual to date
Final
6178
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment outside Australia
Country [1] 3752 0
Germany
State/province [1] 3752 0
Country [2] 3753 0
Austria
State/province [2] 3753 0
Country [3] 3754 0
Czech Republic
State/province [3] 3754 0
Country [4] 3755 0
Italy
State/province [4] 3755 0
Country [5] 3756 0
Switzerland
State/province [5] 3756 0

Funding & Sponsors
Funding source category [1] 267542 0
Government body
Name [1] 267542 0
NHMRC
Country [1] 267542 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australian and New Zealand Children's Haematology/Oncology Group
Address
27-31 Wright St
Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 266579 0
University
Name [1] 266579 0
University Hospital Schleswig-Holstein
Address [1] 266579 0
Campus Kiel,
Brunswiker Str 10
24105 Keil
Country [1] 266579 0
Germany

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 269500 0
The Children's Hospital Westmead
Ethics committee address [1] 269500 0
Cnr Hawkesbury Road and Hainsworth Street, Westmead, NSW Australia
Locked Bag 4001, Westmead 2145, NSW Australia
Ethics committee country [1] 269500 0
Australia
Date submitted for ethics approval [1] 269500 0
Approval date [1] 269500 0
26/07/2010
Ethics approval number [1] 269500 0

Summary
Brief summary
This is a clinical trial investigating improved outcomes for children and adolescents with acute lymphoblastic leukaemia. Who is it for? You (or your child) may be eligible to join this study if you are aged between 1 and 18 years of age, and have been newly diagnosed with acute lymphoblastic leukaemia.The Study 9 research study is being done in order to maximise the chance of curing your child’s ALL while at the same time lowering the chance of significant short- and long-term side effects.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32936 0
Dr Draga Barbaric
Address 32936 0
Centre for Children's Cancer and Blood Disorders Sydney Children's Hospital High Street Randwick NSW 2031
Country 32936 0
Australia
Phone 32936 0
+61 2 93822970
Fax 32936 0
Email 32936 0
draga.barbaric@health.nsw.gov.au
Contact person for public queries
Name 16183 0
Dr Dr Draga Barbaric
Address 16183 0
Centre for Children's Cancer and Blood Disorders
Sydney Children's Hospital
High Street
Randwick NSW 2031
Country 16183 0
Australia
Phone 16183 0
+61 2 93822970
Fax 16183 0
Email 16183 0
draga.barbaric@health.nsw.gov.au
Contact person for scientific queries
Name 7111 0
Dr Draga Barbaric
Address 7111 0
Centre for Children's Cancer and Blood Disorders
Sydney Children's Hospital
High Street
Randwick NSW 2031
Country 7111 0
Australia
Phone 7111 0
+61 2 93822970
Fax 7111 0
Email 7111 0
draga.barbaric@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIMulti-Cohort Transcriptomic Subtyping of B-Cell Acute Lymphoblastic Leukemia2022https://doi.org/10.3390/ijms23094574
N.B. These documents automatically identified may not have been verified by the study sponsor.