ANZCTR - Registration

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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

25/08/2024

Date data sharing statement 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

Secondary ID [1]

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

Condition category

Condition code

Cancer

Leukaemia - Acute leukaemia

Cancer

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]

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]

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]

Randomisation R1: 5 year event-free survival from time of randomization

Primary outcome [2]

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]

Randomization R2: 5 year disease-free survival from time of randomization

Primary outcome [3]

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]

Randomization RHR: rate of MRD highly positive patients (MRD greater than or equal to 10-3) at TP2 (week 12)

Secondary outcome [1]

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]

5 year DFS for this study compared historically with patients on AIEOP-BFM ALL 2000

Secondary outcome [2]

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]

5 year EFS for this study compared historically with patients of AIEOP-BFM ALL 2000

Secondary outcome [3]

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]

For the study question on MRD Non-Responder patients, the main secondary endpoint will be MRD levels after DNX-FLA.

Secondary outcome [4]

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]

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?

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]

Germany

State/province [1]

Country [2]

Austria

State/province [2]

Country [3]

Czech Republic

State/province [3]

Country [4]

Italy

State/province [4]

Country [5]

Switzerland

State/province [5]

Country [6]

Israel

State/province [6]

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

NHMRC

Address [1]

Level 1
16 Marcus Clarke Street
Canberra ACT 2601

Country [1]

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]

University

Name [1]

University Hospital Schleswig-Holstein

Address [1]

Campus Kiel,
Brunswiker Str 10
24105 Keil

Country [1]

Germany

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Children's Hospital Westmead

Ethics committee address [1]

Cnr Hawkesbury Road and Hainsworth Street, Westmead, NSW Australia
Locked Bag 4001, Westmead 2145, NSW Australia

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

26/07/2010

Ethics approval number [1]

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

Dr Draga Barbaric

Address

Centre for Children's Cancer and Blood Disorders Sydney Children's Hospital High Street Randwick NSW 2031

Country

Australia

Phone

+61 2 93822970

Fax

[email protected]

Contact person for public queries

Name

Dr Draga Barbaric

Address

Centre for Children's Cancer and Blood Disorders
Sydney Children's Hospital
High Street
Randwick NSW 2031

Country

Australia

Phone

+61 2 93822970

Fax

[email protected]

Contact person for scientific queries

Name

Draga Barbaric

Address

Centre for Children's Cancer and Blood Disorders
Sydney Children's Hospital
High Street
Randwick NSW 2031

Country

Australia

Phone

+61 2 93822970

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

Results will be published in accredited scientific journal. This will be distributed and explained to
participants who wish to receive study results by their treating doctor.

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

Source	Title	Year of Publication	DOI
Dimensions AI	Multi-Cohort Transcriptomic Subtyping of B-Cell Acute Lymphoblastic Leukemia	2022	https://doi.org/10.3390/ijms23094574

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically