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Trial registered on ANZCTR


Registration number
ACTRN12607000302459
Ethics application status
Approved
Date submitted
18/12/2003
Date registered
18/12/2003
Date last updated
24/03/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Limited Institution Study for Treatment of Acute Lymphoblastic Leukamia for Paediatric Patients in Australia,New Zealand and The Netherlands
Scientific title
A Phase III limited Institution Pilot Study to evaluate the effects of a chemotherapy regimen in the treatment of Acute Lymphoblastic Leukaemia to evaluate toxicity.
Secondary ID [1] 287968 0
Nil known
Universal Trial Number (UTN)
Trial acronym
ANZCHOG ALL8
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute lymphoblastic leukaemia 296844 0
Condition category
Condition code
Cancer 297073 297073 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study involves the administration of Chemotherapy regimes for duration of 2 years. Control group (standard risk and medium risk patients) receives standard chemotherapy regimen for acute lymphoblastic leukaemia in children. Intervention group (high risk and very high risk patients) receives standard chemotherapy regimen similar to the control group plus 2 courses of three different chemotherapy regimes.

Standard chemotherapy regime (given in the following order):

Protocol 1 Days 1-33:
Prednisolone 60mg/m2 intravenous(IV) or per os(PO) ie through the mouth Vincristine 1.5mg/m2 IV L'Asparaginase 5000IU/m2 intramuscular injection (IMI) Daunorubicin 30mg/m2 IV intrathecal (IT) Methotrexate(MTX) Age related dose 1-2years 8mg 2-3 years 10mg >3years 12mg

Protocol 1 Days 36-79:
Cytarabine 75mg/m2 IV or subcutaneous (SC) Mercaptopurine 60mg/m2 PO Cyclophosphamide 1000mg/m2 IV IT MTX age related doses as above

Protocol M Days 1-57:
Mercaptopurine 25mg/m2 PO Methotrexate 5000mg/m2 IV 4500mg/m2 IV IT Methotrexate age related doses as above Folinic Acid 15mg/m2 IV

Protocol II Days 1-36:
Dexamethasone 10mg/m2 PO Vincristine 1.5mg/m2 IV L-Asparaginase 10 000 Iu /m2 IMI Doxorubicin 30mg/m2 IV IT Methotrexate age related dose as above

Protocol II Days 36-49:
Cytarabine 75mg/m2 IV or SC Thioguanine 60mg/m2 PO IT Methotrexate age related dose as above Cyclophosphamide 1000mg/m2 IV

Maintenance Therapy:
Required until a total of 104 weeks of therapy has been completed Mercaptopurine 50mg/m2/day PO Methotrexate 20mg/m2/week PO

Additional chemotherapy regimes (intervention):
Interventional group will receive protocol 1 (as in the standard chemotherapy regime) and then either 1 or 2 courses of three different chemotherapy regimes (described below) depending on risk. Each High Risk block should be given at five week intervals and ideally no break between courses. The patients will then receive protocol II and Maintenance therapy (as in the standard chemotherapy regime). Patients classified as ‘very high risk’ may or may not receive a stem cell transplant depending on if there is a suitable donor. If they do receive a stem cell transplant then these patients do not receive the second chemotherapy course.

High Risk 1 Course 1
6-Mercaptopurine 25mg/m2 PO Methotrexate 5g/m2 IV Vincristine 1.5mg/m2 IV L'Asparaginase 10 000 IU/m2 IMI Etoposide 350mg/m2 IV Cyclophsphamide 1200mg/m2 IV IT Methotrexate Age related dose as above IT Cytaraine Age related dose 1-2 years 20mg 2-3 years 26mg >3 years 30mg IT Hydrocortisone Age related dose 1-2years 30mg 2-3years 40mg >3years 50mg granulocyte colony stimulating factor(GCSF) 10mcg/kg/day SC

High Risk 2 Course 1
Methotrexate 5g/m2 IV Vincristine 1.5mg/m2/day IV L'Asparaginase 10 000 IU/m2/day IMi Cytarabine 2000mg/m2 IV Mitoxantrone 7mg/day IV IT Methotrexate Age related dose as above IT Cytarabine Age related dose as above IT Hydrocortisone Age related doses as above GCSF 5mcg/kg/day SC

High Risk 3 Course 1
Methotrexate 5g/m2 IV Idarubicin 8mg/m2/day IV Cytarabine 2000mg/m2/day IV Fludarabine 30mg/m2/day IV IT Methotrexate Age related dose as above IT Cytarabine Age related dose as above IT Hydrocortisone Age related dose as above GCSF 5mcg/kg/day SC High

High Risk 1 Course 2
Methotrexate 5g/m2 IV Vincristine 1.5mg/m2 IV bolus L'Asparaginase 10 000 IU/day IMI Etoposide 350mg/m2/day IV Cyclophosphamide 1200mg/m2/day IV IT Methotrexate Age related dose as above IT Cytarabine Age related dose as above IT Hydrocortisone Age related dose as above GCSF 5mcg/kg/day SC

High Risk 2 Course 2
Methotrexate 5g/m2 IV Vincristine 1.5mg/m2/day IV L'Asparaginase 10 000 IU /m2/day IMI Cytarabine 2000mg/m2 IV Mitoxantrone 7mg/m2/day IV IT Methotrexate Age related dose as above IT Cytarabine Age related dose as above IT Hydrocortisone Age related dose as above GCSF 5mcg/kg/day

High Risk 3 Course 2
Methotrexate 5g/m2 IV Cytarabine 2000mg/m2/day IV Fludarabine 30mg/m2/day IV IT Methotrexate Age related dose as above IT Cytarabine Age related dose as above IT Hydrocortisone Age related dose as above GCSF 5mcg/kg/day SC
Intervention code [1] 1297 0
Treatment: Drugs
Comparator / control treatment
Patients with standard and medium risk acute lymphoblastic leukaemia will be used as controls
Control group
Active

Outcomes
Primary outcome [1] 296678 0
To assess the efficacy and toxicity of a series of six sequential intensive courses of chemotherapy following the induction of remission in patients with high risk acute lymphoblastic leukaemia
Timepoint [1] 296678 0
Complete remission rate
Secondary outcome [1] 319094 0
To use the predictive value of PCR-based minimal residual disease (MRD) assays to stratify patients at risk of disease relapse into different risk groups
Timepoint [1] 319094 0
Day 15 induction marrow status
Secondary outcome [2] 319095 0
To determine the effectiveness and toxicity of sequential intensive courses of chemotherapy in reducing the MRD burden in high risk ALL
Timepoint [2] 319095 0
MRD levels on Day 33 and Day 79
Secondary outcome [3] 319096 0
To assess whether a reduction in MRD level translates into improved disease-free survival (DFS), event-free survival (EFS) and overall survival (OS) in patients with high risk ALL
Timepoint [3] 319096 0
Toxicity of each of the intensive high risk block of therapy
Secondary outcome [4] 319097 0
To serially monitor MRD throughout therapy, and to determine the accuracy with which MRD levels predict relapse in patients from all risk groups
Timepoint [4] 319097 0
Mortality
Secondary outcome [5] 319098 0
To compare the results of this study directly with those of the German Berlin-Frankfurt-Munster Group for children with standard, medium and high risk ALL
Timepoint [5] 319098 0
Overall survival, DFS and EFS (time to treatment failure)
Secondary outcome [6] 319099 0
To evaluate the effectiveness and toxicity of allogeneic stem cell transplantation (SCT) on MRD levels
Timepoint [6] 319099 0
Nil other known
Secondary outcome [7] 319100 0
To treat children with standard and medium risk ALL with the control arms of the open BFM-2000 study protocol
Timepoint [7] 319100 0
Nil other known
Secondary outcome [8] 319101 0
To collect bone marrow aspirates at diagnosis for concurrent and future laboratory-based studies (eg micro-arrays)
Timepoint [8] 319101 0
Nil other known

Eligibility
Key inclusion criteria
1) All newly diagnosed children with ALL aged between 1 and 17 years of age (inclusive).
2) Written informed consent obtained within 14 days of commencement of systemic therapy since initial induction therapy is a standard 5 drug regimen
3) Patients with any of the following characteristics are also eligible:
- B or T lineage immunophenotype
- co-expression of myeloid and lymphoid antigens
- t(9;22), t(4;11)
- Down syndrome
- central nervous system leukaemia, extramedullary disease or bulky mass disease
- Day 15 bone marrow showing >5% blasts (M2 of M3)
Minimum age
1 Years
Maximum age
17 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Age less than 1 year, or greater than or equal to 18 years
2) ALL occurring as a second malignancy
3) Patients with biphenotypic or bilineage leukaemia
4) Patients who develop a documented switch in the lineage of the leukaemia (after commencing Protocol I)
5) Mature B cell ALL with t(8;14), t(2;8), t(8;22)
6) Previously treated patients:
- systemic corticosteroids administered for any reason at a dose equivalent to or greater than 1mg/kg/day.
- Prednisolone for more than 72 hours within 4 weeks of diagnosis

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/09/2002
Actual
6/09/2002
Date of last participant enrolment
Anticipated
Actual
16/02/2012
Date of last data collection
Anticipated
Actual
16/02/2017
Sample size
Target
500
Accrual to date
Final
658
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA

Funding & Sponsors
Funding source category [1] 292436 0
Self funded/Unfunded
Name [1] 292436 0
Country [1] 292436 0
Primary sponsor type
Other Collaborative groups
Name
ANZCHOG
Address
27-31 Wright St
Clayton
VIC 3168
Country
Australia
Secondary sponsor category [1] 291129 0
None
Name [1] 291129 0
Address [1] 291129 0
Country [1] 291129 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293895 0
The Sydney Children's Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 293895 0
Cnr Hawkesbury Road and Hainsworth Street
Westmead NSW 2145
Ethics committee country [1] 293895 0
Australia
Date submitted for ethics approval [1] 293895 0
Approval date [1] 293895 0
30/04/2002
Ethics approval number [1] 293895 0
2002/030

Summary
Brief summary
Most children with leukaemia are cured, but those with the worst forms do less well. This trial is testing new ways of combining the most effective drugs, and adding a tranplant for children with the worst forms of leukaemia and a suitable donor. This tiral will determine if these new approaches could improve cure rates, and if they could be used more widely.
Trial website
Trial related presentations / publications
Marshall GM, Dalla-Pozza L, Sutton R, Ng A, de Groot-Krusemant HA, et al.(2013) High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation.Leukemia. pp. doi:10.1038/leu.2013.1044
Public notes

Contacts
Principal investigator
Name 35199 0
Dr Luciano Dalla-Pozza
Address 35199 0
Cancer Centre for Children
The Children's Hospital at Westmead
Cnr Hawkesbury Road and Hainsworth Street
Westmead NSW 2145
Country 35199 0
Australia
Phone 35199 0
+61 2 9845 0000
Fax 35199 0
Email 35199 0
[email protected]
Contact person for public queries
Name 10486 0
Anthea Ng
Address 10486 0
Cancer Centre for Children
The Children's Hospital at Westmead
Cnr Hawkesbury Road and Hainsworth Street
Westmead NSW 2145
Country 10486 0
Australia
Phone 10486 0
+61 2 9845 0000
Fax 10486 0
+61 2 9845 2171
Email 10486 0
[email protected]
Contact person for scientific queries
Name 1414 0
Luciano Dalla-Pozza
Address 1414 0
Cancer Centre for Children
The Children's Hospital at Westmead
Cnr Hawkesbury Road and Hainsworth Street
Westmead NSW 2145
Country 1414 0
Australia
Phone 1414 0
+61 2 9845 0000
Fax 1414 0
+61 2 9845 2171
Email 1414 0
[email protected]

No information has been provided regarding IPD availability


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 AIImproving the Identification of High Risk Precursor B Acute Lymphoblastic Leukemia Patients with Earlier Quantification of Minimal Residual Disease2013https://doi.org/10.1371/journal.pone.0076455
EmbaseIncidence and outcome of osteonecrosis in children and adolescents after intensive therapy for acute lymphoblastic leukemia (ALL).2016https://dx.doi.org/10.1002/cam4.645
EmbaseA risk score including microdeletions improves relapse prediction for standard and medium risk precursor B-cell acute lymphoblastic leukaemia in children.2018https://dx.doi.org/10.1111/bjh.15056
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.