ANZCTR - Registration

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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]

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

Condition category

Condition code

Cancer

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]

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]

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]

Complete remission rate

Secondary outcome [1]

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]

Day 15 induction marrow status

Secondary outcome [2]

To determine the effectiveness and toxicity of sequential intensive courses of chemotherapy in reducing the MRD burden in high risk ALL

Timepoint [2]

MRD levels on Day 33 and Day 79

Secondary outcome [3]

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]

Toxicity of each of the intensive high risk block of therapy

Secondary outcome [4]

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]

Mortality

Secondary outcome [5]

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]

Overall survival, DFS and EFS (time to treatment failure)

Secondary outcome [6]

To evaluate the effectiveness and toxicity of allogeneic stem cell transplantation (SCT) on MRD levels

Timepoint [6]

Nil other known

Secondary outcome [7]

To treat children with standard and medium risk ALL with the control arms of the open BFM-2000 study protocol

Timepoint [7]

Nil other known

Secondary outcome [8]

To collect bone marrow aspirates at diagnosis for concurrent and future laboratory-based studies (eg micro-arrays)

Timepoint [8]

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?

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]

Self funded/Unfunded

Name [1]

Address [1]

Country [1]

Primary sponsor type

Other Collaborative groups

Name

ANZCHOG

Address

27-31 Wright St
Clayton
VIC 3168

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Sydney Children's Hospitals Network Human Research Ethics Committee

Ethics committee address [1]

Cnr Hawkesbury Road and Hainsworth Street
Westmead NSW 2145

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

30/04/2002

Ethics approval number [1]

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

Dr Luciano Dalla-Pozza

Address

Cancer Centre for Children
The Children's Hospital at Westmead
Cnr Hawkesbury Road and Hainsworth Street
Westmead NSW 2145

Country

Australia

Phone

+61 2 9845 0000

Fax

[email protected]

Contact person for public queries

Name

Anthea Ng

Address

Cancer Centre for Children
The Children's Hospital at Westmead
Cnr Hawkesbury Road and Hainsworth Street
Westmead NSW 2145

Country

Australia

Phone

+61 2 9845 0000

Fax

+61 2 9845 2171

[email protected]

Contact person for scientific queries

Name

Luciano Dalla-Pozza

Address

Cancer Centre for Children
The Children's Hospital at Westmead
Cnr Hawkesbury Road and Hainsworth Street
Westmead NSW 2145

Country

Australia

Phone

+61 2 9845 0000

Fax

+61 2 9845 2171

[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

Source	Title	Year of Publication	DOI
Dimensions AI	Improving the Identification of High Risk Precursor B Acute Lymphoblastic Leukemia Patients with Earlier Quantification of Minimal Residual Disease	2013	https://doi.org/10.1371/journal.pone.0076455
Embase	Incidence and outcome of osteonecrosis in children and adolescents after intensive therapy for acute lymphoblastic leukemia (ALL).	2016	https://dx.doi.org/10.1002/cam4.645
Embase	A risk score including microdeletions improves relapse prediction for standard and medium risk precursor B-cell acute lymphoblastic leukaemia in children.	2018	https://dx.doi.org/10.1111/bjh.15056
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