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Trial registered on ANZCTR


Registration number
ACTRN12616001394437
Ethics application status
Approved
Date submitted
29/08/2016
Date registered
7/10/2016
Date last updated
8/10/2019
Date data sharing statement initially provided
8/10/2019
Date results information initially provided
8/10/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukaemia
Scientific title
Total body irradiation vs non-total body irradiation myeloablative conditioning regimen for allogeneic stem cell transplantation in children and adolescents with acute lymphoblastic leukaemia.
Secondary ID [1] 290015 0
NCT01949129
Universal Trial Number (UTN)
Trial acronym
ALL SCTped 2012 FORUM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute lymphoblastic leukaemia 300034 0
Condition category
Condition code
Cancer 299929 299929 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a multinational, multi-centre, randomised, phase II/III study comparing chemo based myeloablative conditioning regimen Fludarabine/Thiotepa/Busulphan or Fludarabine/Thiotepa/Treosulfan with Total body irradiation/Etoposide prior to Hematopoetic stem cell transplantation (HSCT) for children and adolescents with Acute lymphoblastic leukaemia (ALL) in complete remission (CR).

Stratum 1 and stratum 2 -
Stratum 1: for patient who are older than age of 4 with a Human leucocyte antigen (HLA) identical sibling donor (MSD) or a HLA matched donor (MD).
Stratum 2: for patients with a HLA mismatched donors, mismatched unrelated donors (MMD), mismatched cord blood or HLA haplo-identical family members.

Fludarabine/Thiotepa/Busulphan or Fludarabine/Thiotepa/Treosulfan according to country's decision.
*Drug: Thiotepa
1x5 mg/kg for 2 day from day -8 of HSCT, intravenous infusion
*Drug: Fludarabine
37.5 mg/m^2 intravenous infusion for 30 mins for 4 days, start on day -6 of HSCT
*Drug: Busulphan
intravenous infusion, dosage according therapeutic drug monitoring, for 4 days start at day -6 of HSCT.
*Drug: Treosulfan
14g/m^2 for 3 days, start on day -6 from HSCT, intravenous infusion.

Intervention code [1] 295731 0
Treatment: Drugs
Comparator / control treatment
Control Arm - Etoposide (VP16)/TBI
*Drug: VP16
60 mg/kg intravenous infusion for 1 day, start on day -3 of HSCT
Other Name: Etoposide
*Radiation: Total body irradiation (TBI)
12 Gy in 6 fractions over 3 days, start on day -6 of HSCT.
Control group
Active

Outcomes
Primary outcome [1] 299416 0
Overall Survival (OS) Stratum 1 (randomisation TBI+ chemo-conditioning vs. chemo-conditioning only)
Timepoint [1] 299416 0
First: 18 months after inclusion of first patient, afterwards annually up to 10 years
Primary outcome [2] 299579 0
Event free survival (EFS) Stratum 2 (mismatched donor transplantation)
The following will be considered as events:
1. disease progression or relapse (defined by >= 5% blasts in bone marrow or CSF or any histological evidence in other tissues).
2. death from any cause
3. secondary neoplasm.
Timepoint [2] 299579 0
First: 18 months after inclusion of first patient, afterwards annually up to 10 years.
This will be assessed by routine bone marrow aspirates and lumber punctures and by the review of medical records.
Secondary outcome [1] 327110 0
Event free survival (EFS)
The following will be considered as events:
1. disease progression or relapse (defined by >= 5% blasts in bone marrow or CSF or any histological evidence in other tissues).
2. death from any cause
3. secondary neoplasm.
Timepoint [1] 327110 0
First: 18 months after inclusion of first patient, afterwards annually up to 10 years.
This will be assessed by routine bone marrow aspirates and lumber punctures and by the review of medical records.
Secondary outcome [2] 327601 0
Cumulative Incidence of Treatment-related mortality (TRM) for Stratum 1 and 2
Timepoint [2] 327601 0
First: 18 months after inclusion of first patient, afterwards annually up to 10 years
This will be assessed by the review of medical records.
Secondary outcome [3] 327602 0
Cumulative Incidence of Relapse for Stratum 1 and 2
Timepoint [3] 327602 0
First: 18 months after inclusion of first patient, afterwards annually up to 10 years
This will be assessed by routine bone marrow aspirates and lumber punctures and by the review of medical records.
Secondary outcome [4] 327603 0
Composite toxicity - Acute and late for Stratum 1 and 2
Timepoint [4] 327603 0
First: 18 months after inclusion of first patient, afterwards annually up to 10 years
This will be assessed by routine blood tests and procedures performed as clinically indicated.
Secondary outcome [5] 327604 0
Overall Survival (OS) (Stratum 2)
Timepoint [5] 327604 0
First: 18 months after inclusion of first patient, afterwards annually up to 10 years

Eligibility
Key inclusion criteria
All patients with ALL (except for patients with mature B-ALL) who fulfil the following criteria:
- Age at diagnosis less than or equal to 18 years. Age at HSCT less than or equal to 21 years.
- indication for allogeneic HSCT
- complete remission (CR) before SCT
- written consent of the parents (legal guardian) and, if necessary, the minor patient via “Informed Consent Form”
- no pregnancy
- no secondary malignancy
- no previous HSCT
- HSCT is performed in a study participating centre
Minimum age
No limit
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Non Hodgkin-Lymphoma
- The whole protocol or essential parts are declined either by patient himself/herself or the respective legal guardian
- No consent is given for saving and propagation of anonymous medical data for study reasons
- Severe concomitant disease that does not allow treatment according to the protocol at the investigator’s discretion:
e. g. malformation syndromes, cardiac malformations, metabolic disorders;
Renal impairment (< 30% of normal glomerular filtration rate)
Severe pulmonary, hepatic or cardial impairment due to toxicity or infection
- Karnofsky / Lansky score < 50%
- Subjects unwilling or unable to comply with the study procedures

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be done using the web-based study site.
Stratification performed by the following factors:
- Country
- Donor type
- CR1/CR2/>CR2
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The primary evaluation will be done according to the intention to treat principle. For question 1, all randomised patients (target 1000 patients) will be analysed according to their randomised arm. Secondary per-protocol and as-treated analysis will be done. The per-protocol analysis excludes patients that do and do not receive TBI in the chemotherapy and TBI-arm, respectively. The as-treated analysis will categorize the patients according to whether TBI is given or not.
The significance level is determined as 0.05 each for all questions.
Question 1: The one-sided confidence interval for the difference of the Kaplan-Meier estimate of the 4-year OS will be calculated.
A total of 1000 patients will be randomised. According to our previous experience, the 4-year OS in the control arm (with TBI) is about 70%. Monte-Carlo simulations show, that with a non-inferiority margin of about 8%, the power will be above 80% (given a one-sided alpha of 5%).
Question 2: Kaplan-Meier estimates will be used to estimate EFS. Log-rank test and Cox-regression will be used to compare HSCT using mismatched unrelated donors, haplo-identical family donors or mismatched cord blood.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Due to the results to the interim analysis, participating Australian and New Zealand sites have decided to close this study to further recruitment.
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment hospital [1] 6544 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 6545 0
Sydney Children's Hospital - Randwick
Recruitment hospital [3] 6546 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [4] 9086 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [5] 11770 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 14133 0
2031 - Randwick
Recruitment postcode(s) [2] 14132 0
2145 - Westmead
Recruitment postcode(s) [3] 17581 0
3052 - Parkville
Recruitment postcode(s) [4] 14134 0
4101 - South Brisbane
Recruitment postcode(s) [5] 23865 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 8124 0
New Zealand
State/province [1] 8124 0

Funding & Sponsors
Funding source category [1] 294388 0
Government body
Name [1] 294388 0
Cancer Australia
Address [1] 294388 0
Level 14, 300 Elizabeth Street, Surry Hills NSW 2010
Country [1] 294388 0
Australia
Primary sponsor type
Other Collaborative groups
Name
St. Anna Kinderkrebsforschung
Address
St. Anna Kinderkrebsforschung
Zimmermannplatz 10
A-1090 Vienna
Austria
Country
Austria
Secondary sponsor category [1] 293236 0
Other Collaborative groups
Name [1] 293236 0
Australian and New Zealand Children's Haematology/Oncology Group (ANZCHOG)
Address [1] 293236 0
Hudson Institute of Medical Research
27-31 Wright St, Clayton, VIC 3168
Country [1] 293236 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295818 0
The Sydney Children's Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 295818 0
Corner Hawkesbury Road and Hainsworth Street, Westmead, NSW, 2145
Ethics committee country [1] 295818 0
Australia
Date submitted for ethics approval [1] 295818 0
14/08/2013
Approval date [1] 295818 0
11/05/2014
Ethics approval number [1] 295818 0
HREC/13/SCHN/357
Ethics committee name [2] 295948 0
Ethikkommission der der Medizinischen Universitat Wien
Ethics committee address [2] 295948 0
Borschkegasse 8b/6, A-1090 Wien
Ethics committee country [2] 295948 0
Austria
Date submitted for ethics approval [2] 295948 0
24/09/2012
Approval date [2] 295948 0
11/02/2013
Ethics approval number [2] 295948 0
1778/2012

Summary
Brief summary
The ALL SCTped 2012 FORUM is a multinational study that explore the efficacy and efficiency of two different chemo-conditioning regimens (Flu/Thio with Treo or ivBu) in comparison to the standard conditioning regimen (TBI/VP16) for children and adolescents with Acute Lymphoblastic Leukaemia undergoing Allogeneic Stem Cell Transplantation.

Who is it for?
Patients with Acute lymphoblastic leukaemia diagnosed before or equal to the age of 18 and will be undergoing an Allogeneic stem cell transplantation before or equal to the age of 21.

Study details:
This study will compare 2 different conditioning regimens. Eligible patients will be randomised (allocated by chance) to either total body irradiation containing regimen (TBI) or to non-total body irradiation regimen (non-TBI) and this will be followed by haematopoietic stem cell transplant (HSCT).
The study will compare the outcome of children with ALL who receive a total body irradiation conditioning regimen versus irradiation free conditioning followed by haematopoietic stem cell transplant (HSCT). The study will also compare the outcome after mismatched donors, haploidentical family donors or mismatched cord blood.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes

Contacts
Principal investigator
Name 68550 0
Prof Peter Shaw
Address 68550 0
The Children's Hospital at Westmead
Cnr Hawkesbury Road & Hainsworth Street, Westmead, NSW 2145
Country 68550 0
Australia
Phone 68550 0
+612 98450000
Fax 68550 0
+612 98452171
Email 68550 0
peter.shaw@health.nsw.gov.au
Contact person for public queries
Name 68551 0
Miss Jun Cai
Address 68551 0
The Children's Hospital at Westmead
Cnr Hawkesbury Road & Hainsworth Street, Westmead, NSW 2145
Country 68551 0
Australia
Phone 68551 0
+612 98452174
Fax 68551 0
+612 98452171
Email 68551 0
jun.cai@health.nsw.gov.au
Contact person for scientific queries
Name 68552 0
Prof Peter Shaw
Address 68552 0
The Children's Hospital at Westmead
Cnr Hawkesbury Road & Hainsworth Street, Westmead, NSW 2145
Country 68552 0
Australia
Phone 68552 0
+612 98450000
Fax 68552 0
+612 98452171
Email 68552 0
peter.shaw@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
The results of the study will be made publically once the study have completed, individual participant data will not be released.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary