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1. To improve the overall outcome as compared to the previous protocols of the DCOG, especially ALL-9 and ALL-10. This is aimed for by decreasing therapy for part of the patients (TEL/AML1, Down syndrome, PPR only), increasing therapy for…
ID
NL-OMON29675
Source
NTR
Brief title
ALL11
Condition
- Leukaemias
Health condition
Acute lymfatische leukemie bij kinderen acute lymphoblastic leukemia in children
Research involving
Human
Sponsors and support
Primary sponsor
:
Prinses Máxima Centrum voor kinderoncologie
Source(s) of monetary or material Support
:
Dutch Childhood Ongology Group
Intervention
Explanation
Outcome measures
Primary outcome
2. Primary endpoint is the number of allergic reactions/silent inactivation; secondary endpoints are toxicity, EFS and survival.
3. Primary endpoint is the number of admissions for fever and the number of courses with therapeutic antibiotics in both groups.
4. Primary endpoint is the number of patients with allergic reaction or silent inactivation to PEGasparaginase and who are therefore switched to Erwinase. Secondary endpoints are the average cumulative dose of PEGasparaginase administered to patients in the MR arm A compared to the historical control of the ALL-10 MR study.
Background summary
Since 1999, infants with ALL diagnosed <1 year of age are treated on specific protocols of the Interfant collaborative group. Patients with the Philadelphia chromosome positive ALL chromosomes are treated on specific protocols of the EsPhALL group since 2004. All other ALL patients were treated according to the ALL-10 protocol that started in 2004. This treatment protocol included 3 different stratification arms (standard risk, medium risk and high risk) which are very different in their intensity. The factors used for risk group stratification in the ALL-10 protocol were the presence of t[4;11], a poor response to initial therapy, as measured in the peripheral
blood by response to prednisone and one intrathecal dose of methotrexate (MTX) after one week of therapy (so-called prednisone response), induction failure after 33 days of combination chemotherapy and the minimal residual disease measured by PCR at day 33 and day 79. The ALL-10 protocol was the first DCOG protocol where therapy stratification was done by analysis of MRD. MRD was used for this purpose because an earlier study showed that MRD had a very strong prognostic value: patients with very low levels of MRD (standard risk group) had an excellent outcome, patients with high levels of MRD (high risk group) a poor outcome and patients with intermediate levels (medium risk group) had an intermediate outcome.
The ALL-10 protocol is - based upon its very good outcome - used as basis for the ALL-11 protocol.
Study objective
2. Does a continuous schedule of Asparaginase lead to less allergic reaction/inactivation of Asparaginase than the standard non continuous schedule of Asparaginase? Patients are randomized to receive noncontinuous PEGasparaginase in IA (induction) and intensification of the Medium Risk group (standard arm A) or to receive continuous PEGasparaginase in IA, IB, M and intensification, (continuous arm B) with the same cumulative number of doses of PEGasparaginase.
3. Does prophylactic administration of intravenous immunoglobulins reduce the number of infections during the intensive treatment phases? Patients are randomized in the induction and MR treatment group to receive or not receive prophylactic immunoglobulins
4. Individualize the dose schedule of asparaginase by therapeutic drug monitoring in order to detect silent inactivation of asparaginase, to prevent allergic/anaphylactic reactions, to switch Asparaginase preparation in time and to prevent too high levels with possible toxicity.
Study design
1) Stratificatie into risk groups, based upon riskfactors
Standard risk (SR) group:
• MRD-negativity at TP1 (day 33) and at TP2 (day 79 before start of Protocol M) AND
• no CNS involvement or testis involvement at diagnosis AND
• no prednisone poor response at day 8 AND
• absence of any HR criterion
Medium risk (MR) group
• inconclusive/missing MRD results or MRD-positivity at TP1 (day 33) and/or at TP2 (day 79 before the start of protocol M), but MRD level at day 79 < 10–3 AND
• absence of any HR criterion
High Risk (HR) group:
• MRD level > 10-3 or unknown at TP1 and MRD level of ≥ 10–3 at TP2, OR
• presence of the t(4;11)(q11;q23) translocation or the corresponding fusion gene MLL/AF4, OR
• no complete remission at day 33
• Note: children with Down syndrome that fulfill the HR criteria are assigned to the MR group
2) Randomisations:
A. Does a continuous schedule of Asparaginase lead to less allergic reaction/inactivation of Asparaginase than the standard non continuous schedule of Asparaginase? Patients are randomized to receive noncontinuous PEGasparaginase in IA (induction) and intensification of the Medium Risk group (standard arm A) or to receive continuous PEGasparaginase in IA, IB, M and intensification, (continuous arm B) with the same cumulative number of doses of PEGasparaginase.
B. Does prophylactic administration of intravenous immunoglobulins reduce the number of infections during the intensive treatment phases? Patients are randomized in the induction and MR treatment group to receive or not receive prophylactic immunoglobulins
Intervention
PEG-L-asparaginase (Oncospar)
Study burden and risks
Public
Prinses Máxima Centrum voor kinderoncologie
Prof. dr. R. Pieters
Heidelberglaan 25
3584 CS
Utrecht
The Netherlands
The Netherlands
088-972 72 72
R.Pieters@prinsesmaximacentrum.nl
Prof. dr. R. Pieters
Heidelberglaan 25
3584 CS
Utrecht
The Netherlands
The Netherlands
088-972 72 72
R.Pieters@prinsesmaximacentrum.nl
Scientific
Prinses Máxima Centrum voor kinderoncologie
Prof. dr. R. Pieters
Heidelberglaan 25
3584 CS
Utrecht
The Netherlands
The Netherlands
088-972 72 72
R.Pieters@prinsesmaximacentrum.nl
Prof. dr. R. Pieters
Heidelberglaan 25
3584 CS
Utrecht
The Netherlands
The Netherlands
088-972 72 72
R.Pieters@prinsesmaximacentrum.nl
Age
Babies and toddlers (28 days-23 months)
Babies and toddlers (28 days-23 months)
Children (2-11 years)
Children (2-11 years)
Adolescents (12-15 years)
Adolescents (12-15 years)
Adolescents (16-17 years)
Adolescents (16-17 years)
Inclusion criteria
2. Age between > 1 and < 19 years
3. Informed consent signed by parents/guardians and patient if 12 years or older
4. Diagnosis ALL confirmed by DCOG laboratory
5. Patient should be treated in a Dutch Childhood Oncology Centre
6. Patient should be >3 months settled in The Netherlands at diagnosis
Exclusion criteria
2. Age < 366 days at diagnosis (infant ALL); these patients are eligible for the Interfant protocol
3. Patients with secondary ALL
4. Patients with mature B-ALL (immunophenotypical or documented presence of karyotype t(8;14), t(2;8), t(8;22) and breakpoint as in B-ALL)
5. Patients with relapsed ALL
6. Pre-existing contra-indications for treatment according to (parts of) protocol ALL-11.
7. Essential data missing (in consultation with the protocol chairman)
8. Treatment with systemic corticosteroids and/or cytostatics in a 4-week interval prior to diagnosis. One exception is the use of corticosteroids as emergency treatment.
9. Patients with Ph-positive ALL (documented presence of t(9;22)(q34;q11) and/or of the BCR/ABL fusion transcript). These patients will be transferred to the EsPhALL protocol in induction according to the guidelines of the EsPhALL protocol.
Design
Study phase
:
3
Study type
:
Interventional
Intervention model
:
Other
Allocation
:
Randomized controlled trial
Masking
:
Open (masking not used)
Control
:
N/A , unknown
Primary purpose
:
Treatment
Recruitment
NL
Recruitment status
:
Recruitment stopped
Start date (anticipated)
:
Enrollment
:
630
Type
:
Actual
IPD sharing statement
Plan to share IPD
:
No
Approved WMO
Date
:
Application type
:
First submission
Review commission
:
METC Erasmus MC, Universitair Medisch Centrum Rotterdam (Rotterdam)
Followed up by the following (possibly more current) registration
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
NTR-new | NL3227 |
NTR-old | NTR3379 |
EudraCT | 2012-000067-25 |
CCMO | NL39400.078.12 |
OMON | NL-OMON47149 |
Results posted
:
Actual enrolment
:
819
Summary results
"The DCOG ALL11 showed that the five-year survival for children with acute lymphatic leukaemia increased to 94%. The ALL11 included 800 Dutch children and examined modified treatment protocols for four subgroups. The modifications were found to have a positive effect on survival and quality of life.
The effect of modified treatment in specific groups of children with leukaemia, including those with a so-called Ikaros abnormality (IFZF1del), was examined. In this study, these children received an extra year of chemotherapy in the 'maintenance phase' on top of the first two years of treatment. This modification led to a nearly three times lower risk of cancer recurrence: it only happened in 9% of them, compared to 26% of children in the previous treatment protocol.
In the ALL-11 protocol, doctors and researchers also looked at the effect of less intensive treatment for three other groups of children. These included children with a DNA abnormality in their leukaemia cells that is associated with a very high cure rate (ETV6::RUNX1), and children with Down's syndrome who suffer a lot of side effects from therapy. These children were given a lower amount of anthracyclines, a particular type of chemotherapy that increases the risk of heart damage and infections. The modification proved to be a good choice: the children had the same or even better survival rate while their quality of life improved due to a lower risk of infections and less risk of heart damage."
The effect of modified treatment in specific groups of children with leukaemia, including those with a so-called Ikaros abnormality (IFZF1del), was examined. In this study, these children received an extra year of chemotherapy in the 'maintenance phase' on top of the first two years of treatment. This modification led to a nearly three times lower risk of cancer recurrence: it only happened in 9% of them, compared to 26% of children in the previous treatment protocol.
In the ALL-11 protocol, doctors and researchers also looked at the effect of less intensive treatment for three other groups of children. These included children with a DNA abnormality in their leukaemia cells that is associated with a very high cure rate (ETV6::RUNX1), and children with Down's syndrome who suffer a lot of side effects from therapy. These children were given a lower amount of anthracyclines, a particular type of chemotherapy that increases the risk of heart damage and infections. The modification proved to be a good choice: the children had the same or even better survival rate while their quality of life improved due to a lower risk of infections and less risk of heart damage."
Baseline characteristics
Patients with ALL, 1-19 years old