|- candidate number||12154|
|- NTR Number||NTR3379|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||28-mrt-2012|
|- Secondary IDs||2012-000067-25 EMEA|
|- Public Title||Protocol DCOG ALL-11.|
|- Scientific Title||Treatment study protocol of the Dutch Childhood Oncology Group for children and adolescents (1-19 year) with newly diagnosed acute lymphoblastic leukemia.|
|- hypothesis||1. To treat children with ALL with the best available treatment as possible, based upon the risk factors of the patient at diagnosis;|
2. Reduction of toxicity of treatment;
3. Reduction of allergic reactions on chemotherapy;
4. Reduction of infections during intensification of treatment.
|- Healt Condition(s) or Problem(s) studied||Acute Lymfatic Leukemia (ALL), Children|
|- Inclusion criteria||1. Newly diagnosed patients with T-lineage or precursor-B lineage ALL (patients with mature B-ALL are not eligible);|
2. Age > 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||1. Age ≥ 19 years at diagnosis;|
2. Age < 366 days at diagnosis (infant ALL);
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;
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.
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||2 or more arms, randomized|
|- planned startdate ||1-apr-2012|
|- planned closingdate||1-apr-2018|
|- Target number of participants||630|
|- Interventions||Stratification into risk groups, based upon riskfactors:|
Standard risk (SR) group:
1. MRD-negativity at TP1 (day 33) and at TP2 (day 79 before start of Protocol M) AND;
2. No CNS involvement or testis involvement at diagnosis AND;
3. No prednisone poor response at day 8 AND;
4. Absence of any HR criterion.
Medium risk (MR) group:
1. 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;
2. Absence of any HR criterion.
High Risk (HR) group:
1. MRD level > 10-3 or unknown at TP1 and MRD level of ≥ 10–3 at TP2, OR;
2. Presence of the t(4;11)(q11;q23) translocation or the corresponding fusion gene MLL/AF4, OR;
3. No complete remission at day 33;
4. Note: children with Down syndrome that fulfill the HR criteria are assigned to the MR group.
1. 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.
2. 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
|- Primary outcome||1. Survival;|
2. The number of allergic reactions/silent
inactivation of asparaginase;
3. The number of infectious episodes for which
patients are admitted to the hospital and receive therapeutic antibiotics or antifungals;
4. The number of patients with allergic reaction or
silent inactivation to PEGasparaginase and who are therefore switched to Erwinase.
|- Secondary outcome||1. EFS, CIR, death in induction, death in remission and toxicity;|
2. Toxicity, EFS and survival;
3. 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.
|- Timepoints||During interim analyses and also at the end of this protocol, expected in 2018.|
|- Trial web site||www.skion.nl|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES||Dr. J.G. Ridder-Sluiter, de|
|- CONTACT for SCIENTIFIC QUERIES||Prof. Dr. Rob Pieters|
|- Sponsor/Initiator ||Dutch Childhood Oncology Group (DCOG)|
(Source(s) of Monetary or Material Support)
|Dutch Childhood Oncology Group (DCOG)|
|- Brief summary||Treatment study protocol of the Dutch Childhood Oncology Group for children and adolescents (1-19 year) with newly diagnosed acute lymphoblastic leukemia.
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 outome - used as basis for the ALL-11 protocol.
|- Main changes (audit trail)||28-jul-2014: "ALL-11 add on study: ‘Towards evidence-based use of ciprofloxacin prophylaxis and glucocorticoids
for children with cancer’ |
This add on study focusses on the pharmacokinetics and pharmacodynamics of the glucocorticoids
prednisone and dexamethasone and the antibiotic ciprofloxacin in the treatment of pediatric acute
lymphoblastic leukemia. Blood serum levels of these drugs will be collected throughout therapy.
Population pharmacokinetics of these data will be determined with NONMEM (NON-linear Mixed
Effects Modelling). The correlation between mean residual disease (MRD) and pharmacokinetic
parameters will be evaluated to study the glucocorticoid pharmacodynamics and the 24 hour area
under the curve (AUC24) divided by the mean inhibitory concentrations (MIC) for ciprofloxacin.
The objective of this study is to develop individualized dosing. By determining the pharmacokinetic
parameters and the clinically significant covariables affecting the pk (e.g. age, co-medication, organ
function, etc), the administered dose can be adjusted accordingly in order to keep the drug levels
within the therapeutic window. Thus limiting side effects and maintain effective levels for each
individual patient." - AB
|- RECORD||28-mrt-2012 - 28-jul-2014|