E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
acute lymphoblastic leukemia in children and adolescents 1 to <18 years of age |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000845 |
E.1.2 | Term | Acute lymphoblastic leukemia |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. Non-HR pB-ALL patients with TEL/AML1-negative ALL or unknown TEL/AML1 status and FCM-MRD in bone marrow on day 15 < 0.1 % or with TEL/AML1-positive ALL (randomized study question): can the daunorubicin dose in Protocol IA be safely reduced by 50 % with a non-inferior EFS and a reduction of toxicity (treatment-related mortality and AE/SAE in Protocol I)? 2. Patients with precursor-B ALL and risk group MR (randomized study question): can the clinical outcome be improved by protracted asparagine depletion achieved through application of intensified pegylated L-asparaginase during reintensification and early maintentance? 3. High Risk patients (as identified by day 33 - randomized study question): can the clinical outcome be improved by protracted exposure to PEG-L-asparaginase during Protocol IB?
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E.2.2 | Secondary objectives of the trial |
1. Standard risk pts identified by at least one sensitive marker: Is the clinical outcome comparable to that obtained in SR pts AIEOP-BFM ALL 2000, or can the outcome even be improved with the use of PEG-L-asparaginase instead of native E. coli L-Asparaginase? 2. T-ALL non HR pts: Can the high level of outcome obtained in study AIEOP-BFM ALL 2000 be preserved or even improved with the use of PEG-L-ASP instead of native E.coli L-ASP? 3. HR pts with persistingly high MRD levels: Is it possible to improve the outcome and to achieve a further reduction of leukemic cell burden by administration of an innovative treatment schedule (DNX-FLA) 4. Pts participating in the randomized asparaginase studies: Are ASP activity and ASP antibodies associated with allergic reactions, and do they have an effect on the outcome? 5. What is the relative value of different methods of MRD monitoring in the definition of alternative stratification systems within a BFM-oriented protocol? |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Dates and versions are the same as of the main study. 1. Microarray analysis-based studies 1.1 Early diagnosis of very high-risk (refractory) childhood acute lymphoblastic leukemia 1.2 Integration of genotyping, gene and microRNA expression in MRD-based subgroups of B-cell precursor patients 1.3 Integration of genotyping, gene expression and miRNA expression in BCP-ALL 'others' patients 2. Comprehensive characterization of extramedullary disease 2.1 Flow-cytometric study on cerebrospinal fluid 2.2 PCR-based detection of leukemia-specific immunoglobulin and T-cell receptor rearrangements in cerebrospinal fluid in comparison to cytomorphological analysis 2.3 Prospective assessment of the diagnostic qualities of leukemic expression of a gene set including IL-15 for an improved characterization of leukemic involvement of the CNS and other extramedullary sites 2.4 Modeling pathomechanisms of extramedullary leukemia 3. Prospective evaluation of genetic aberrations and genetic variants of currently unknown prognostic value 4. PAX5 abnormalities: functional roles of PAX5/fusion proteins 5. Infectious disease-associated toxicity 6. Relapse-predicting value of increasing MRD levels during and after maintenance therapy in patients with (1) T-ALL/nonHR with MRD positivity at week 12, (2) all T-ALL/HR, (3) pB-ALL with MRD ≥ 10-3 at week 12 (MRD-HR) without stem cell transplantation in 1st CR 7. ALL in Down syndrome – a model for high risk B cell precursor leukemia7 |
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E.3 | Principal inclusion criteria |
1. newly diagnosed acute lymphoblastic leukemia 2. age ≥ 1 year (> 365 days) and < 18 years (up to 17 years and 365 days) 3. no Ph+ (BCR/ABL or t(9;22)-positive) ALL 4. no evidence of pregnancy or lactation period 5. no participation in another clinical study 6. patient enrolled in a participating center 7. written informed consent
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E.4 | Principal exclusion criteria |
1. pre-treatment with cytostatic drugs 2. steroid pre-treatment with ≥ 1 mg/kg/d for more than two weeks during the last month before diagnosis 3. treatment started according to another protocol 4. underlying diseases that prohibit treatment according to the protocol 5. ALL diagnosed as second malignancy
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Randomization R1: Event-free survival from time of randomization 2. Randomization R2: Disease-free survival from time of randomization 3. Randomization RHR: rate of MRD highly positive patients (MRD ≥ 10-3) at TP2 (week 12) 4. Historical comparison SR and T-ALL: Disease-free survival from start of Protocol M 5. Historical comparison HR pts with persistingly high MRD levels: Event-free survival from start of DNX-FLA (morphological non-response after HR-3’ is no event for this study question) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
historical controls with other treatment |
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E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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For each patient, a last study-related visit is planned 5 years after diagnosis/start of study treatment. Patient recruitment is planned for 5 years. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 0 |