E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
acute lymphoblastic leukemia in children and adolescents <18 years of age |
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E.1.1.1 | Medical condition in easily understood language |
acute lymphoblastic leukemia in children and adolescents <18 years of age |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024338 |
E.1.2 | Term | Leukemia lymphoblastic acute |
E.1.2 | System Organ Class | 100000004864 |
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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 |
- Randomization R-eHR: Early high-risk (early HR) pB-ALL defined by genetics and/or inadequate treatment response over the course of induction: Can the pEFS from time of randomization be improved by additional therapy with the proteasome inhibitor Bortezomib during an extended consolidation treatment phase compared to standard extended consolidation? - Randomization R-HR: High-risk (HR) pB-ALL defined by genetics and/or inadequate treatment response by the end of consolidation: Can the pEFS from time of randomization be improved by a treatment concept including two cycles of post-consolidation immunotherapy with Blinatumomab (15 µg/m²/d for 28 days per cycle) plus 4 doses intrathecal Methotrexate compared to two conventional highly intensive chemotherapy courses? (continued in field for another language)
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- Randomization R-MR: Intermediate risk (MR) pB-ALL defined by genetics and intermediate MRD response: Can the probability of disease-free survival (pDFS) from time of randomization be improved by additional therapy with one cycle of post-reintensification immunotherapy with Blinatomomab (15 µg/m²/d for 28 days)? - Randomization R-T: Early non-standard risk (early non-SR) T-ALL patients defined by treatment response over the course of induction: Can the pEFS from time of randomization be improved by the extension of the standard of care consolidation phase by 14 days with an increase of the consolidation cumulative doses of Cyclophosphamide, Cytarabine and 6-Mercaptopurine by 50%? |
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E.2.2 | Secondary objectives of the trial |
- All randomizations: Can the overall survival be improved by the treatment in the experimental arm? - All randomizations: What is the incidence of treatment-related toxicities and mortality in the experimental arm compared to the standard arm? - Randomization R-eHR: Can the MRD load after consolidation treatment be reduced by the additional treatment with Bortezomib? - Randomization R-HR: Can treatment-related life-threatening complications and mortality during the intensified consolidation phase of high-risk treatment be reduced when replacing two intensive chemotherapy courses by two cycles of immunotherapy with Blinatumomab? (continued in field for another language)
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- Randomization R-HR: What is the proportion of patients with insufficient MRD response to Blinatumomab as defined in the protocol (section 3.1.7) as compared to the MRD response after the HR-2’ block in the control arm? - Randomization R-HR: Can the MRD load after the first treatment cycle (HR-2’/Blinatumomab) and the second cycle (HR-3’/Blinatumomab) be reduced in the experimental arm when compared with conventional intensive chemotherapy? - Randomization R-MR: What is the proportion of patients with positive MRD after reintensification Protocol II who become MRD-negative over the Blina cycle compared to 4 weeks of standard maintenance therapy? - Randomization R-T: Can the MRD load after consolidation treatment be reduced by extension of the consolidation phase? - Standard-risk patients: Is the clinical outcome comparable to that obtained for standard-risk patients in study AIEOP-BFM ALL 2009?
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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 |
1. Characterization of mechanisms of response and resistance and identification of therapeutic targets. 2. Pre-clinical models including patient-derived xenografts (PDX) to investigate mechanisms of response and resistance, identify new biomarkers and therapeutic strategies 3. Evaluation of drug response profiles (DRP) by screening diagnostic samples from HR-ALL patients to identify alternative therapeutic strategies 4. Activity-based profiling of proteasome components and ex-vivo drug profiling of diagnostic samples from Patients with Early High Risk B-cell precursor ALL and matched controls to establish predictive markers of response to Bortezomib in ALL 5. Genetic predisposition to ALL and influence of germline genetic variants on treatment response and toxicity 6. Molecular characterization of leukemia occurring in patients that had a prior neoplasia (observation patients) 7. Influence of host immune system for outcome of targeted immunotherapy: immunological studies for patients treated with Blinatumomab 8. Effect of host commensal microorganisms for leukemia development and toxicity 9. Integrated genomic platform – merging clinical, diagnostic and research information for better outcomes 10. Novel approaches for diagnostics and treatment of CNS-involvement 11. Identification of new markers for detection of clinically relevant subgroups in ALL by flow cytometry and to improve detection of minimal residual disease 12. Development of next generation diagnostics for the detection of minimal residual disease 13. Metabolomic profiling at onset and in different treatment phases 14. Characterization of genetic signatures in childhood Down-Syndrome ALL |
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E.3 | Principal inclusion criteria |
- newly diagnosed acute lymphoblastic leukemia or - newly diagnosed mixed phenotype acute leukemia (MPAL) meeting one of the following criteria: • biphenotypic with a dominant T or B lineage assignment •bilineal either with a dominant lymphoblastic population or if another reasonable rationale exists to treat the patient with an ALL-based therapy regimen - newly diagnosed acute undifferentiated leukemia - age < 18 years (up to 17 years and 365 days) at the day of diagnosis - patient enrolled in a participating center - written informed consent to trial participation and transfer and processing of data
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E.4 | Principal exclusion criteria |
- Ph+ (BCR-ABL1 or t(9;22)-positive) ALL - bilineal leukemia with a lymphoblastic and a separate non-lymphoblastic (≥ 10% of total cells) blast subset - pre-treatment with cytostatic drugs - glucocorticoid pre-treatment with ≥ 1 mg/kg/d Prednisolone equivalent for more than two weeks during the last month before diagnosis - treatment started according to another protocol - underlying diseases that does not allow treatment according to the protocol - ALL diagnosed as second malignancy and preceding chemotherapy and/or radiotherapy - evidence of pregnancy or lactation period - Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of anti-leukemic therapy - participation in another clinical trial that interferes with the protocol - other condition (either pre-existing or related to leukemia biology as present at diagnosis) or circumstances that significantly conflict with the treatment according to the protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
For the randomized study questions, the primary endpoint will be the time from randomization until the first event defined as follows: Randomization R-eHR, R-HR and R-T: Cytomorphological or molecular non-response (resistance to protocol treatment, considered as event at day zero), relapse, second malignancy or death from any cause. This will be called EFS time. Randomization R-MR: Relapse, second malignancy or death from any cause. This will be called DFS time.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
EFS and DFS time: end of study |
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E.5.2 | Secondary end point(s) |
- Survival starting at the same time point as the EFS/DFS - Frequency and incidence of treatment-related mortality in induction or CCR - Frequency and incidence of AE of interest and SAE in specific protocol phases, randomized arms and overall during follow-up - MRD load after the randomized treatment phases (R-eHR, R-HR, R-MR and R-T) - MRD load after the first/second cycle of Blinatumomab or after the HR 2’/HR 3’ block (R-HR) - Proportion of patients with poor MRD response to the first Blinatumomab cycle (“Blinatumomab Poor-Response”) (R HR)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Survival, treatment-related mortality, AE and SAE: end of study MRD related endpoints: after the repective MRD evaluation of the last patient in study |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 14 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 104 |
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 | No |
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 |
Australia |
Israel |
Austria |
Switzerland |
Czechia |
Germany |
Italy |
Slovakia |
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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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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 | 0 |
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 |
E.8.9.2 | In all countries concerned by the trial days | 0 |