E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myeloid Leukemia in Children with Down Syndrome |
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E.1.1.1 | Medical condition in easily understood language |
Myeloid Leukemia in Children with Down Syndrome |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• Achieving an EFS, which is not inferior to the ML-DS 2006 trial: 5yr-EFS; 87±3% |
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E.2.2 | Secondary objectives of the trial |
• Reduction of toxicity: severe adverse events (CTCAE v4.0 grade III or higher) • Identification of prognostic factors concerning the risk of relapse, toxicity and poor outcome • Evaluate the role of different methods in the determination of minimal residual disease measurement • Evaluation of somatic SNVs as a predictive biomarker: relation of patients’ outcome to the specific somatic SNVs • Exploration of the role of trisomy 8 as a predictive biomarker • Exploration of molecular resistance/relapse mechanisms
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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 |
An extensive research program will be performed, comprising molecular analyses (whole genome and transcriptome sequencing), xenograft mouse modeling and drug screening using left over material from bone marrow aspirations at diagnosis and during treatment. The role of coding and non-coding RNAs in the pathogenesis of ML-DS will be explored. |
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E.3 | Principal inclusion criteria |
• Myeloid Leukemia (ML) or Myelodysplastic Syndrome (MDS), according to WHO • Trisomy 21: Down syndrome or mosaic • Age: > 6 months and ≤ 4 years of age with/without GATA1 mutation OR > 4 years of age < 6 years of age with GATA1 mutation • Morphology/Immunophenotyping: FAB M0, M6 or M7 • Lansky performance score at least equal to 50; or Karnofsky performance status at least equal to 50, whichever is applicable • Understand and voluntarily provide written permission of parental/legal representative(s) to the ICF prior to conducting any study related assessments/procedures, also concerning data and tumor material transfer according to ICH/GCP and national/local regulations • Able to adhere to the study visit schedule and other protocol requirements • Acceptance that vaccination with live vaccines is not possible while participating in the trial |
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E.4 | Principal exclusion criteria |
• Children with Transient Abnormal Myelopoiesis (TAM), according to WHO
• Cytogenetics: AML with recurrent genetic abnormalities (WHO 2016)
• Previous allogeneic bone marrow, stem cell or organ transplantation
• Evidence of invasive fungal infection or other severe systemic infection requiring treatment doses of systemic/parenteral therapy including known active viral infection with human immunodeficiency virus (HIV) or Hepatitis Type B and C
• Symptomatic cardiac disorders (CTCAE 4.0 Grade 3 or 4)
• Diagnosed Wilson’s Disease
• Major surgery within 21 days of the first dose.
• Any anti-cancer therapy (e.g., intensive chemotherapy, biologics or radiotherapy) for more than 14 days or within 4 weeks before start of therapy, except low-dose cytarabine for the treatment of TAM.
• Concomitant treatment with any other anticancer therapy except those specified in protocol during the study therapy
• Treated by any investigational agent in a clinical study within previous 4 weeks
• History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product
• Former Enrolment to this study
• The patient concerned has been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities |
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E.5 End points |
E.5.1 | Primary end point(s) |
Event-free survival (EFS), defined as time from diagnosis to the first event or last follow-up. Events are death from any cause, failure to achieve remission, relapse, and secondary malignancy. Failure to achieve remission is considered as an event on day 0.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 150 are included and the 5-yrs-follow up is over. |
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E.5.2 | Secondary end point(s) |
• Overall survival (OS), as defined as the time of diagnosis to death from any cause or last follow-up. • Disease-free survival (DFS) • Early Response Rate (CR, CRp, CRi)) after induction • Treatment-related mortality (TRM) • Minimal residual disease (FACS and NGS) • Adverse events (according to NCI CTCAE v4.0) • Duration of myelosuppression
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 150 are included and the 5-yrs-follow up is over. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
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 | Yes |
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 | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Prospective, open-label, non-randomized, historically-controlled phase II/III trial |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 30 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Austria |
Denmark |
France |
Germany |
Hungary |
Italy |
Netherlands |
Norway |
Poland |
Portugal |
Slovakia |
Slovenia |
Spain |
Sweden |
Switzerland |
European Union |
Czechia |
Greece |
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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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Last patient first visit (LPFV): Q1 2028 |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |