| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| atypical teratoid/rhabdoid tumours (ATRT) |
|
| E.1.1.1 | Medical condition in easily understood language |
| atypical teratoid/rhabdoid tumours |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| 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 |
Part A: To test the non-inferiority, as evaluated by OS, of three courses of HDCT compared to focal RT plus conventional chemotherapy as consolidation therapy following conventional chemotherapy in children with ATRT aged 12 – 35 months at consolidation therapy.
Part B: To assess the efficacy, as evaluated by OS, of three courses of HDCT as a consolidation measure following conventional-type chemotherapy in children with ATRT aged <12 months at the time of HDCT and not eligible for randomization within Part A of this protocol, compared to historical controls.
Part C: To assess the efficacy, as evaluated by overall survival, of RT as a consolidation measure combined with conventional-type chemotherapy in children aged ≥36 months with ATRT, compared to historical controls. |
|
| E.2.2 | Secondary objectives of the trial |
Part A: Comparison of the neurocognitive outcome in the two treatment arms, QoL, EFS, PFS and OS, incidence and severity of AEs and late effects; Assessment of the response to induction chemotherapy and compare it with that of historical controls
Part B: Assessment of the efficacy, as evaluated by OS (5-year follow-up) compared to historical controls, the neurocognitive outcome, the QoL, the incidence and severity of AEs and late effects, and the response to induction chemotherapy; Comparison of EFS and PFS to historical controls
Part C: Assessment of the efficacy, as evaluated by OS (5-year follow-up), of RT as a consolidation measure combined with conventional-type chemotherapy compared to historical controls, the neurocognitive outcome, the QOL, the incidence and severity of AEs and late effects, and the response to induction chemotherapy compared to historical controls; Comparison of EFS and PFS to historical controls |
|
| 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 |
Exemplary biological studies:
Molecular subgrouping by Illumina 850K EPIC BeadChIP arrays (level 2):
The main purpose of this first level of research is to identify potential prognostic markers and, in particular, to unravel the clinical significance of molecular subgroups among a homogeneously treated cohort of patients. Since the analysis of the clinical impact of molecular subgroups is a secondary objective of the trial, this ancillary study will be prioritized among all others.
At this aim, all ATRT included in the study will be molecularly subgrouped by DNA methylation profiling using Illumina 850K EPIC BeadChIP arrays. Methylation profiling will be performed with DNA extracted from either frozen or paraffin-embedded samples, stored in the national reference laboratory. Real-time subgrouping will not be mandatory.
Other genome wide approaches (level 3):
After diagnostic procedures, left-over DNA may be used for other genome-wide sequencing approaches such as whole genome sequencing or whole exome sequencing. At this aim, in order to allow appropriate analysis of any tumour genome wide sequencing, constitutional DNA will be stored and
informed consent for sequencing of germ line DNA will be asked for.
Exemplary specific sub-studies:
- Identifying differences between primary and relapse sample pairs - A comparative analysis using histology, gene expression, DNA sequencing and methylation
- Detection of tumour heterogeneity of primary and relapsed ATRT - Characterising inter- and intratumoural cell heterogeneity in tumour and tumour microenvironment of primary and relapsed ATRT to detect prognostic biomarkers using scRNA and multiplex IHC
- Single cell analysis of tumour and stroma cells on primary and relapsing tumours
- Analysis of the ATRT surfaceome using discovery proteomics (unlabelled SWATH) and cyTOF as a means to identify and validate dual-CAR-T and other targets for immune therapy
- Functional role and clinical relevance of mutated SMARCB1/INI1 protein in atypical teratoid/rhabdoid tumours (AT/RT) |
|
| E.3 | Principal inclusion criteria |
Registration Into Umbrella Trial
- Age at diagnosis less than 18 years
- Pathology compatible with ATRT and INI1 loss or SMARCB1 or SMARCA4 deficiency confirmed by local pathology lab
- Written informed consent and/or assent for study participation according to national legislation
- Patient agrees to use effective contraception whilst on treatment (patients of childbearing potential)
Part A:
1 Enrolled in the umbrella trial
2. Received 3 courses of induction chemotherapy according to the protocol and following induction in SD or better
3. Expected age 12-35 months at time of consolidation therapy (RT or HDCT)
4. Written informed consent and/or assent for randomization according to national legislation
5. Central review of pathology confirmed ATRT
6. MRI and CSF examination after 3 courses of chemotherapy and, if applicable, later showing SD or better (central review – national or regional centre)
7. ALT or AST ≤3.0 x ULN, bilirubin ≤ 1.5 x ULN
8. Creatinine ≤ 1.5 x ULN and measured GFR within published defined age-related values according to national standard methods.
9. EF ≥50% or FS ≥29% by echocardiography.
Part B:
1. Enrolled in the umbrella trial
2. Received 3 courses of induction chemotherapy according to the protocol
3. Radiotherapy not admissible (e.g. <12 months or other contraindications)
4. Not eligible for the randomized trial (Part A) (e.g. refusal of randomization)
5. Written informed consent and/or assent for inclusion according to national legislation
6. Central review of pathology confirmed ATRT
7. MRI and CSF examination after 3 courses of chemotherapy and, if applicable, later showing clinically significant sensitivity to chemotherapy (central review – national or regional centre)
8. ALT or AST ≤3.0 x ULN, bilirubin ≤ 1.5 x ULN
9. Creatinine ≤ 1.5 x ULN and measured GFR within published defined age-related values according to national standard methods.
10. EF ≥50% or FS ≥29% by echocardiography.
Part C:
1. Enrolled in the umbrella trial
2. Received 3 courses of induction chemotherapy according to the protocol
3. Aged 36 months or above OR
4. HDCT not possible OR
5. Not eligible for the randomized trial (Part A)
6. Written informed consent and/or assent for inclusion according to national legislation
7. Central review of pathology confirmed ATRT
8. MRI and CSF examination after 3 courses of chemotherapy and, if applicable, later showing SD or better (central review – national or regional centre)
9. ALT or AST ≤3.0 x ULN, bilirubin ≤ 1.5 x ULN
10. Creatinine ≤ 1.5 x ULN and measured GFR within published defined age-related values according to national standard methods.
11. EF ≥50% or FS ≥29% by echocardiography |
|
| E.4 | Principal exclusion criteria |
Part A:
1. Previous or concomitant tumour directed chemotherapy, RT or small molecule therapy, other than within the SIOPE ATRT01 trial
2. Metastatic disease at primary diagnosis
3. At time of inclusion Diarrhoea grade 3 or worse according to the CTCAE v5.0, if uncontrolled despite optimal supportive therapy
4. History or presence of clinically significant cardiac disease, including, but not limited to, any of the following, if uncontrolled despite optimal supportive care:
a. Sustained ventricular tachyarrhythmia
b. Any ventricular fibrillation or torsade de pointes,
5. At time of inclusion bradycardia defined as persistent heart rate < 50/minute if uncontrolled despite optimal supportive therapy Screening ECG with a QTcB >450msec minute if uncontrolled despite optimal supportive therapy
6. Pulmonary hypertension as diagnosed by a paediatric cardiologist with indirect (echocardiography) or direct signs (pulmonary artery pressure ≥25mmHg)
7. Any contraindication to any planned chemotherapy drug according to SmPC
8. Known active HBV, HCV or HIV infection
9. Participation in another interventional therapeutic clinical trial
10. Patients on coumarin-derivative anticoagulants
11. History of thrombosis or SOS
12. Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
13. Neutropenia (ANC <0.5 x109/L) lasting 6 weeks from the start of the previous course of chemotherapy
14. Synchronous multifocal rhabdoid tumours
15. Hypersensitivity to the active compounds or other
Part B:
1. Previous or concomitant tumour directed chemotherapy, radiotherapy or small molecule therapy, other than within the SIOPE ATRT01 trial
2. At time of inclusion Diarrhoea grade 3 or worse according to the CTCAE v5.0, if uncontrolled despite optimal supportive therapy
3. History or presence of clinically significant cardiac disease, including, but not limited to, any of the following, if uncontrolled despite optimal supportive therapy:
a. Sustained ventricular tachyarrhythmia
b. Any ventricular fibrillation or torsade de pointes
c. Current bradycardia defined as heart rate < 50/minute
d. Screening ECG with a QTcB >450msec
4. Pulmonary hypertension as diagnosed by a paediatric cardiologist with indirect (echocardiography) or direct signs (pulmonary artery pressure ≥25mmHg)
5. Any contraindication to any planned chemotherapy drug according to SmPC
6. Known active HBV, HCV or HIV infection
7. Participation in another interventional therapeutic clinical trial
8. Patients on coumarin-derivative anticoagulants
9. History of thrombosis or SOS
10. Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
11. Neutropenia (ANC <0.5 x109/L) lasting 6 weeks from the start of the previous course of chemotherapy
12. Hypersensitivity to the active substance or other excipients contained in one of the investigational medical products listed in the SmPC.
Part C:
1. Previous or concomitant tumour directed chemotherapy, RT or small molecule therapy, other than within the SIOPE ATRT01 trial
2. Any contraindication to any planned chemotherapy drug according to SmPC
3. Participation in another interventional therapeutic clinical trial
4. Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
5. Hypersensitivity to the active substance or other excipients contained in one of the investigational medical products listed in the SmPC. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival (2-year follow-up, for Part A non-inferiority of the HDCT arm) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 2 year follow up last patient |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints specific for Part A = randomized trial:
• Test the non-inferiority, as evaluated by OS (5-year follow-up), of three courses of HDCT compared to focal RT plus conventional chemotherapy
• Compare the neurocognitive outcome in the two treatment arms before randomization, 2 and 5 years after randomization, including demonstration and quantification of the superiority of neuropsychological performance in children and adolescents with ATRT following treatment by HDCT, compared to those treated with RT; identification of risk factors for differences in outcome
• Compare the quality of life in the two treatment arms before randomization, 2 and 5 years following randomization
• Compare event-free survival (EFS), progression-free survival (PFS) and OS between arms and to historical controls
• Compare the incidence and severity of Adverse Events (AEs) in each of the arms
• Compare the incidence and severity of late effects in each of the arms
• Assess the response to induction chemotherapy and compare it with that of historical controls.
Secondary endpoint specific for Part B:
• Assess the efficacy, as evaluated by OS (5-year follow-up), of three courses of HDCT as a consolidation measure following conventional-type chemotherapy in children with ATRT aged <12 months at the time of HDCT and not eligible for randomization in Part A of this protocol, compared to historical controls.
Secondary endpoint specific for Part C:
• Assess the efficacy, as evaluated by OS (5-year follow-up), of RT as a
consolidation measure combined with conventional-type chemotherapy in children aged ≥36 months with ATRT and not eligible for randomization in Part A of this protocol, compared to historical controls.
Secondary endpoints (Parts B and C):
• Assess the neurocognitive outcome in the cohorts following induction at diagnosis, 2 and 5 years after diagnosis
• Assess the quality of life in the cohort following induction at diagnosis, 2 and 5 years after diagnosis
• Compare EFS and PFS to that of historical controls
• Assess the incidence and severity of AEs
• Assess the incidence and severity of late effects
• Assess the response to induction chemotherapy and compare it with that of historical controls. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 5 year follow-up last patient |
|
| 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 | No |
| 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 | 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 26 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Hong Kong |
| Austria |
| Finland |
| France |
| Sweden |
| Netherlands |
| Spain |
| Switzerland |
| Czechia |
| Germany |
| Italy |
| Belgium |
| Denmark |
| Hungary |
| Ireland |
| Norway |
| Portugal |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| For the purposes of the Competent Authorities, the end of trial will be 24 months after the last enrolled patient has completed treatment. This will allow sufficient time for the completion of protocol procedures, data collection and input. For the purpose of the secondary endpoint (neurocognitive outcome) the trial end is 5 years after the last patient has completed the 5-year follow-up exams. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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