atypical teratoid/rhabdoid tumours
Conditions
Interventions
Part A: Patients will be allocated in a 1:1 ratio to each arm: HDCT arm versus
RT arm
Part B: HDCT
Part C: RT
Sponsors
German Paediatric Oncology Group, GPOH gGmbH
Eligibility
Age
No minimum to 17 Years
Inclusion criteria
Inclusion criteria: Umbrella trial: 1. Age at diagnosis from birth to 18 years 2. Pathology compatible with ATRT and INI1 loss or SMARCB1 or SMARCA4 deficiency confirmed by local pathology lab 3. Written informed consent and/or assent for study participation according to national legislation 4. 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 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 (magnetic resonance imaging) and CSF examination after 3 courses of chemotherapy and, if applicable, later showing SD or better (central review - national or regional centre) 7. Alanine transaminase (ALT) or aspartate transaminase (AST) =50% or fractional shortening (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. =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 =50% or FS >=29% by echocardiography
Exclusion criteria
Exclusion criteria: Part A: 1. Previous or concomitant tumour directed chemotherapy, RT or targeted 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 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 summary of medical product chart (SmPC) 8. Known active hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunedeficiency virus (HIV) infection 9. Participation in another interventional therapeutic clinical trial 10. Patients on coumarin-derivative anticoagulants 11. History of thrombosis or sinusoidal obstruction syndrome (SOS) 12. Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal) 13. Neutropenia (absolute neutrophil count (ANC) 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 sma
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary endpoint for all parts: Overall survival (2-year follow-up, for Part A non-inferiority of the HDCT arm) | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 =36 months with ATRT and not eligible 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. Exploratory/Teritary endpoints (all Parts): -Identify and describe new clinical and biological risk factors in children with ATRT -Explore the relationshi | — |
Countries
Netherlands
Outcome results
None listed