An international prospective umbrella trial for children with atypical teratoid/rhabdoid tumours (ATRT) includingA randomized phase III study evaluating the non-inferiority of three courses of high-dose chemotherapy (HDCT) compared to focal radiotherapy as consolidation therapy
- Conditions
- C72Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- All
- Target Recruitment
- 152
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) =3.0 x upper limit of normal (ULN) and bilirubin =1.5 x ULN
8. Creatinine = 1.5 x ULN and measured glomerular filtration rate (GFR) defined age-related values according to national standard methods.
9. Ejection fraction (EF) =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. <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 cerebrospinal fluid 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
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 < 50/minute if uncontrolled despite optimal supportive therapy
Screening electrocardiogram (ECG) with a QT corrected by Bazett’s (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 summary of medical product chart (SmPC)
8. Known active hepatitis B virus (HBV), hepatitis C virus (HCV) or human immune-deficiency 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) <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 excipients contained in one of the investigational medical products listed in the SmPC.
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.
Study & Design
- Study Type
- interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Overall survival (2-year follow-up, for Part A non-inferiority of the HDCT arm)
- Secondary Outcome Measures
Name Time Method