C72
Conditions
Interventions
Group 1: RT-Arm:
Radiation therapy +
a total of 12 courses of DOX (Courses 1, 5, 9
Day 1 and 2
37,5 mg/m2)
ICE (Courses 2, 4, 6, 8, 11):
Ifosfamid: Day 1, 2, 3
2000 mg/m2 over 1h
Carboplatin: Day 1
500 mg/m2 over 1h
Etoposide: Day 1, 2, 3
100 mg/m2 over 1h
VCA (Courses 3, 7, 10, 12):
Vincristine: Day 1 , 8
1,5 mg/m2 max 2 mg
Cyclophosphamide: Day 1
1500 mg/m² over 1 h
Actinomycin-D: Day 1, 2
0.025mg/kg +
intrathecal Methotrexate (4-6 Courses, doses age-dependent)
Group 2: HDCT-Arm:
A minimum of three and a maximum of 6 Courses of DOX (Courses 1, 5
ICE (Courses 2, 4):
Ifosfamid: Day 1, 2, 3
Sponsors
Gesellschaft für pädiatrische Onkologie und Hämatologie (GPOH)
Eligibility
Sex/Gender
All
Age
No minimum to 18 Years
Inclusion criteria
Inclusion criteria: Umbrella: 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 trial 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) =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) within normal published 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 normal 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
Exclusion criteria
Exclusion criteria: Umbrella: 1. Previous or concomitant tumour directed chemotherapy (more than one course of standard treatment), RT or small molecule therapy, other than within the SIOPE ATRT01 trial 2. Any contraindications to any planned conventional chemotherapy drug according to SmPC 3. Hypersensitivity to the active compounds or other excipients contained in one of the investigational medical products listed in the SmPC 4. Participation in another interventional therapeutic clinical trial 5. Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal) 6. Receipt of a live attenuated vaccine 30 days or fewer prior to inclusion or planned vaccination with a live attenuated vaccine during treatment or within 3 months after the last dose administration 7. History or presence of non-infectious pneumonitis requiring steroids 8. Pregnancy or breastfeeding 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 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. 16. Receipt of a live attenuated vaccine 30 days or fewer prior to inclusion or planned Vaccination with a live attenuated vaccine during treatment or within 3 months after the last dose administration 17. History or presence of non-infectious pneumonitis requiring steroids 18. Pregnancy or breastfeeding 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 v
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Overall survival (2-year follow-up, for Part A non-inferiority of the HDCT arm) | — |
Secondary
| Measure | Time frame |
|---|---|
| PART A: - 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 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. 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. PART 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 i | — |
Countries
Belgium, Czechia, Denmark, Finland, France, Germany, Hungary, Italy, Netherlands, Norway, Spain, Sweden, Switzerland
Contacts
Public ContactMichael C. Frühwald
Schwäbisches Kinderkrebszentrum
Outcome results
None listed