An international trial for children with atypical teratoid/rhabdoid tumours (ATRT)

Prior treatment

• Part A: Previous or concomitant tumour directed chemotherapy, RT or small molecule therapy, other than within the SIOPE ATRT01 trial
• Part B: Any contraindication to any planned chemotherapy drug according to SmPC
• Part C: Previous or concomitant tumour directed chemotherapy, RT or small molecule therapy, other than within the SIOPE ATRT01 trial
• Part C: Any contraindication to any planned chemotherapy drug according to SmPC
• Part A: Any contraindication to any planned chemotherapy drug according to SmPC
• Umbrella: Any contraindications to any planned conventional chemotherapy drug according to SmPC
• Umbrella: 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
• Umbrella: 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
• Part A: 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
• Part B: 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
• Part C: 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
• Part B: Previous or concomitant tumour directed chemotherapy, radiotherapy or small molecule therapy, other than within the SIOPE ATRT01 trial
• Part B: At time of inclusion Diarrhoea grade 3 or worse according to the CTCAE v5.0, if uncontrolled despite optimal supportive therapy

Other illness

• Part B: Pulmonary hypertension as diagnosed by a paediatric cardiologist with indirect (echocardiography) or direct signs (pulmonary artery pressure ≥25mmHg)
• Part A: Metastatic disease at primary diagnosis
• Part B: Known active HBV, HCV or HIV infection
• Part B: History of thrombosis or SOS
• Part B: Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
• Part B: Hypersensitivity to the active substance or other excipients contained in one of the investigational medical products listed in the SmPC
• Part A: History of thrombosis or SOS
• Part A: 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
• Part C: Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
• Part C: Hypersensitivity to the active substance or other excipients contained in one of the investigational medical products listed in the SmPC
• Part A: 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
• Part A: Pulmonary hypertension as diagnosed by a paediatric cardiologist with indirect (echocardiography) or direct signs (pulmonary artery pressure ≥25mmHg)
• Part A: Known active HBV, HCV or HIV infection
• Part A: Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
• Umbrella: Hypersensitivity to the active compounds or other excipients contained in one of the investigational medical products listed in the SmPC
• Umbrella: Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
• Umbrella: History or presence of non-infectious pneumonitis requiring steroids
• Part A: History or presence of non-infectious pneumonitis requiring steroids
• Part B: History or presence of non-infectious pneumonitis requiring steroids
• Part C: History or presence of non-infectious pneumonitis requiring steroids
• Part A: Hypersensitivity to the active compounds or other
• Part B: 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

Lab values

• Part B: Neutropenia (ANC <0.5 x109/L) lasting 6 weeks from the start of the previous course of chemotherapy
• Part A: Neutropenia (ANC <0.5 x109/L) lasting 6 weeks from the start of the previous course of chemotherapy

Other

• Part B: Participation in another interventional therapeutic clinical trial
• Part B: Patients on coumarin-derivative anticoagulants
• Part C: Participation in another interventional therapeutic clinical trial
• Part A: Participation in another interventional therapeutic clinical trial
• Part A: Patients on coumarin-derivative anticoagulants
• Umbrella: Participation in another interventional therapeutic clinical trial
• Umbrella: Pregnancy or breastfeeding
• Part A: Pregnancy or breastfeeding
• Part B: Pregnancy or breastfeeding
• Part C: Pregnancy or breastfeeding
• Part A: Synchronous multifocal rhabdoid tumours

• Umbrella: Age at diagnosis less than 18 years
• Part A: MRI and CSF examination after 3 courses of chemotherapy and, if applicable, later showing SD or better (central review – national or regional centre)
• Part A: ALT or AST ≤3.0 x ULN, bilirubin ≤ 1.5 x ULN
• Part A: Creatinine ≤ 1.5 x ULN and measured GFR within normal published defined age-related values according to national standard methods
• Part A: EF ≥50% or FS ≥29% by echocardiography
• Part B: Enrolled in the umbrella trial
• Part B: Received 3 courses of induction chemotherapy according to the protocol
• Part B: Radiotherapy not admissible (e.g. <12 months or other contraindications)
• Part B: Not eligible for the randomized trial (Part A) (e.g. refusal of randomization)
• Part B: Written informed consent and/or assent for inclusion according to national legislation
• Part B: Central review of pathology confirmed ATRT
• Umbrella: Pathology compatible with ATRT and INI1 loss or SMARCB1 or SMARCA4 deficiency confirmed by local pathology lab
• Part B: 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)
• Part B: ALT or AST ≤3.0 x ULN, bilirubin ≤ 1.5 x ULN
• Part B: Creatinine ≤ 1.5 x ULN and measured GFR within normal published defined age-related values according to national standard methods
• Part B: EF ≥50% or FS ≥29% by echocardiography
• Part C: Enrolled in the umbrella trial
• Part C: Received 3 courses of induction chemotherapy according to the protocol
• Part C: Aged 36 months or above OR HDCT not possible OR Not eligible for the randomized trial (Part A)
• Part C: Written informed consent and/or assent for inclusion according to national legislation
• Part C: Central review of pathology confirmed ATRT
• Part C: MRI and CSF examination after 3 courses of chemotherapy and, if applicable, later showing SD or better (central review – national or regional centre)
• Umbrella: Written informed consent and/or assent for trial participation according to national legislation
• Part C: ALT or AST ≤3.0 x ULN, bilirubin ≤ 1.5 x ULN
• Part C: Creatinine ≤ 1.5 x ULN and measured GFR within normal published defined age-related values according to national standard methods
• Part C: EF ≥50% or FS ≥29% by echocardiography
• Umbrella: Patient agrees to use effective contraception whilst on treatment
• Part A: Enrolled in the umbrella trial
• Part A: Received 3 courses of induction chemotherapy according to the protocol and following induction in SD or better
• Part A: Expected age 12-35 months at time of consolidation therapy (RT or HDCT)
• Part A: Written informed consent and/or assent for randomization according to national legislation
• Part A: Central review of pathology confirmed ATRT