An international prospective umbrella trial for children with atypical teratoid/rhabdoid tumours (ATRT) including A randomized phase III study evaluating the non-inferiority of three courses of high-dose chemotherapy (HDCT) compared to focal radiotherapy as consolidation therapy

Phase 3

• Conditions: atypical teratoid/rhabdoid tumours; brain tumours; 10029211

• Registration Number: NL-OMON51928
• Lead Sponsor: German Paediatric Oncology Group, GPOH gGmbH

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 15 April 2024

Recruitment & Eligibility

• Status: Pending
• Sex: Not specified
• Target Recruitment: 10

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) <=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

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 <
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
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) <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 sma

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Primary endpoint for all parts: Overall survival (2-year follow-up, for Part A<br /><br>non-inferiority of the HDCT arm)</p><br>