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
- Trial ID
- 2022-501456-28-00
- Protocol
- SIOPEATRT01
- Sponsor
- GPOH gGmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **non-inferiority** of three courses of high-dose chemotherapy (HDCT) compared to focal radiotherapy (RT) plus conventional chemotherapy as consolidation therapy in children with atypical teratoid/rhabdoid tumours (ATRT). This is assessed by overall survival (OS) in children aged 12-35 months. Additionally, the study aims to assess the efficacy of HDCT as a consolidation measure in children under 12 months and the efficacy of RT combined with conventional chemotherapy in children aged 36 months and older, both compared to historical controls. The clinical relevance of these objectives lies in determining effective consolidation therapies for ATRT, potentially improving survival outcomes and reducing treatment-related morbidity.
Secondary objectives include:
- Part A: Comparison of neurocognitive outcomes, quality of life (QoL), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), and the incidence and severity of adverse events (AEs) and late effects between treatment arms. Additionally, the response to induction chemotherapy is assessed and compared with historical controls.
- Part B: Assessment of efficacy by OS over a 5-year follow-up compared to historical controls, along with evaluations of neurocognitive outcomes, QoL, incidence and severity of AEs and late effects, and response to induction chemotherapy. EFS and PFS are also compared to historical controls.
- Part C: Evaluation of the efficacy of RT as a consolidation measure combined with conventional chemotherapy, assessed by OS over a 5-year follow-up, compared to historical controls. Neurocognitive outcomes, QoL, incidence and severity of AEs and late effects, and response to induction chemotherapy are also assessed, with comparisons of EFS and PFS to historical controls.
Participants
The clinical trial involves a total of **7 participants** diagnosed with **atypical teratoid/rhabdoid tumours (ATRT)**. The study population includes both male and female subjects, with an age range of less than 18 years at diagnosis. Participants were selected based on specific inclusion criteria, including age and health status, such as liver and kidney function within defined limits and cardiac function as measured by echocardiography. The trial population is considered vulnerable due to the young age of the participants. Lifestyle considerations such as diet and physical activity are not specified. The trial does not provide additional information on the general health status or lifestyle habits of the participants.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of high-dose chemotherapy (HDCT) compared to focal radiotherapy (RT) as consolidation therapy in children with **atypical teratoid/rhabdoid tumours (ATRT)**. This is a randomized, double-blind, controlled trial with a prospective umbrella design, encompassing multiple parts to assess different age groups and treatment modalities. The trial is expected to run from June 2021 to May 2031, with a primary focus on overall survival (OS) as the primary endpoint, evaluated over a two-year follow-up period for Part A. Secondary endpoints include neurocognitive outcomes, quality of life, event-free survival (EFS), progression-free survival (PFS), and the incidence and severity of adverse events (AEs).
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, MRI and CSF examination results, and organ function tests. Following the screening, participants will receive three courses of induction chemotherapy. Subsequent visits will include assessments after each chemotherapy course to evaluate response and determine eligibility for randomization or continuation in the trial. The end-of-study visit will occur after the completion of the consolidation therapy and follow-up assessments.
The expected length of participant involvement varies depending on the trial part, with the maximum treatment period being 26 weeks. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or failure to meet ongoing eligibility criteria. The trial aims to provide comprehensive data on the comparative effectiveness of HDCT and RT in improving survival outcomes and quality of life for children with ATRT.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Doxorubicin hydrochloride** is provided as a 2 mg/ml concentrate for solution for infusion, marketed under the name Doxorubicinhydrochlorid Teva®. It is administered intravenously with a maximum daily dose of 37.50 mg/m² and a total dose not exceeding 225 mg/m² over a treatment period of 25 weeks.
**Etoposide** is available as a 20 mg/ml concentrate for solution for infusion, produced by Accord Healthcare Ireland Limited. It is also administered intravenously, with a maximum daily dose of 100 mg/m² and a total dose of up to 1500 mg/m² over 26 weeks.
**Vincristine sulfate** is supplied as a 1 mg/ml injection solution, known as Vincristinsulfat-TEVA®. This medication is administered intravenously, with a maximum daily dose of 1.25 mg/m² and a total dose of 5 mg/m² over 26 weeks.
**Methotrexate** is provided as a 50 mg/2 ml injection solution by Pfizer Healthcare Ireland. It is administered via injection, with a maximum daily dose of 2 mg and a total dose of 24 mg over 26 weeks.
**Carboplatin** is available as a 10 mg/ml concentrate for solution for infusion, produced by Accord Healthcare B.V. It is administered intravenously, with a maximum daily dose of 500 mg/m² and a total dose of 2500 mg/m² over 25 weeks.
**Dactinomycin**, also known as Actinomycin D, is provided as a 0.5 mg powder for solution for injection, marketed as LYOVAC*-COSMEGEN®. It is administered intravenously, with a maximum daily dose of 25 µg/kg and a total dose of 150 µg/kg over 25 weeks.
**Cyclophosphamide** is supplied as a 500 mg powder for solution for injection or infusion by Sandoz Ltd. It is administered intravenously, with a maximum daily dose of 1500 mg/m² and a total dose of 6000 mg/m² over 25 weeks.
**Thiotepa** is available as a 15 mg powder for concentrate for solution for infusion, marketed as TEPADINA. It is administered intravenously, with a maximum daily dose of 10 mg/kg and a total dose of 60 mg/kg over 26 weeks.
**Ifosfamide** is provided as a 500 mg powder for solution for injection, known as HOLOXAN, produced by Baxter SA. It is administered via injection, with a maximum daily dose of 2000 mg/m² and a total dose of 30000 mg/m² over 26 weeks.
All medications are administered intravenously, except for Methotrexate and Ifosfamide, which are administered via injection. Participant compliance is monitored throughout the trial to ensure adherence to dosing schedules and to evaluate the efficacy and safety of the treatments. No non-experimental treatments, such as standard-of-care therapy or placebo, are used in this study.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **overall survival (OS)**. The primary endpoint for Part A of the trial is to test the non-inferiority of three courses of high-dose chemotherapy (HDCT) compared to focal radiotherapy (RT) plus conventional chemotherapy as consolidation therapy, with a follow-up period of two years. Secondary endpoints include a five-year follow-up to further evaluate OS, as well as comparisons of neurocognitive outcomes, quality of life, event-free survival (EFS), progression-free survival (PFS), and the incidence and severity of adverse events (AEs) and late effects between the treatment arms. Additionally, the response to induction chemotherapy will be assessed and compared with historical controls.
For Part B, the efficacy will be assessed by evaluating OS over a five-year follow-up period for children with atypical teratoid/rhabdoid tumors (ATRT) aged less than 12 months at the time of HDCT, compared to historical controls. Part C will assess the efficacy of RT as a consolidation measure combined with conventional-type chemotherapy in children aged 36 months or older, also compared to historical controls, with a similar five-year follow-up for OS. Both Parts B and C will also evaluate neurocognitive outcomes, quality of life, EFS, PFS, and the incidence and severity of AEs and late effects, comparing these to historical controls.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Umbrella: Age at diagnosis less than 18 years
- Umbrella: Pathology compatible with ATRT and INI1 loss or SMARCB1 or SMARCA4 deficiency confirmed by local pathology lab
- Umbrella: Written informed consent and/or assent for trial participation according to national legislation
- 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
- 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
- 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)
- 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
Exclusion Criteria
- Part A: Previous or concomitant tumour directed chemotherapy, RT or small molecule therapy, other than within the SIOPE ATRT01 trial
- Part A: History of thrombosis or SOS
- Part A: Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
- Part A: Neutropenia (ANC <0.5 x109/L) lasting 6 weeks from the start of the previous course of chemotherapy
- Part A: Synchronous multifocal rhabdoid tumours
- Part A: Hypersensitivity to the active compounds or other
- 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
- 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
- Part B: Pulmonary hypertension as diagnosed by a paediatric cardiologist with indirect (echocardiography) or direct signs (pulmonary artery pressure ≥25mmHg)
- Part B: Any contraindication to any planned chemotherapy drug according to SmPC
- Part A: Metastatic disease at primary diagnosis
- Part B: Known active HBV, HCV or HIV infection
- Part B: Participation in another interventional therapeutic clinical trial
- Part B: Patients on coumarin-derivative anticoagulants
- Part B: History of thrombosis or SOS
- Part B: Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
- Part B: Neutropenia (ANC <0.5 x109/L) lasting 6 weeks from the start of the previous course of chemotherapy
- Part B: Hypersensitivity to the active substance or other excipients contained in one of the investigational medical products listed in the 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 C: Participation in another interventional therapeutic clinical trial
- 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: Any contraindication to any planned chemotherapy drug according to SmPC
- Part A: Known active HBV, HCV or HIV infection
- Part A: Participation in another interventional therapeutic clinical trial
- Part A: Patients on coumarin-derivative anticoagulants
- 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: Hypersensitivity to the active compounds or other excipients contained in one of the investigational medical products listed in the SmPC
- Umbrella: Participation in another interventional therapeutic clinical trial
- Umbrella: Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
- 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
- Umbrella: History or presence of non-infectious pneumonitis requiring steroids
- Umbrella: Pregnancy or breastfeeding
- 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 A: History or presence of non-infectious pneumonitis requiring steroids
- Part A: Pregnancy or breastfeeding
- 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 B: History or presence of non-infectious pneumonitis requiring steroids
- Part B: Pregnancy or breastfeeding
- 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 C: History or presence of non-infectious pneumonitis requiring steroids
- Part C: Pregnancy or breastfeeding
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 01 Jun 2021 | 16 |
 Czechia | Recruiting | 01 Jun 2021 | 3 |
 Denmark | Recruiting | 01 Jun 2021 | 15 |
 Finland | Recruiting | 01 Jun 2021 | 6 |
 France | Recruiting | 01 Jun 2021 | 48 |
 Germany | Recruiting | 01 Jun 2021 | 70 |
 Hungary | Recruiting | 01 Jun 2021 | 12 |
 Italy | Recruiting | 01 Jun 2021 | 35 |
 The Netherlands | Recruiting | 01 Jun 2021 | — |
 Norway | Recruiting | 01 Jun 2021 | 16 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Vincristinsulfat-TEVA® 1 mg/ml Injektionslösung | Test | INJEKTIONSLÖSUNG | INTRAVENOUS USE | 1.25 | 26 | PRD664685 |
Methotrexate 50mg/2 ml Injection. | Test | INJECTION | INJECTION | 2 | 26 | PRD1172585 |
Doxorubicinhydrochlorid Teva® 2 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 37.50 | 25 | PRD4131412 |
Cyclophosphamide 500 mg Powder for Solution for Injection or Infusion | Test | POWDER FOR SOLUTION FOR INJECTION OR INFUSION | INTRAVENOUS USE | 1500 | 25 | PRD1649348 |
Carboplatin 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 500 | 25 | PRD2005404 |
TEPADINA 15 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 10 | 26 | PRD444115 |
HOLOXAN 500 mg Pulver zur Herstellung einer Injektionslösung | Test | PULVER ZUR HERSTELLUNG EINER INJEKTIONSLÖSUNG | INJECTION | 2000 | 26 | PRD1606821 |
LYOVAC*-COSMEGEN® 0,5mg Pulver zur Herstellung einer Infusionslösung | Test | PULVER ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 25 | 25 | PRD1808077 |
Etoposide 20 mg/ml Concentrate for Solution for Infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 100 | 26 | PRD1800135 |