atypical teratoid/rhabdoid tumours (ATRT)
Conditions
Interventions
Product Name: Actinomycin D
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: Actinomycin D
CAS Number: 50-76-0
Current Sponsor code: Actinomycin D
Other descriptive name: DACT
Sponsors
German Pediatric Oncology Group, GPOH gGmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Registration Into Umbrella Trial - Age at diagnosis less than 18 years - Pathology compatible with ATRT and INI1 loss or SMARCB1 or SMARCA4 deficiency confirmed by local pathology lab - Written informed consent and/or assent for study participation according to national legislation - 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 the 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 and CSF examination after 3 courses of chemotherapy and, if applicable, later showing SD or better (central review – national or regional centre) 7. ALT or AST =3.0 x ULN, bilirubin = 1.5 x ULN 8. Creatinine = 1.5 x ULN and measured GFR within published defined age-related values according to national standard methods. 9. EF =50% or 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. =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Part A: 1. Previous or concomitant tumour directed chemotherapy, RT or small molecule 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 SmPC 8. Known active HBV, HCV or HIV infection 9. Participation in another interventional therapeutic clinical trial 10. Patients on coumarin-derivative anticoagulants 11. History of thrombosis or SOS 12. Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal) 13. Neutropenia (ANC 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. Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal) 5. Hypersensitivity to the active substance or other excipients contained in one of the investigational medical products listed in the SmPC.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part A: To test the non-inferiority, as evaluated by OS, of three courses of HDCT compared to focal RT plus conventional chemotherapy as consolidation therapy following conventional chemotherapy in children with ATRT aged 12 – 35 months at consolidation therapy. Part B: To assess the efficacy, as evaluated by OS, 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 within Part A of this protocol, compared to historical controls. Part C: To assess the efficacy, as evaluated by overall survival, of RT as a consolidation measure combined with conventional-type chemotherapy in children aged =36 months with ATRT, compared to historical controls.;Secondary Objective: Part A: Comparison of the neurocognitive outcome in the two treatment arms, QoL, EFS, PFS and OS, incidence and severity of AEs and late effects; Assessment of the response to induction chemotherapy and compare it with that of historical controls Part B: Assessment of the efficacy, as evaluated by OS (5-year follow-up) compared to historical controls, the neurocognitive outcome, the QoL, the incidence and severity of AEs and late effects, and the response to induction chemotherapy; Comparison of EFS and PFS to historical controls Part C: Assessment of the efficacy, as evaluated by OS (5-year follow-up), of RT as a consolidation measure combined with conventional-type chemotherapy compared to historical controls, the neurocognitive outcome, the QOL, the incidence and severity of AEs and late effects, and the response to induction chemotherapy compared to historical controls; Comparison of EFS and PFS to historical controls;Primary end point(s): Overall survival (2-year follow-up, for Part A non-inferiority of the HDCT arm);Timepoint(s) of evaluation of this end point: 2 year follow up last patient | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints specific for Part A = randomized trial: • 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 to induction chemotherapy and compare it with that of historical controls. Secondary endpoint specific for 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. Secondary endpoint specific for 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. Secondary endpoints (Parts 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 afte | — |
Countries
Austria, Belgium, Czechia, Denmark, Finland, France, Germany, Hong Kong, Hungary, Ireland, Italy, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland
Contacts
Public ContactKatharina Waack-Buchholz
Pädiatrisches Forschungsnetzwerk
Outcome results
None listed