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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

GPOH gGmbH

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Jul 2020 → ongoing

Decision date (initial)

2024-01-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Deutsche Kinderkrebsstiftung · Augsburger Elternverein

External identifiers

EU CT number

2022-501456-28-00

EudraCT number

2018-003335-29

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

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 objectives 3

1. 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
2. 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
3. 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

Conditions and MedDRA coding

atypical teratoid/rhabdoid tumours (ATRT)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 32

1. Umbrella: Age at diagnosis less than 18 years
2. Umbrella: Pathology compatible with ATRT and INI1 loss or SMARCB1 or SMARCA4 deficiency confirmed by local pathology lab
3. Umbrella: Written informed consent and/or assent for trial participation according to national legislation
4. Umbrella: Patient agrees to use effective contraception whilst on treatment
5. Part A: Enrolled in the umbrella trial
6. Part A: Received 3 courses of induction chemotherapy according to the protocol and following induction in SD or better
7. Part A: Expected age 12-35 months at time of consolidation therapy (RT or HDCT)
8. Part A: Written informed consent and/or assent for randomization according to national legislation
9. Part A: Central review of pathology confirmed ATRT
10. 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)
11. Part A: ALT or AST ≤3.0 x ULN, bilirubin ≤ 1.5 x ULN
12. Part A: Creatinine ≤ 1.5 x ULN and measured GFR within normal published defined age-related values according to national standard methods
13. Part A: EF ≥50% or FS ≥29% by echocardiography
14. Part B: Enrolled in the umbrella trial
15. Part B: Received 3 courses of induction chemotherapy according to the protocol
16. Part B: Radiotherapy not admissible (e.g. <12 months or other contraindications)
17. Part B: Not eligible for the randomized trial (Part A) (e.g. refusal of randomization)
18. Part B: Written informed consent and/or assent for inclusion according to national legislation
19. Part B: Central review of pathology confirmed ATRT
20. 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)
21. Part B: ALT or AST ≤3.0 x ULN, bilirubin ≤ 1.5 x ULN
22. Part B: Creatinine ≤ 1.5 x ULN and measured GFR within normal published defined age-related values according to national standard methods
23. Part B: EF ≥50% or FS ≥29% by echocardiography
24. Part C: Enrolled in the umbrella trial
25. Part C: Received 3 courses of induction chemotherapy according to the protocol
26. Part C: Aged 36 months or above OR HDCT not possible OR Not eligible for the randomized trial (Part A)
27. Part C: Written informed consent and/or assent for inclusion according to national legislation
28. Part C: Central review of pathology confirmed ATRT
29. 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)
30. Part C: ALT or AST ≤3.0 x ULN, bilirubin ≤ 1.5 x ULN
31. Part C: Creatinine ≤ 1.5 x ULN and measured GFR within normal published defined age-related values according to national standard methods
32. Part C: EF ≥50% or FS ≥29% by echocardiography

Exclusion criteria 48

1. Part A: Previous or concomitant tumour directed chemotherapy, RT or small molecule therapy, other than within the SIOPE ATRT01 trial
2. Part A: History of thrombosis or SOS
3. Part A: Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
4. Part A: Neutropenia (ANC <0.5 x109/L) lasting 6 weeks from the start of the previous course of chemotherapy
5. Part A: Synchronous multifocal rhabdoid tumours
6. Part A: Hypersensitivity to the active compounds or other
7. Part B: Previous or concomitant tumour directed chemotherapy, radiotherapy or small molecule therapy, other than within the SIOPE ATRT01 trial
8. Part B: At time of inclusion Diarrhoea grade 3 or worse according to the CTCAE v5.0, if uncontrolled despite optimal supportive therapy
9. 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
10. Part B: Pulmonary hypertension as diagnosed by a paediatric cardiologist with indirect (echocardiography) or direct signs (pulmonary artery pressure ≥25mmHg)
11. Part B: Any contraindication to any planned chemotherapy drug according to SmPC
12. Part A: Metastatic disease at primary diagnosis
13. Part B: Known active HBV, HCV or HIV infection
14. Part B: Participation in another interventional therapeutic clinical trial
15. Part B: Patients on coumarin-derivative anticoagulants
16. Part B: History of thrombosis or SOS
17. Part B: Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
18. Part B: Neutropenia (ANC <0.5 x109/L) lasting 6 weeks from the start of the previous course of chemotherapy
19. Part B: Hypersensitivity to the active substance or other excipients contained in one of the investigational medical products listed in the SmPC
20. Part C: Previous or concomitant tumour directed chemotherapy, RT or small molecule therapy, other than within the SIOPE ATRT01 trial
21. Part C: Any contraindication to any planned chemotherapy drug according to SmPC
22. Part C: Participation in another interventional therapeutic clinical trial
23. 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
24. Part C: Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
25. Part C: Hypersensitivity to the active substance or other excipients contained in one of the investigational medical products listed in the SmPC
26. 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
27. Part A: Pulmonary hypertension as diagnosed by a paediatric cardiologist with indirect (echocardiography) or direct signs (pulmonary artery pressure ≥25mmHg)
28. Part A: Any contraindication to any planned chemotherapy drug according to SmPC
29. Part A: Known active HBV, HCV or HIV infection
30. Part A: Participation in another interventional therapeutic clinical trial
31. Part A: Patients on coumarin-derivative anticoagulants
32. Umbrella: Any contraindications to any planned conventional chemotherapy drug according to SmPC
33. 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
34. Umbrella: Hypersensitivity to the active compounds or other excipients contained in one of the investigational medical products listed in the SmPC
35. Umbrella: Participation in another interventional therapeutic clinical trial
36. Umbrella: Any ongoing, uncontrolled, clinically significant infection (viral, bacterial or fungal)
37. 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
38. Umbrella: History or presence of non-infectious pneumonitis requiring steroids
39. Umbrella: Pregnancy or breastfeeding
40. 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
41. Part A: History or presence of non-infectious pneumonitis requiring steroids
42. Part A: Pregnancy or breastfeeding
43. 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
44. Part B: History or presence of non-infectious pneumonitis requiring steroids
45. Part B: Pregnancy or breastfeeding
46. 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
47. Part C: History or presence of non-infectious pneumonitis requiring steroids
48. Part C: Pregnancy or breastfeeding

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival (2-year follow-up, for Part A non-inferiority of the HDCT arm)

Secondary endpoints 15

1. specific for 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
2. specific for Part A: 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
3. specific for Part A: Compare the quality of life in the two treatment arms before randomization, 2 and 5 years following randomization
4. specific for Part A: Compare event-free survival (EFS), progression-free survival (PFS) and OS between arms and to historical controls
5. specific for Part A: Compare the incidence and severity of Adverse Events (AEs) in each of the arms
6. specific for Part A: Compare the incidence and severity of late effects in each of the arms
7. specific for Part A: Assess the response to induction chemotherapy and compare it with that of historical controls
8. 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.
9. 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
10. Parts B and C: Assess the neurocognitive outcome in the cohorts following induction at diagnosis, 2 and 5 years after diagnosis
11. Parts B and C: Assess the quality of life in the cohort following induction at diagnosis, 2 and 5 years after diagnosis
12. Parts B and C: Compare EFS and PFS to that of historical controls
13. Parts B and C: Assess the incidence and severity of AEs
14. Parts B and C: Assess the incidence and severity of late effects
15. Parts B and C: Assess the response to induction chemotherapy and compare it with that of historical controls

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

GPOH gGmbH

Sponsor organisation

GPOH gGmbH

Address

Chausseestraße 128, Mitte Mitte

City

Berlin

Postcode

10115

Country

Germany

Scientific contact point

Organisation

GPOH gGmbH

Contact name

Prof. Dr. Dr. Michael Frühwald

Public contact point

Organisation

GPOH gGmbH

Contact name

Prof. Dr. Dirk Reinhardt

Third parties 6

Locations

12 EU/EEA countries · 76 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 206 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

17 submissions — initial application plus substantial / non-substantial modifications