Eine internationale klinische Studie für Kinder und Jugendliche mit atypischen teratoiden/rhabdoiden Tumoren

Zusammenfassende Beschreibung der Studie (Datenquelle: BASEC)

Atypische Teratoide, Rhabdoide Tumoren (ATRT) sind seltene, hoch aggressive Tumoren des Zentralnervensystems (Gehirn und Rückenmark). Von dieser Erkrankung sind vor allem sehr junge Kinder unter 22 Monaten betroffen. Die Heilungsaussichten von Patientinnen und Patienten mit einem ATRT konnten in den letzten Jahren zwar verbessert werden, sind aber trotz intensiver Behandlungsansätze insgesamt nach wie vor ungünstig. SIOPE ATRT01 ist eine internationale Therapieoptimierungsstudie. Die Studie wurde für Kinder und Jugendliche entworfen, um einen entscheidenden Schritt in Richtung einer Therapieverbesserung zu gehen, die Heilungsraten zu erhöhen und gleichzeitig die Nebenwirkungen so niedrig wie möglich zu halten. Die Studie soll einige entscheidende Fragen in Bezug auf die Behandlung von ATRT klären. Dazu gehört unter anderem die Frage, ob eine Hochdosis-Chemotherapie mit anschliessender Stammzelltransplantation nicht weniger wirksam ist als eine Strahlentherapie, aber weniger Spätfolgen hat.

Untersuchte Krankheiten(Datenquelle: BASEC)

Atypische Teratoide, Rhabdoide Tumoren (ATRT)

Health conditions (Datenquelle: WHO)

atypical teratoid/rhabdoid tumours (ATRT);Therapeutic area: Diseases [C] - Cancer [C04]

Seltene Krankheit (Datenquelle: BASEC)

Nein

Untersuchte Intervention (z.B. Medikament, Therapie, Kampagne) (Datenquelle: BASEC)

Entsprechend der Standardtherapie erhalten alle Teilnehmenden nach der Operation zunächst drei Zyklen Chemotherapie. Patientinnen und Patienten, bei denen die Erkrankung nach den drei Zyklen weiter fortgeschritten ist, werden außerhalb dieser Studie behandelt. Alle anderen Patientinnen und Patienten werden je nach Alter und Risikoprofil einem von drei Behandlungsteilen zugeordnet:

Teil A: Für Patientinnen und Patienten im Alter von 12-35 Monaten ist das primäre Ziel dieser Studie die Nicht-Unterlegenheit einer Hochdosis-Chemotherapie mit anschliessender Stammzelltransplantation gegenüber einer Strahlentherapie zu prüfen. Teilnehmende erhalten entweder eine Hochdosis-Chemotherapie mit einer autologen Stammzelltransplantation oder eine herkömmliche Chemotherapie und eine Strahlentherapie. Die Ergebnisse in beiden Gruppen werden hinsichtlich der Wirkungen und Nebenwirkungen miteinander verglichen, um zu sehen, ob die eine Behandlung wirksamer ist als die andere. Um sicher zu gehen, dass die Patientinnen und Patienten in den beiden Gruppen gleich verteilt sind, werden die Kinder mittels Zufallsprinzip einer der beiden Gruppen zugeordnet.

Teil B: Als Standardtherapie für Kinder unter zwölf Monaten gilt in der Schweiz eine konventionelle Chemotherapie gefolgt von einer Hochdosis-Chemotherapie mit anschliessender Stammzelltransplantation. Dies entspricht auch der Studientherapie. Das primäre Ziel dieses Studienteils ist es, Therapiedaten inklusive der Nebenwirkungen aller Patientinnen und Patienten zu erfassen und auszuwerten.

Teil C: Für Patientinnen und Patienten im Alter von über 36 Monaten gilt eine Strahlentherapie als vertretbar. Kinder dieser Altersgruppe werden mit einer konventionellen Chemotherapie behandelt und zusätzlich bestrahlt. Auch bei diesem Studienteil werden Therapiedaten inklusive der Nebenwirkungen erfasst und ausgewertet.

Begleitend zur medizinischen Behandlung werden alle Teilnehmenden neuropsychologisch untersucht. Mittels speziell zusammengestellten Test werden die kognitive Entwicklung und Lebensqualität der Patientinnen und Patienten überprüft. Diese Untersuchungen sollen ermöglichen, Folgen der Erkrankung und der Therapie auf die kognitive Entwicklung frühzeitig zu erkennen und entsprechende Maßnahmen zu ergreifen. Es wird überprüft, ob Kinder, die in jungem Alter eine Strahlentherapie erhalten, später in ihrer kognitiven Entwicklung stärker beeinträchtigt sind als solche, die eine Hochdosis-Chemotherapie erhalten haben. Die Ergebnisse der Untersuchungen sollen langfristig helfen, die Therapiemethoden der Patientinnen und Patienten zu verbessern, um Nebenwirkungen der Behandlung zu verringern und die Therapien besser verträglich zu machen.

Interventions (Datenquelle: WHO)

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: DACTINOMYCIN
Concentration unit: ?g/kg microgram(s)/kilogram
Concentration type: up to
Concentration number: 25-

Product Name: Carboplatin
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Carboplatin
CAS Number: 41575-94-4
Other descriptive name: CARBOPLATIN
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: up to
Concentration number: 500-

Product Name: Cyclophosphamide
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 50-18-0
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: up to
Concentration number: 1500-

Product Name: Doxorubicin
Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: DOXORUBICIN
CAS Number: 23214-92-8
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: up to
Concentration number: 37.5-

Product Name: Etoposide
Pharmaceutical Form: Concentrate for solution for injection/infusion
INN or Proposed INN: Etoposid
CAS Number: 33419-42-0
Other descriptive name: ETOPOSIDE
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: up to
Concentration number: 100-

Product Name: Ifosfamide
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: IFOSFAMIDE
CAS Number: 3778-73-2
Current Sponsor code: Ifosfamide
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: up to
Concentration number: 2000-

Product Name: Thiothepa
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: THIOTEPA
CAS Number: 52-24-4
Current Sponsor

Kriterien zur Teilnahme an der Studie (Datenquelle: BASEC)

Alter bei Diagnose unter 18 Jahren
Referenzpathologisch bestätigte Diagnose eines ATRT
Schriftliche Einwilligungsbestätigung zur Studienteilnahme

Ausschlusskriterien (Datenquelle: BASEC)

Vorangegangene Chemotherapie, Strahlentherapie oder anderweitige Behandlung ausserhalb dieser Studie
Zusätzliche spezifische Ausschlusskriterien je nach Behandlungsteil (A, B oder C)

Inclusion/Exclusion Criteria (Datenquelle: WHO)

Gender:
Female: yes
Male: yes

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. <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 CSF 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
Are the trial subjects under 18? yes
Number of subjects for this age range: 152
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 < 50/minute if uncontrolled despite optimal supportive therapy Screening ECG with a 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 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 <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

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 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.

Weitere Angaben zur Studie im WHO-Primärregister

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-003335-29

Weitere Angaben zur Studie aus der Datenbank der WHO (ICTRP)

https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2018-003335-29

Weitere Informationen zur Studie

Datum der Studienregistrierung

14.04.2022

Einschluss der ersten teilnehmenden Person

22.07.2022

Rekrutierungsstatus

Not Recruiting

Wissenschaftlicher Titel (Datenquelle: WHO)

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

Studientyp (Datenquelle: WHO)

Interventional clinical trial of medicinal product

Design der Studie (Datenquelle: WHO)

Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2

Phase (Datenquelle: WHO)

Human pharmacology (Phase I): noTherapeutic exploratory (Phase II): noTherapeutic confirmatory - (Phase III): yesTherapeutic use (Phase IV): no

Primäre Endpunkte (Datenquelle: WHO)

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

Sekundäre Endpunkte (Datenquelle: WHO)

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 after diagnosis
? Compare EFS and PFS to that of historical controls
? Assess the incidence and severity of AEs
? Assess the incidence and severity of late effects
? Assess the response to induction chemotherapy and compare it with that of historical controls.;Timepoint(s) of evaluation of this end point: 5 year follow-up last patient

Kontakt für Auskünfte (Datenquelle: WHO)

Augsburg Elternverein

Ergebnisse der Studie (Datenquelle: WHO)

Zusammenfassung der Ergebnisse

Link zu den Ergebnissen im Primärregister

noch keine Angaben verfügbar

Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten

noch keine Angaben verfügbar

Studiendurchführungsorte

Durchführungsorte in der Schweiz (Datenquelle: BASEC)

Aarau, Basel, Bellinzona, Bern, Genf, Lausanne, Luzern, St Gallen, Zürich

Durchführungsländer (Datenquelle: WHO)

Austria, Belgium, Czechia, Denmark, Finland, France, Germany, Hong Kong, Hungary, Ireland, Italy, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland

Kontakt für weitere Auskünfte zur Studie

Angaben zur Kontaktperson in der Schweiz (Datenquelle: BASEC)

Prof. Dr. med. Katrin Scheinemann
+41 71 243 71 50
katrin.scheinemann@kispisg.ch

Kontakt für allgemeine Auskünfte (Datenquelle: WHO)

Katharina Waack-Buchholz
Holsterhauser Platz 2
Zentrum f?r Forschungsf?rderung in der P?diatrie
+4902017494960
k.waack@forschung-paediatrie.de

Kontakt für wissenschaftliche Auskünfte (Datenquelle: WHO)