This study has been transitioned to CTIS with ID 2022-501456-28-00 check the CTIS register for the current data. Primary objectives Part A:To test the non-inferiority, as evaluated by OS, of three courses of HDCT compared to focal RT plus…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint for all parts: Overall survival (2-year follow-up, for Part A
non-inferiority of the HDCT arm)
Secondary outcome
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
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.
Exploratory/Teritary endpoints (all Parts):
-Identify and describe new clinical and biological risk factors in children
with ATRT
-Explore the relationship between molecular subgroups as assessed by 850k
methylation array and clinical characteristics
-Evaluate the feasibility of reference evaluation (imaging and pathology,
molecular genetics, cerebrospinal fluid (CSF) and biological specimen
collection for all enrolled patients
-Detect, quantify and identify risk factors for increased cognitive sequelae
over time following treatment among patients in the three parts of the study
-Compare the cognitive functions of children to the results of patients with
other central nervous system (CNS) tumour entities.
Background summary
Intracranial rhabdoid tumours (ATRT) are a rare and clinically rather
challenging entity. Survival rates have remained poor despite aggressive
multimodal treatment approaches. Controlled clinical trials are scarce and
difficult to perform due to ATRT infrequency and presence mainly in very young
children.
As over 70% of patients with ATRT are diagnosed before 3 years of age the
current trial targets this highly vulnerable population, to evaluate whether
three courses of HDCT are non-inferior to radiotherapy in terms of 2- and
5-year overall survival (primary endpoint).
Although evidence and studies on late-effects of paediatric brain tumours are
well established and monitoring neuropsychological and QoS aspects in
paediatric brain tumour trials is to be accepted as state-of-the-art, knowledge
on neuropsychological sequelae and the impact on QoS in patients with ATRT are
still scarce.
The lack of specific studies on late-effects in this group is even more
crucial, when considering that young age at the time of treatment for brain
tumours treated with radiotherapy is associated with increased cognitive
sequelae.
As survival rates in increase, the question of neuropsychological late-effects
and questions of QoS need to be taken into account for the development of
further medical treatments and are necessary for a better understanding of the
needs of affected patients regarding participation and reintegration following
treatment. Thus, it is important to compare cognitive sequelae and late-effects
in affected patients treated with RT versus patients treated with HDCT
according to the present protocol. Additionally, it is important to validate
the commonly known
risk factors for late-effects in paediatric brain tumour patients for the
ATRT-cohort.
In summary, the following essential scientific research questions remain open:
1) Is HDCT inferior to conventional type chemotherapy with focal RT in terms of
2- and 5-year overall survival in young children with ATRT?
2) Can young children with ATRT survive with a markedly better neurocognitive
outcome if focal RT is replaced by three courses of HDCT?
Study objective
This study has been transitioned to CTIS with ID 2022-501456-28-00 check the CTIS register for the current data.
Primary objectives 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.
Primary objectives 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.
Primary objectives 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 Part A:
a) To test the non-inferiority, as evaluated by OS (5-year follow-up), of three
courses of HDCT compared to focal RT plus conventional chemotherapy
b) Compare the neurocognitive outcome in the two treatment arms before
randomization, 2 and 5 years after randomization, including (b1) demonstrating
and quantifying the superiority of neuropsychological performance in children
and adolescents with ATRT following treatment by
HDCT, compared to those treated with RT, (b2) identifying risk factors for
differences in outcome
c) Compare the QOL in the two treatment arms before randomization, 2 and 5
years after randomization
d) Compare EFS, PFS and OS between arms and to historical controls
e) Compare the incidence and severity of AEs in each of the arms
f) Compare the incidence and severity of late effects in each of the arms
g) Assess the response to induction chemotherapy and compare it with that of
historical controls.
Secondary objectives Part B:
a) 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 <36 months at the time of HDCT and not eligible for
randomization in Part A of this protocol, compared
to historical controls
b) Assess the neurocognitive outcome at diagnosis, 2 and 5 years after
diagnosis in cohort
c) Assess the quality of life at diagnosis, 2 and 5 years after diagnosis in
the cohort
d) Compare EFS and PFS to that of historical controls
e) Assess the incidence and severity of AEs
f) Assess the incidence and severity of late effects
g) Assess the response to induction chemotherapy and compare it with that of
historical controls.
Secondary objectives Part C:
a) 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, compared to historical controls
b) Assess the neurocognitive outcome at diagnosis, 2 and 5 years after
diagnosis in cohort
c) Assess the QOL at diagnosis, 2 and 5 years after diagnosis in the cohort
d) Compare EFS and PFS to that of historical controls
e) Assess the incidence and severity of AEs
f) Assess the incidence and severity of late effects
g) Assess the response to induction chemotherapy and compare it with that of
historical controls.
Study design
Prospective, open label multicentre, international, umbrella trial including a
randomized phase III study evaluating the non-inferiority of 3 courses of
high-dose chemotherapy compared to focal radiotherapy plus standard
chemotherapy as a consolidation measure following conventional chemotherapy in
children with ATRT ranging from 12 - 35 months at the time of consolidation (RT
vs. HDCT).
Intervention
Part A: Patients will be allocated in a 1:1 ratio to each arm: HDCT arm versus
RT arm
Part B: HDCT
Part C: RT
Study burden and risks
This study compares two SoC therapies (HDCT versus RT), which the patients
would have received outside of the study as well.
Chausseestr. 128/129
Berlijn 10115
DE
Chausseestr. 128/129
Berlijn 10115
DE
Listed location countries
Age
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 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
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2022-501456-28-00 |
| EudraCT | EUCTR2018-003335-29-NL |
| CCMO | NL78097.041.22 |