The hypothesis is that personalised and risk-adapted treatment will improve outcome and reduce toxicity in post-pubertal patients with medulloblastoma.A further hypothesis is that clinical, magnetic resonance imaging (MRI) and voxel-based…
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Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To compare progression-free survival (PFS) by central review of a
personalized intensity-modulated therapy (experimental arm; sonidegib)
vs. standard therapy in the SHH-activated subgroup in post-pubertal
patients with newly diagnosed standard risk medulloblastoma.
Secondary outcome
In experimental versus standard arm and in the 3 molecular subgroups
separately (except otherwise stated):
• To compare PFS by central reviewer in WNT & Group 4 subgroups
• To compare PFS by local investigator in 3 molecular subgroups
• To compare overall survival (OS) in 3 molecular subgroups
• To evaluate safety and tolerability profile
• To evaluate short- and long-term health-related quality of life (HRQoL)
with a particular emphasis on the social functioning scale
• To evaluate issues linked to survivorship (fear of recurrence, having
problems with insurance/mortgage, work opportunities, life plans/goals
and relationships with family or friends)
• To evaluate short- and long-term neurocognitive function (NCF)
• To evaluate short- and long-term endocrine function
• To assess the incidence of second malignancies
Background summary
The medulloblastoma is a rare, malignant primary brain tumour which occurs more
in children than in adults: in 70% of patients the tumour is diagnosed before
the age of 15 and in adults the incidence is 0.5/100 000 per year in The
Netherlands. Medulloblastoma are almost exclusively primarily located in the
cerebellum and have the propensity to spread through the CSF and leptomeninges.
Medulloblastoma are classified into 5 main molecular subgroups: WNT-activatd,
SHH-activated TP53 wild-type, SHH-activated TP53 mutant, group 3 and group 4.
The distribution of the subgroups is age dependant and prognosis is in part
determined by the molecular subgroup, at least in children.Group 3
medulloblastoma almost never occur in adults.
Currently, the cornerstone of treatment of patients with medulloblastoma is
radiotherapy of the entire craniospinal axis with a boost on the primary tumour
and, if present, macroscopic metastases. Radiotherapy has side-effects: on the
short term it can lead to hematologic toxicity and fatigue, on the long term to
irreversible deterioration of cognition, social skills, attention,
concentration and reading as well as growth abnormalities and endocrine
changes. Toxicity is dose- and age dependant. Some of these side-effects are
likely to be less if proton radiotherapy is used instead of photon; proton
craniospinal radiotherapy is currently considered standard treatment in
medulloblastoma in The Netherlands if clinically feasible. Studies in children
have shown that reducing the craniospinal dose from 36 Gy to 23.4 Gy does not
lead to worse prognosis. Whether this also holds true for adults is not yet
known.
Alongside and after the radiotherapy patients are treated with systemic
chemotherapy. Although no randomised studies have been performed regarding this
subject several large retrospective series show that prognosis is improved by
the addition of chemotherapy. Therefore this is internationally currently
considered standard treatment.
In patients with SHH-activated tumours the SHH pathway can be addressed by
targeted treatment with a Hedgehog inhibitor. Most data regarding such
treatment are from patients with other SHH-activated solid tumours but the
available data suggest that this will also be the case in SHH-activated
medulloblastoma. Because SHH-inhibitors can lead to growth arrest in young
children these agents can only be utilised in post-pubertal patients and only
post-pubertal patients will be included in this study.
Study objective
The hypothesis is that personalised and risk-adapted treatment will improve
outcome and reduce toxicity in post-pubertal patients with medulloblastoma.
A further hypothesis is that clinical, magnetic resonance imaging (MRI) and
voxel-based radiotherapy planning data as well as biomarkers extracted from
liquid biopsies and tumour tissue samples can be processed in a way that allows
to improve diagnosis and treatment and to reduce toxicity.
Primary objective:
• To compare progression-free survival (PFS) by central review of a
personalized intensity-modulated therapy (experimental arm; sonidegib) vs.
standard therapy (craniospinal irradiation and chemotherapy according to the
modified NOA-07 schedule) in the SHH-activated subgroup in post-pubertal
patients with newly diagnosed standard risk medulloblastoma
Secondary objectives:
In experimental versus standard arm and in 3 molecular subgroups separately
(except otherwise stated):
• To compare PFS by central reviewer in WNT & Group 4 subgroups
• To compare PFS by local investigator in 3 molecular subgroups
• To compare overall survival (OS) in 3 molecular subgroups
• To evaluate safety and tolerability profile
• To evaluate short- and long-term health-related quality of life (HRQoL) with
a particular emphasis on the social functioning scale
• To evaluate issues linked to survivorship (fear of recurrence, having
problems with insurance/mortgage, work opportunities, life plans/goals and
relationships with family or friends)
• To evaluate short- and long-term neurocognitive function (NCF)
• To evaluate short- and long-term endocrine function
• To assess the incidence of second malignancies
Exploratory objectives:
• To report response, PFS, OS, safety and tolerability, NCF and HRQoL in the
standard arm of pooled subgroups
• To compare response, PFS, Event Free Survival (EFS), OS and toxicity data of
post-pubertal patients with medulloblastoma treated in this study vs. patients
treated in the PNET5 study (a currrently activated international study in
children)
• To evaluate the association between NCF and HRQoL over time
• To describe the difference in safety and tolerability, maintenance
chemotherapy delivery, HRQoL, neurocognitive function, survivorship, and
endocrine /fertility function between proton- and photon-based cranio-spinal
radiotherapy
• To describe the difference in safety and tolerability, maintenance
chemotherapy delivery, HRQoL, neurocognitive function, survivorship, and
endocrine /fertility function between 35.2 Gy and 23.4 Gy as part of the
cranio-spinal radiotherapy
Translational research objectives:
• To provide a histopathological review and molecular classification of
post-pubertal medulloblastoma including molecular subtyping
• To establish and analyze copy number variation profiles in medulloblastoma
• To assess known predictive biomarkers for response and non-response to SMO
inhibition
• To detect new molecular targets, pathway modifiers and resistance mechanisms
in SHH-activated tumours
• To evaluate biomarkers from tumour tissue within the SHH subtype that may
explain early side effects
• To assess the transcriptomic landscape of post-pubertal SHH medulloblastoma
• To evaluate molecular characteristics within SHH activated medulloblastoma
correlated with response and resistance
• To evaluate biomarkers from tumour tissue of SHH activated medulloblastoma
that may explain treatment-related side effects
• To test the feasibility of using ctDNA from CSF for molecular analyses and
treatment monitoring (minimal residual disease)
• To investigate the genotype/imaging phenotype relationship in medulloblastoma
(radiogenomics).
• To deepen the understanding of patterns of treatment failure and
radiotherapy-associated neurotoxicity.
Study design
Phase II, comparative, randomized (experimental: standard arm 1:1), no
blinding, no active or placebo control, parallel group, therapeutic.
Intervention
1. patients with SHH-activated medulloblastoma without metastases (M0) or with
only microscopic metastases in the CSF (M1) will be randomised between standard
chemotherapy (modified NOA-7) combined with sonidegib and standard treatment
alone, where sonidegib treatment (200 mg/d orally) will start on the first day
of radiotherapy and end at the end of maintenance chemotherapy.
2. all enrolled patients with medulloblastoma without metastases (M0) will be
randomized between standard dose of craniospinal irradiation (35.2 Gy) and
reduced dose (23.4 Gy)
Study burden and risks
Standard post-operatieve treatment for patients with medulloblastoma consists
of craniospinal irradiation with concurrent and maintenance chemotherapy of
which the total duration is almost 1 year. Treatment duration within the
current study is the same as outside of the study except for a reduction of 3
days in the experimental (lower dose radiotherapy) arm.
The extra burden for the study consists of 1-3 additional outpatient visits
before start of the study for the informed consent procedure and for performing
physical and neurological examination, an ECG, audiometry, a quality of life
questionnaire, a cognitive test and some additional bloodtests in a single
sample including pregnancy test in female patients.
During treatment no additional blood sampling will need to take place above
standard sampling for the evaluation of toxicity but some additional tests will
be performed in these samples. Additionally during the treatment period 4 ECGs
will be done, a monthly pregnancytest in blood or urine of female patients, 2
cognitive tests, 2 quality of life questionnaires and 2 audiometry tests will
be done. The number of visits to the outpatient clinic will be the same as
during standard treatment but the visits may last longer as a result of more
extensive physical examination and the above mentioned additional tests.
After treatment the number of outpatient visits will be the same as outside the
study: every 3 months in the fist 2 years, 3 times in the 3rd year and twice in
the 4th and 5th years. Because of additional tests (see below) the visits may
last longer.
Additional tests will be a maximum of 11 quality of life questionnaires, 6
cognitive tests, 2 audiometry tests and monthly in the first 12 months (without
sonidegib) or 20 mponths (with soidegib) a pregnancytest will be performed in
female patients of reproductive age.
Sonidegib is taken in tablets and ingeneral has a mild side-efect profile. It
has been approved in The Netherlands for other diseases, eg SHH-activated
basalcell carcinoma. The most frequent side-effects are fatigue, muscle cramps,
muscle pain, nausea and laboratory changes in liver enzymes and creatin kinase.
In a minority of patients more serious weight loss, muscle pains, increased
liverenzymes, dizziness and fatigue has been reported. In other studies
sonidegib has been shown to be safe in combination with chemotherapy. There is,
however, no experience yet of the commbination of sonidegib with radiotherapy.
For this reason the first 10 patients included in the study in the sonidegib
arm will be monitored extra closely and if necessary treatment will be modified.
The lower dose of radiotherapy that will be given to some of the patients in
this study is likely to reduce the burden of the radiotherapy, especially the
long-term toxicity. There is a theoretical risk that this lower dose may be
less effectiv in tumour control. However, in children this has been previously
investigated and it was shown that the dose could be safely reduced without
compromising efficacy. It seems unlikely that in adults this will not be the
case.
The study is linked to the group and can only be performed in patients with
this disease
Avenue E. Mounierlaan 83 / 11
Brussel 1200
BE
Avenue E. Mounierlaan 83 / 11
Brussel 1200
BE
Listed location countries
Age
Inclusion criteria
•Newly diagnosed, histologically proven, genetically classified, centrally
confirmed medulloblastoma (WNT M0-1, SHH (p53wt) M0-1, Group 4 M0-1)
• Molecular subtype: medulloblastoma, SHH-activated and TP53-wildtype, M0-1;
medulloblastoma, WNT-activated, M0-1; medulloblastoma, Group 4, M0-1
• Histologic subtype: medulloblastoma, classic (CMB); medulloblastoma,
desmoplastic/nodular (DNMB); medulloblastoma, with extensive nodularity (MBEN);
medulloblastoma, large cell/anaplastic (LCA)
• Adults (>=18 years) in WNT-activated and Group 4 medulloblastoma
• Post-pubertal patients (<18 y of age) or adult (18 y of age or above) in
SHH-activated and TP53-wildtype medulloblastoma
Exclusion criteria
• Prior treatment for medulloblastoma
• Unavailability of central review pathology results
• Known prognostic markers (MYC/MYCN amplification, MYC/MYCN mutation)
• Patients with germline alterations that are prognostically linked to
medulloblastoma (e.g., TP53, PTCH, SUFU, BRCA2, PALB2) and that are already
known before randomization will not be eligible.
• Inability to start radiotherapy within 43 days after surgery
• Significant sensorineural hearing deficit as defined by pure tone audiometry
with bone conduction or air conduction and normal tympanogram showing
impairment >= 20 dB at 1-3 kHz
• Any medical contraindication to radiotherapy or chemotherapy
• Hypersensitivity to contrast medium for MRI
• Hypersensitivity towards the active substance of any of study drugs or their
excipients
• Concurrent severe or uncontrolled medical disease (e.g., active
systemic infection, diabetes, psychiatric disorder) that, in the opinion of
the investigator, would compromise the safety of the patient or
compromise the ability of the patient to complete the study
• Prior or second invasive malignancy, except non-melanoma skin
cancer, completely resected cervical carcinoma in situ, low risk prostate
cancer (cT1-2a N0 and Gleason score <= 6 and PSA < 10 ng/mL), either
totally resected or irradiated with curative intent (with PSA of less than
or equal to 0.1 ng/mL) or under active surveillance as per ESMO
guidelines. Other cancers for which the subject has completed
potentially curative treatment more than 5 years prior to diagnosis of
medulloblastoma study entry are allowed
• Known history or current evidence of active Hepatitis B (e.g., positive
HBV surface antigen) or C (e.g., HCV RNA [qualitative] is detected)
• Known or current evidence of Human Immunodeficiency Virus (HIV)
infection (positive HIV-1/2 antibodies)
• Presence of any psychological, familial, sociological or geographical
condition potentially hampering compliance with the study protocol and
follow-up schedule; those conditions sh
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 |
|---|---|
| EudraCT | EUCTR2020-003063-26-NL |
| ClinicalTrials.gov | NCT04402073 |
| CCMO | NL83456.078.23 |