AN INTERNATIONAL PROSPECTIVE TRIAL ON HIGHRISK MEDULLOBLASTOMA IN PATIENTS OLDER THAN 3 YEARS

Medulloblastoma (MB) is the most common malignant brain tumour in children and
young people,
accounting for approximately 650 new cases per year in the European Union (EU).
These tumours of the posterior fossa account for 20% of all brain tumours in
children. The median age of diagnosis is 7 years, but medulloblastoma occurs at
all ages and into adulthood.
MB can be defined according to histological and genetic subtypes. Our
understanding of these variants, and their clinical relevance is evolving and
altering our understanding of prognosis and risk and are creating a shifting
scope of disease stratification. However, the challenge of high -risk
medulloblastoma (HRMB) remains predominantly a clinical one and the same
dichotomy of improving survival rates and reducing toxicity and late effects
remains.
Around 30% of MB patients are diagnosed as HR-MB; currently defined clinically
by the presence of
one or more of the following high-risk factors; metastatic disease, large
cell/anaplastic histology, MYC or MYCN amplification or significant residual
disease post-surgery. HR-MB is associated with a 5-year event-free survival
(EFS) of about 60%. Moreover, those patients that are cured have significant
long-term toxicities (including neurocognitive and endocrinological).
Initial studies indicate the severity of toxicity and late-effects may be
associated with treatment given, clinico-biological disease features, and host
genetic factors. There is therefore an urgent need to improve survival in
patients with HR-MB, whilst at the same time limit acute and long-term
toxicities that have significant detrimental impact on the quality of life of
survivors. It is also vital to undertake biological analysis of tumour samples
to identify those patients currently defined as having high risk disease but
have a better prognosis and may be better treated as standard risk patients and
identify those patients who are unlikely to be cured by current conventional
therapy, and/or in whom the evaluation of novel therapies at an earlier stage
may be appropriate.

To date, there has been a worldwide paucity of large clinical trials for HR-MB
to support the systematic development of optimal evidence-based treatment
approaches for this disease group. The major alternative approaches to date
include (i) high-dose chemotherapy prior to (or occasionally post-)
craniospinal radiotherapy (RT), (ii) hyperfractionated and accelerated RT
(HART; twice daily) and (iii) conventional craniospinal (RT) (once daily), most
commonly prior to maintenance chemotherapy. Most importantly, the relative
merits of these approaches have not been tested in a systematic way and have
not taken into account the heterogeneous disease biology we now appreciate. In
addition, the relative associated toxicities or late-effects of the different
treatment strategies have not been assessed. A randomised multi-national trial
to ascertain whether any of these strategies offers a survival advantage is
needed.

This study has been transitioned to CTIS with ID 2024-510578-25-00 check the CTIS register for the current data.

Primary objectives:
- To evaluate whether the outcome in children, young people and adults with
HR-MB is improved over standard therapy i.e. conventional (once a day)
radiotherapy (RT) (standard therapy), for those treated with:
hyperfractionated-accelerated radiotherapy (HART), or high-dose therapy (HDT)
with thiotepa followed by conventional RT.
- To evaluate whether the outcome in HR-MB is different for those treated with
two different maintenance chemotherapy therapies.

Secondary objectives:
- To study the late effects of treatment and their impact on quality of
survival (QoS), including
neurocognitive function, neurological impairment, endocrine impairment,
audiological function and secondary tumours.
- To conduct comprehensive prospective biological studies in HR-MB, with the
aims of (i) understanding the biological basis of HR-MB, (ii) identification
and validation of diagnostic and prognostic biomarkers, and (iii)
identification and validation of molecular targets with therapeutic potential
and associated predictive biomarkers.
- To conduct prospective QoS, toxicity and pharmacogenomic studies with the aim
of exploring clinical, host and tumour factors, and genetic variants, that
relate to early and late side-effects of treatment and survival parameters.

An international, prospective, phase III randomised trial in patients aged 3
years and older with *high-risk* medulloblastoma with a high-risk biological
profile.
Patients eligible for the trial will be randomized for radio(chemo)therapy
(R1), and maintenance chemotherapy (R2).

Induction chemotherapy:
Carboplatin and etoposide (2 cycles of 3 weeks)

Randomization 1: radio(chemo)therapy
Arm A: conventional radiotherapy ( 1x/day for 6 weeks)
Arm B: Hyperfractionated-Accelerated Radiotherapy (HART; 2x/day for 23 days)
Arm C: high-dose chemotherapy with thiotepa (2 cycles of 3 weeks) followed by
conventional radiotherapy ( 1x/day for 6 weeks)

Randomization 2: maintenance chemotherapy (applies only for arm A and B)
Arm D: 4 AB cycles. Cycle A: vincristine, lomustine, cisplatin (6 weeks); cycle
B: vincristine and cyclophosphamide (3 weeks) (total of 36 weeks)
Arm E: 6 cycles of temozolomid (4 weeks) (total of 24 weeks)

Patients randomized to arm C will receive automatically 6 cycles of
temozolomide (alike arm E)

Burden:
Compared to arm A:
Arm B: patients will receive radiotherapy twice a day in stead of once per day.
Patients will finish radiotherapy one week earlier. Patients will not be
hospitalized for radiotherapy, which is comparable to patients from arm A.
Arm C: apheresis will be conducted during induction chemotherapy. Depending on
the harvest of stem cells during the first cycle, a second harvest during the
second cycle of induction chemotherapy may be needed. Patients receive two
high-dose chemotherapy before radiotherapy. During this high-dose chemotherapy
patients will be hospitalized. The duration of hospitalization is depending on
the amount of side effects. Radiotherapy is equal to arm A.

Compared to arm D:
Arm E and patients from arm C: maintenance chemotherapy will take place at
home. Patients only have control visits at the hospital and have to receive the
medication at the hospital. Patients will be less often hospitalized than
patients from arm D.

All included patients will receive questionnaires regarding Quality of Life at
different time points (max. 4 times) and neuropsychological testing at the same
time points.
Independent from study arm, for patients with CSF positive for tumor cells at
day 15 after surgery, CSF sampling will be repeated for 3 to 4 times (depending
of study arm) during the study.

Risks:
It is unsure whether patients from arm B have a higher risk for side effects or
not compared to patients receiving radiotherapy once a day.
Patients from arm C have a higher risk for infections during high-dose
chemotherapy. They also have a higher risk for infertility compared to other
patients in the study. All included patients will be advised regarding
fertility preservation.