Evaluation of Hyperfractionated-Accelerated Radiotherapy and High-Dose Thiotepa Therapy in High-Risk Medulloblastoma Patients Aged Over 3 Years

The primary objective of this study is to evaluate whether the outcome in children, young people, and adults with clinically high-risk **medulloblastoma** (HR-MB) is improved over standard therapy. This includes assessing the efficacy of hyperfractionated-accelerated radiotherapy (HART) or high-dose therapy (HDT) with thiotepa followed by conventional radiotherapy (RT) compared to conventional once-a-day RT. Additionally, the study aims to determine if the outcome differs for those treated with two different maintenance chemotherapy regimens. This is clinically relevant as it seeks to enhance treatment protocols and improve survival rates for patients with HR-MB.

Secondary objectives include:

• Studying the late effects of treatment and their impact on quality of survival (QoS), including neurocognitive function, neurological impairment, endocrine impairment, audiological function, and secondary tumors.
• Conducting comprehensive prospective biological studies in HR-MB to understand the biological basis, identify and validate diagnostic and prognostic biomarkers, and identify molecular targets with therapeutic potential and associated predictive biomarkers.
• Conducting prospective QoS, toxicity, and pharmacogenomic studies to explore clinical, host, and tumor factors, as well as genetic variants related to early and late side effects of treatment and survival parameters.

The clinical trial involves a total of **443 participants** diagnosed with **high-risk medulloblastoma**, a condition characterized by specific histological subtypes and high-risk features. The study population includes both male and female subjects, with an age range starting from 3 years old. Participants were selected based on their diagnosis of high-risk medulloblastoma, confirmed through histological review, and must meet specific health criteria, including adequate hepatic, renal, and hematological function. The trial also considers lifestyle factors such as the requirement for effective contraception for patients of childbearing potential. Participants must be medically fit to receive treatment and have no significant hearing deficits. The trial includes a vulnerable population, ensuring comprehensive evaluation across diverse demographic groups.

The clinical trial is designed to evaluate the efficacy of different treatment regimens in patients with high-risk **medulloblastoma**. This is a Phase III, randomized, double-blind, controlled trial. The trial aims to compare the outcomes of hyperfractionated-accelerated radiotherapy (HART) and high-dose therapy (HDT) with **thiotepa** followed by conventional radiotherapy, against standard therapy. Additionally, the trial will assess the efficacy of two different maintenance chemotherapy regimens. The primary endpoint is event-free survival, with secondary endpoints including overall survival and progression-free survival. The trial is expected to conclude by April 2032, with recruitment starting in January 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven high-risk medulloblastoma and adequate organ function. Following the screening, participants will be randomized into treatment arms. Regular follow-up visits will be scheduled to monitor treatment response and adverse events. The end-of-study visit will occur after the completion of the treatment regimen and follow-up period, to assess long-term outcomes and collect final data.

The expected duration of participant involvement in the trial is contingent upon the treatment arm and individual response, with a maximum treatment period of up to 33 weeks for certain regimens. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study protocols. Participants will be closely monitored throughout the trial to ensure safety and adherence to the study protocol.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Carboplatin** is provided as a concentrate for solution for infusion, administered intravenously. The maximum daily dose is 400 mg/m², with a total maximum dose of 1600 mg/m² over a treatment period of 27 days.

**Cisplatin** is also administered as a concentrate for solution for infusion via the intravenous route. The maximum daily dose is 70 mg/m², with a total maximum dose of 280 mg/m² over 27 days.

**Temozolomide** is available in a hard capsule form for oral administration. The maximum daily dose is 150 mg/m², with a total maximum dose of 4500 mg/m² over a 21-day treatment period. This formulation is repeated in multiple entries, indicating its use in various treatment regimens within the trial.

**Cyclophosphamide** is provided as a powder for solution for injection or infusion, administered intravenously. The maximum daily dose is 1000 mg/m², with a total maximum dose of 8000 mg/m² over a 33-day treatment period.

**Lomustine** is administered in capsule form for oral use. The maximum daily dose is 75 mg/m², with a total maximum dose of 300 mg/m² over 27 days. This medication is also listed under the name "Lomustine caps 10 mg," indicating a specific dosage form used in the trial.

**Vincristine sulfate** is provided as a solution for injection or infusion, administered intravenously. The maximum daily dose is 2 mg/m², with a total maximum dose of 24 mg/m² over a 33-day treatment period.

**Thiotepa** is available as a powder for concentrate for solution for infusion, administered intravenously. The maximum daily dose is 200 mg/m², with a total maximum dose of 1200 mg/m² over a 4-day treatment period.

All medications are of chemical origin and are not formulated for pediatric use. The trial does not involve any orphan drug designations. Participant compliance with dosing schedules is monitored throughout the trial to ensure adherence to the specified treatment regimens. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the provided data.

The efficacy of the clinical trial for high-risk **medulloblastoma** (HR-MB) will be assessed using specific primary and secondary endpoints. The primary endpoint is event-free survival, which will be measured to determine the time until the occurrence of any event such as disease progression, relapse, or death. Secondary endpoints include overall survival and progression-free survival, which will provide additional insights into the long-term benefits of the treatment regimens being evaluated.

The trial aims to compare the outcomes of patients treated with hyperfractionated-accelerated radiotherapy (HART) or high-dose therapy (HDT) with thiotepa followed by conventional radiotherapy, against standard therapy. The efficacy assessments will be conducted at various timepoints throughout the trial, with the estimated end date set for April 1, 2032. The trial is designed to evaluate whether these treatment approaches improve outcomes in children, young people, and adults with HR-MB compared to standard therapy.