Evaluation of Carboplatin and Chemotherapeutic Regimen in Pediatric Patients with Standard-Risk and High-Risk Medulloblastoma: A Multinational Prospective Study

The primary objective of this study is to evaluate the **Event-Free Survival (EFS)** rates in children and adolescents with different risk profiles of medulloblastoma. For the LR-Arm, the aim is to confirm that the 3-year EFS rate remains above 80% in patients with standard-risk medulloblastoma and a low-risk biological profile when treated with 18.0 Gy neuraxis irradiation plus a boost to the primary tumor, along with reduced-intensity chemotherapy. In the SR-Arm, the study seeks to determine if the EFS differs in patients with standard-risk medulloblastoma and an average-risk biological profile when treated with or without carboplatin concomitantly with radiotherapy, followed by modified maintenance chemotherapy. For the WNT-HR-Arm, the objective is to confirm a 3-year EFS rate of 80% in high-risk medulloblastoma patients with a low-risk biological profile when treated with 23.4 Gy (35.2 Gy) neuraxis irradiation plus a boost to the primary tumor and metastases, if applicable, along with reduced-intensity chemotherapy. Lastly, the SHH-TP53-Arm aims to determine the superiority of EFS in medulloblastoma SHH-TP53-mutant patients receiving treatment adapted to the presence of somatic or germline TP53 mutation compared to a historical cohort.

Secondary objectives include: - Investigating the Overall Survival (OS) rate and relapse patterns across all arms. - Studying late effects focusing on hearing, endocrine, and neurologic function, as well as health status, executive function, behavioral outcomes, and quality of life. - Conducting comprehensive studies on the biological basis of WNT-subgroup and standard-risk medulloblastoma to identify and validate biomarkers and drug targets. - Evaluating progression-free survival rates in randomized treatment arms and testing the feasibility of carboplatin treatment with radiotherapy. - Assessing responses after chemotherapy and radiotherapy, frequency of second malignancies, and increased treatment toxicity in SHH-TP53 patients. - Conducting studies on the biological basis of SHH-activated TP53-mutant medulloblastoma to evaluate germline-somatic correlations and genotype-phenotype correlations.

The clinical trial involves a total of **41 participants** diagnosed with **medulloblastoma**, a type of brain cancer. The study population includes both male and female subjects, with an age range starting from 3 to less than 22 years, depending on the specific arm of the trial. Participants are children and adolescents with a standard-risk or high-risk biological profile of medulloblastoma. The trial population was selected based on specific genetic and histological criteria, ensuring a well-defined diagnosis according to the WHO classification. Participants are required to have no prior therapy for medulloblastoma other than surgery, and they must not have significant sensineural hearing deficits. The study also considers the general health status of participants, requiring CTC grades less than 2 for liver, renal, and hematological function. The trial includes a vulnerable population, as it involves children and adolescents, and requires written informed consent and ethical committee approval according to the laws of each participating country. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of various chemotherapeutic agents in the treatment of **medulloblastoma** in children and adolescents. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The study is expected to run until December 31, 2027, with recruitment having commenced on June 25, 2014. Participants will be involved in the study for a maximum treatment period of 48 months, depending on the specific treatment arm they are assigned to.

Study visits are structured to include an initial screening visit, where eligibility is confirmed based on inclusion criteria such as age, histological and genetic confirmation of medulloblastoma, and absence of prior therapy other than surgery. Following the screening, participants will undergo regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the primary outcome measure, which is event-free survival (EFS), along with secondary outcomes such as overall survival (OS) and progression-free survival (PFS).

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it in the participant's best interest. The trial involves the administration of chemotherapeutic agents such as **carboplatin**, **methotrexate**, **cisplatin**, **cyclophosphamide**, **doxorubicin hydrochloride**, **vinblastine sulfate**, **vincristine**, and **lomustine**, delivered through various routes including intravenous and oral administration. The study aims to confirm the 3-year EFS rate in different risk groups and to evaluate the feasibility and safety of the treatment regimens.

The clinical trial involves the administration of several **chemotherapeutic agents**. **Carboplatin** is provided as a solution for infusion, with a maximum daily dose of 400 mg/m² and a total dose not exceeding 2650 mg/m². It is administered intravenously over a treatment period of up to 48 weeks. Participant compliance is monitored through regular assessments of infusion records and dosage calculations.

**Methotrexate** is utilized in two forms: as a solution for injection and for intraventricular use. The intravenous form has a maximum daily dose of 5 g/m² and a total dose of 20 g/m², administered over 12 weeks. The intraventricular form is dosed at a maximum of 2 mg per day, with a total dose of 48 mg over the same period. Compliance is ensured through monitoring of administration records and patient follow-up.

**Cisplatin** is administered as a solution for infusion with a maximum daily dose of 70 mg/m² and a total dose of 280 mg/m². The administration is intravenous, spanning a treatment period of up to 48 weeks. Compliance is tracked through infusion logs and patient assessments.

**Cyclophosphamide** is provided as a powder for solution for injection, with a maximum daily dose of 1000 mg/m² and a total dose of 16000 mg/m². It is administered via intravenous infusion over a 12-week period. Compliance is monitored through infusion records and dosage checks.

**Doxorubicin Hydrochloride** is administered as a solution for infusion, with a maximum daily dose of 37.5 mg/m² and a total dose of 150 mg/m². The administration is intravenous, over a 12-week period. Compliance is ensured through monitoring of infusion records and patient evaluations.

**Vinblastine Sulfate** is provided as a solution for injection, with a maximum daily dose of 10 mg/m² and a total dose of 240 mg/m². It is administered intravenously over a 12-week period. Compliance is tracked through administration logs and patient follow-up.

**Vincristine** is administered as a solution for injection, with a maximum daily dose of 1.5 mg/m² and a total dose of 24 mg/m². The administration is intravenous, over a 12-week period. Compliance is monitored through infusion records and patient assessments.

**Lomustine** is provided in capsule form, with a maximum daily dose of 75 mg/m² and a total dose of 280 mg/m². It is administered orally over a treatment period of up to 48 weeks. Compliance is ensured through pill counts and patient diaries.

Efficacy in this clinical trial will be assessed primarily through the measurement of **event-free survival (EFS)** across all study arms. The primary endpoint is to confirm that the 3-year EFS rate in children and adolescents with standard-risk medulloblastoma having a low-risk biological profile remains in excess of 80% when treated with specific irradiation and chemotherapy regimens. Secondary endpoints include the rate of overall survival (OS) and progression-free survival (PFS), which will be estimated using the Kaplan-Meier method. Additionally, the pattern of relapse, including the site and time to local progression, will be evaluated, with particular attention to posterior fossa relapse.

Further secondary outcome measures involve the feasibility of carboplatin treatment concomitantly with radiotherapy, assessed by the timely delivery of maintenance chemotherapy and associated toxicities. Indirect measures of quality of survival (QoS) will be evaluated using standardized scales such as the Health Utilities Index (HUI3), the Behavior Rating Inventory of Executive Function (BRIEF), and the Pediatric Quality of Life Inventory (PedsQL). Audiological toxicity will be assessed through Pure Tone Audiometry (PTA) graded by the Chang criteria, and endocrine function will be evaluated using biomarkers like FSH levels and growth retardation metrics. Neurological function will be measured by the occurrence and severity of posterior fossa syndrome and persisting cerebellar symptoms. The prognostic value of biological tumor markers will also be assessed through protein, RNA, and DNA analysis assays.