Neurocognitive Outcomes in Low-Risk Medulloblastoma: Methotrexate, Etoposide, Cyclophosphamide, Carboplatin, Vincristine, Cisplatin, and Thiotepa Evaluation

The primary objective of this study is to compare **neurocognitive outcomes** 2.5 years after diagnosis between patients with newly diagnosed, non-metastatic, SHH-activated, TP53-wt, non-MYC amplified medulloblastoma randomized to the interventional arms A ("Head Start" 4) and B (HITSKK). This is clinically relevant as it aims to determine the impact of different treatment regimens on cognitive function, which is a critical aspect of quality of life in pediatric patients with medulloblastoma.

Secondary objectives include:

• Progression-free survival (PFS) compared between randomized groups.
• Radiotherapy-free/progression-free survival (rtPFS) compared between randomized groups.
• Overall survival (OS) compared between randomized groups.
• Incidence of second malignancies compared between randomized groups.
• Acute toxicities compared between randomized groups.
• Incidence of therapy-related deaths compared between randomized groups.
• Neurocognitive outcomes at baseline and 5 years after diagnosis compared between randomized groups.
• Subdomain-specific neurocognitive outcome parameters (2.5 and 5 years after diagnosis) compared between randomized groups.
• Development and adaptive functioning (at diagnosis, 2.5 and 5 years after diagnosis) compared between randomized groups.
• Quality of Life (QoL) at diagnosis, 2.5 and 5 years after diagnosis between randomized groups.
• Longitudinal development of neurocognitive, QoL, and behavioral outcomes 5 years after diagnosis compared between randomized groups.
• Ototoxicity at 2.5 years and 5 years after diagnosis compared between randomized groups.
• Leukoencephalopathy (LEP) 2.5 and 5 years after diagnosis compared between randomized groups.
• Comparison of PFS, rtPFS, OS between randomized groups in patients in complete remission at the end of study therapy.
• Comparison of PFS, rtPFS, OS between subtypes of SHH-MB as defined by classification based on the Heidelberg brain tumor classifier Version 11 (or higher).
• Assessment of the rate of patients with genetically confirmed basal-cell nevus syndrome (BCNS, Gorlin-Syndrome, OMIM: 109400), ELP1 and GPR161 cancer predisposition syndromes among eligible enrolled patients.

The clinical trial involves a study population of children under the age of 5 years, diagnosed with **newly diagnosed, non-metastatic, SHH-activated, TP53-wt, non-MYC amplified medulloblastoma**. The trial includes both male and female participants, and the population is considered vulnerable due to the young age of the subjects. The sponsor has not provided the total number of participants. Selection criteria include the ability of the patient and their family to participate in neuropsychological follow-up, as well as the capacity of parents or legal representatives to understand and sign informed consent. Participants are required to be in social circumstances that support the study's follow-up requirements. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **neurocognitive** outcomes in patients with newly diagnosed, non-metastatic, SHH-activated, TP53-wt, non-MYC amplified **medulloblastoma**. This study employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. Participants will be randomly assigned to one of two interventional arms, A ("Head Start" 4) or B (HITSKK), with the primary objective of comparing neurocognitive outcomes 2.5 years post-diagnosis. The trial is expected to commence recruitment on July 1, 2025, and conclude by March 31, 2036, with a maximum treatment period of 9 months for each participant.

Study visits are structured to include an initial screening visit, multiple follow-up visits, and an end-of-study visit. The inclusion visit will assess eligibility based on criteria such as age at diagnosis being less than 5 years, institutional suspicion or diagnosis of SHH-activated medulloblastoma, and the ability of the patient and family to comply with neuropsychological follow-up. Follow-up visits will occur at regular intervals to monitor progression-free survival, overall survival, and other secondary endpoints such as quality of life and toxicity. The end-of-study visit will evaluate the primary endpoint, which is the Full-Scale Intelligence Quotient (IQ) measured by the Wechsler Pre-school and Primary Scale of Intelligence (WPPSI-IV) at 2.5 years after diagnosis.

Participant involvement is anticipated to last up to 9 months, with additional follow-up assessments extending to 5 years post-diagnosis. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial will utilize chemotherapeutic agents such as **methotrexate**, **etoposide**, **cyclophosphamide**, **carboplatin**, **vincristine**, **cisplatin**, and **thiotepa**, administered via intravenous or intraventricular routes, depending on the specific regimen. The study aims to provide comprehensive data on the long-term neurocognitive and quality of life outcomes for this patient population.

The clinical trial involves the administration of several **chemotherapeutic agents** to evaluate their effects on neurocognitive outcomes in patients with low-risk medulloblastoma. **Methotrexate** is utilized in two forms: a solution for infusion and a solution for injection. The solution for infusion is administered **intravenously** with a maximum daily dose of 400 mg/kg and a total dose not exceeding 2000 mg/kg over a treatment period of 9 weeks. The solution for injection is administered **intraventricularly** with a maximum daily dose of 2 mg and a total dose of 72 mg over the same period.

**Etoposide** is provided as a solution for infusion, administered **intravenously**. The dosing regimen allows for a maximum daily dose of 150 mg/m² and a total dose of 2250 mg/m² over 9 weeks. **Cyclophosphamide** is supplied as a powder for solution for infusion, also administered **intravenously**. The maximum daily dose is 65 mg/kg, with a total dose limit of 650 mg/kg over the treatment period.

**Carboplatin** is administered as a solution for infusion **intravenously**, with a maximum daily dose of 200 mg/ml and a total dose of 3000 mg/ml over 9 weeks. **Vincristine** is provided as a solution for injection, administered **intravenously**. The dosing schedule permits a maximum daily dose of 1.5 mg/m² and a total dose of 16.5 mg/m² over the treatment duration.

**Cisplatin** is administered as a solution for infusion **intravenously**, with a maximum daily dose of 3.5 mg/kg and a total dose of 17.5 mg/kg over 9 weeks. **Thiotepa** is supplied as a powder for solution for injection, administered **intravenously**. The dosing regimen allows for a maximum daily dose of 10 mg/kg and a total dose of 30 mg/kg over the treatment period.

All medications are classified as chemotherapeutic agents and are not formulated for pediatric use. The trial does not involve any orphan drug designations. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy in the clinical trial titled "Comparison of neurocognitive outcome in two standard regimen for treatment of low-risk medulloblastoma (COGNITO-MB)" will be assessed using a range of primary and secondary endpoints. The primary endpoint is the Full-Scale Intelligence Quotient (IQ) as measured by the Wechsler Pre-school and Primary Scale of Intelligence (WPPSI-IV). This assessment will be administered to participants aged between 2 years and 6 months to 7 years and 7 months, 2.5 years after diagnosis, with a permissible range of +/- 6 months.

Secondary endpoints include several measures of survival and neurocognitive outcomes. These are: Progression-free survival (PFS), survival free of radiotherapy and progression (rtPFS), overall survival (OS), and time to first second malignancy. Additionally, neurocognitive outcomes will be evaluated using the WPPSI-IV and WISC-V scales, with specific focus on subdomain-specific parameters such as Verbal Comprehension Index, Visual Spatial Index, Fluid Reasoning Index, Working Memory Index, and Processing Speed Index. Other assessments include the Beery Visual Motor Integration (VMI) Test, Purdue Pegboard Test, and the Adaptive Behavior Assessment System (ABAS).

Quality of Life (QoL) will be measured using the PedsQL Infant Scale, PedsQL 4.0, PedsQL Fatigue Scale, BRIEF-P, BRIEF, BRIEF 2, and the Strengths and Difficulties Questionnaire (SDQ). These assessments will be conducted at diagnosis, 2.5 years, and 5 years after diagnosis. Longitudinal development of neurocognitive, QoL, and behavioral outcomes will also be evaluated to assess potential changes over time. Additional assessments include ototoxicity evaluation using the SIOP Boston Scales and Chang-Scale, and leukoencephalopathy assessment using the modified Fazekas scale at 2.5 and 5 years post-diagnosis.