Evaluation of Chemotherapy Regimens Including Cisplatin, Cyclophosphamide, and Etoposide in Pediatric and Young Adult Ependymoma Treatment

The primary objective of the study is to assess whether the evaluation of **residual disease** can be enhanced through a centralized review of post-operative MRI, and if this approach increases the rate of complete resection compared to historical controls. This is clinically relevant as improving resection rates could potentially lead to better outcomes in patients with ependymoma, a type of brain tumor. Additionally, the study aims to test the hypothesis that progression-free survival is improved in patients receiving 16 weeks of chemotherapy (VEC+CDDP) following surgical resection and conformal radiotherapy, compared to those undergoing surgical resection and radiotherapy alone. Furthermore, the study seeks to compare the efficacy of two post-operative chemotherapy regimens, VEC or VEC+HD-MTX, in patients with incompletely resected tumors. Lastly, the study evaluates progression-free survival in children unable to receive radiation therapy who are treated with valproate, a histone deacetylase inhibitor, in addition to the primary chemotherapy strategy, compared to those receiving chemotherapy without valproate.

Secondary objectives include: - Evaluating second look surgery rates compared to historical controls. - Describing the efficacy in each molecular sub-group in both study arms. - Assessing whether overall survival is improved in patients in the experimental arm compared to the standard arm. - Comparing neuroendocrine morbidity in each treatment arm. - Evaluating neuropsychological morbidity in each treatment arm. - Assessing the quality of survival in each treatment arm. - Determining the safety and tolerance of patients in the experimental arm compared to the standard arm. - Describing the concordance between central and local radiological assessment of post-operative chemotherapy efficacy. - Evaluating whether progression-free survival is improved in patients receiving VEC + HD-MTX following surgical resection compared to those receiving VEC alone. - Assessing whether radiotherapy-free survival is improved by adding valproate to the primary chemotherapy strategy compared to primary chemotherapy alone.

The clinical trial involves a total of **340 participants** who have been newly diagnosed with an intracranial or spinal **ependymoma**, including all WHO grades and variants such as cellular, papillary, myxopapillary, clear-cell, tanycytic, or anaplastic ependymoma. The study population includes both male and female subjects, with an age range of greater than 12 months and less than 22 years at the time of study entry. Participants are required to have no previous chemotherapy, except for steroids, and must not have any co-existent unrelated diseases that would impede their ability to receive chemotherapy. The trial population was selected based on specific inclusion criteria, including adequate bone marrow, liver, and renal function, and no signs of infection. Additionally, participants must not have undergone previous radiotherapy. The study also considers lifestyle factors such as the ability to comply with scheduled visits and treatment plans. The trial includes a vulnerable population, as it involves children and young adults. Participants and their legal guardians must provide written informed consent and be affiliated with a Social Security System where applicable. The trial aims to assess the effectiveness of different chemotherapy regimens and the impact of centralized reviews on surgical outcomes.

The clinical trial is designed to evaluate the efficacy of various chemotherapy regimens in patients newly diagnosed with **ependymoma**, a type of brain or spinal cord tumor. The trial is structured as a randomized, double-blind, controlled study, with an estimated duration extending until December 31, 2028. Participants will be involved in the study for a maximum treatment period of up to 23 weeks, depending on the specific stratum they are assigned to. The trial includes multiple strata, each with distinct objectives and treatment protocols, such as the use of chemotherapy agents like **cisplatin**, **cyclophosphamide**, **etoposide**, **vincristine sulfate**, and **methotrexate**.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed, including age, absence of previous chemotherapy (except steroids), and adequate organ function. Following the screening, participants will undergo a series of follow-up visits to monitor treatment response and adverse events. These visits will include assessments such as MRI scans and laboratory tests. The end-of-study visit will conclude the participant's involvement, where final evaluations of treatment efficacy and safety are conducted.

Participants may be terminated early from the study 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 primary endpoints of the trial include the rate of Gross Total Resection (GTR) and Progression-Free Survival (PFS), while secondary endpoints focus on overall survival, neuroendocrine and neuropsychological outcomes, and quality of survival. The trial aims to improve the understanding of chemotherapy's role in treating ependymoma and to optimize treatment strategies for this condition.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Cisplatin** is provided as a 1 mg/ml concentrate for solution for infusion. It is administered via infusion with a maximum daily dose of 160 mg and a total dose not exceeding 480 mg over a treatment period of 11 weeks. The pharmaceutical form is a solution for infusion, and the product is manufactured by Accord Healthcare Limited.

**Cyclophosphamide** is available in three different formulations: 500 mg, 1000 mg, and 2000 mg powders for solution for injection or infusion. The administration route is infusion, with a maximum daily dose of 6000 mg for the 500 mg and 2000 mg formulations, and 1500 mg/m² for the 1000 mg formulation. The total dose for the 500 mg formulation is capped at 24000 mg over 16 weeks, while the 2000 mg formulation allows for a total of 42000 mg over 23 weeks. The 1000 mg formulation has a total dose limit of 10500 mg over 11 weeks. Sandoz Ltd is the manufacturer of these formulations.

**Etoposide** is administered as a 20 mg/ml concentrate for solution for infusion. The route of administration is infusion, with a maximum daily dose of 200 mg and a total dose of 2400 mg over a 16-week period. Accord Healthcare Limited is responsible for the production of this medication.

**Vincristine sulfate** is provided in two formulations: a 1 mg/ml solution for injection and a 1 mg/ml solution for injection or infusion. The administration is via intravenous bolus use or infusion, with a maximum daily dose of 2 mg and a total dose of 20 mg over 23 weeks for the injection form, and 42 mg over 12 weeks for the solution form. The manufacturers are Teva UK Limited and Pfizer Healthcare Ireland, respectively.

**Sodium valproate** is administered as Epilim Syrup 200 mg/5 ml, with an oral route of administration. The maximum daily dose is 70 mg/kg, with a total dose of 51100 mg over a 24-week period. Aventis Pharma Ltd is the manufacturer of this anticonvulsive medication.

**Methotrexate** is available as a 100 mg/ml solution for injection. It is administered via infusion, with a maximum daily dose of 16000 mg and a total dose of 48000 mg over a 7-week period. Hospira UK Limited is the manufacturer of this antineoplastic agent.

**Carboplatin** is provided as a 10 mg/ml intravenous infusion solution. The administration route is infusion, with a maximum daily dose of 550 mg/m² and a total dose of 3850 mg over an 11-week period. Hospira UK Limited is responsible for the production of this medication.

All medications are chemically derived and are not formulated for pediatric use. Participant compliance is monitored throughout the trial to ensure adherence to dosing schedules and treatment protocols. The trial aims to evaluate the efficacy and safety of these medications in the treatment of ependymoma in children, adolescents, and young adults.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the Gross Total Resection (GTR) rate for the overall program, **Progression Free Survival (PFS)** for Stratum 1 and 3, and the number of treatment responders according to central radiological review for Stratum 2. Secondary endpoints encompass a range of measures such as the second look surgery rate, efficacy in each molecular sub-group in terms of PFS and Overall Survival (OS), neuroendocrine and neuropsychological outcomes, quality of survival, and adverse events as per CTCAE v4.03. Additionally, for Stratum 2, the proportion of patients in whom the central radiological review confirms the local review and PFS will be evaluated, while Stratum 3 will assess the radiotherapy-free survival rate.

The trial aims to determine whether the assessment of residual disease can be improved by a centralized review of post-operative MRI, potentially increasing the rate of complete resection compared to historical controls. The trial will also test the hypothesis that progression-free survival improves in patients receiving 16 weeks of chemotherapy (VEC+CDDP) following surgical resection and conformal radiotherapy, compared to those undergoing surgical resection and radiotherapy alone. Furthermore, the activity of two post-operative chemotherapy schedules, VEC or VEC+HD-MTX, will be compared in patients with incompletely resected tumors. For children unable to receive radiation therapy, the trial will evaluate the progression-free survival when valproate is added as a histone deacetylase inhibitor to the primary chemotherapy strategy, compared to chemotherapy without valproate.