Phase II Evaluation of Metronomic and Targeted Anti-Angiogenic Therapy with Bevacizumab in Pediatric Recurrent/Progressive Medulloblastoma, Ependymoma, and ATRT

The primary objective of the study is to determine the **response rate** in patients with recurrent or progressive medulloblastoma, ependymoma, and atypical teratoid rhabdoid tumor (ATRT) following treatment with an antiangiogenic multidrug regimen. The response rate is defined as the percentage of patients achieving complete response (CR), partial response (PR), stable disease (SD), or lack of recurrence at 6 months post-treatment initiation. This objective is clinically relevant as it provides insight into the efficacy of the treatment regimen in managing these aggressive pediatric brain tumors.

Secondary objectives include:

• Determining the overall survival rate at 6, 12, 24, and 36 months post-treatment.
• Assessing progression-free survival at the same intervals.
• Evaluating and documenting toxicities from chronic drug administration in patients with recurrent or progressive medulloblastoma.
• Assessing quality of life using the KINDL® questionnaire.
• Evaluating performance status at 6 months using the Karnofsky performance status for children aged 12 and older, and the Lansky play scale for younger children.
• Evaluating prognostic factors, including tumor biology and patient demographics, in a descriptive manner.
• Assessing tumor and angiogenic markers in serum and cerebrospinal fluid (CSF).

These secondary objectives aim to provide a comprehensive understanding of the treatment's impact on survival, disease progression, quality of life, and potential prognostic indicators, which are crucial for optimizing therapeutic strategies in this patient population.

The clinical trial involves a total of **20 participants** diagnosed with **recurrent/progressive medulloblastoma, ependymoma, and atypical teratoid rhabdoid tumor (ATRT)**. The study population includes both male and female subjects, aged from 0 to less than 20 years at the time of their original diagnosis. Participants are required to have normal organ and bone marrow function, with specific laboratory values outlined for ALT, creatinine, white blood cell count, and platelet count. The trial does not include a vulnerable population. Participants must have a Karnofsky performance status of 50 or higher, or for those under 12 years of age, a Lansky play scale of 50% or higher. The selection criteria ensure that all participants have histological confirmation of their condition at diagnosis or relapse. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided. The trial population was selected based on the presence of at least one site of untreated recurrent disease in the specified conditions, and informed consent was obtained from patients and/or their parents.

The clinical trial is designed to evaluate the efficacy of a metronomic and targeted anti-angiogenesis therapy for children with **recurrent/progressive medulloblastoma**, ependymoma, and atypical teratoid rhabdoid tumor (ATRT). This is a Phase II, randomized, double-blind, controlled trial. The primary objective is to determine the response rate, defined as the percentage of patients with complete response (CR), partial response (PR), stable disease (SD), or lack of recurrence at six months after the start of antiangiogenic treatment. The trial is expected to conclude by August 31, 2029, with recruitment having commenced on April 9, 2014.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histological confirmation of the disease, age, and organ function. Following the screening, participants will be randomized into treatment groups. The trial includes regular follow-up visits every 12 weeks to monitor the number and relative frequency of toxicities, as well as to assess performance status and quality of life using the KINDL assessments. The end-of-study visit will evaluate the overall response to the treatment and collect final data on survival rates and progression-free survival.

The expected length of participant involvement is up to 104 weeks, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or disease progression that necessitates alternative treatment. The trial will utilize a variety of pharmaceutical forms, including solutions for injection and infusion, and hard capsules, with active substances such as **cytarabine**, **celecoxib**, **cyclophosphamide**, **etoposide**, **bevacizumab**, **fenofibrate**, and **thalidomide**. The trial will adhere to rigorous scientific and ethical standards to ensure the safety and well-being of all participants.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Cytarabine**, marketed as Cytarabine 100 mg/ml Solution for Injection, is provided as a solution for injection. It is administered via intrathecal bolus injection into the intrathecal space. The maximum daily dose is 30 mg, with a total dose not exceeding 2.8 g over a treatment period of up to 104 weeks. The product is manufactured by Pfizer Healthcare Ireland.

**Celecoxib**, under the brand name CELEBREX® 200 mg Hartkapseln, is available in hard capsule form. It is administered orally with a maximum daily dose of 800 mg and a total dose limit of 582 g over a 104-week period. This product is produced by Viatris Pharma GmbH.

**Cyclophosphamide** is provided as Cyclophosphamide Injection 1 g, a solution for injection. It is administered orally with a maximum daily dose of 200 mg and a total dose limit of 36 g over a 52-week period. Baxter Healthcare Ltd. is the manufacturer of this product.

**Etoposide** is available in two formulations: Eto-GRY® 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung and Etoposid Ebewe 20 mg/ml - Konzentrat zur Herstellung einer Infusionslösung. The former is administered via intrathecal bolus injection, with a maximum daily dose of 0.5 mg and a total dose limit of 60 g over 104 weeks. The latter is administered orally, with a maximum daily dose of 50 mg and a total dose limit of 9.1 g/m² over 52 weeks. The manufacturers are Teva GmbH and EBEWE Pharma, respectively.

**Bevacizumab**, marketed as Avastin 25 mg/ml concentrate for solution for infusion, is administered via intravenous infusion. The maximum daily dose is 10 mg/kg, with a total dose not exceeding 520 mg/kg over a 104-week period. This product is manufactured by Roche Registration GmbH.

**Fenofibrate**, under the brand name Lipcor 200 mg-Kapseln, is provided in hard capsule form. It is administered orally with a maximum daily dose of 90 mg/m² and a total dose limit of 65 g/m² over a 104-week period. The product is produced by Viatris Austria GmbH.

**Thalidomide**, marketed as Thalidomide 50 mg capsules, hard, is available in hard capsule form. It is administered orally with a maximum daily dose of 3 mg/kg and a total dose limit of 2100 mg/kg over a 104-week period. Zentiva Pharma UK Limited is the manufacturer of this product.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this study.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the response rate, defined as the percentage of patients achieving complete response (CR), partial response (PR), stable disease (SD), or lack of recurrence at 6 months following the initiation of antiangiogenic treatment. The probability for response, denoted as π, will be evaluated with a null hypothesis (H0) of π ≤ 15%, indicating the therapy is ineffective, and an alternative hypothesis (H1) of π ≥ 35%, suggesting the therapy is effective. The type I error rate is set at α=0.05, and the type II error rate is β=0.10 for Stratum I and β=0.20 for Stratum II+III.

Secondary endpoints include Kaplan-Meier survival estimates for overall survival and progression-free survival at 6, 12, 24, and 36 months, with 95% confidence intervals. These will be compared to historical samples. Additionally, the frequency and severity of toxicities, graded according to CTCAE Version 3, 4, and 5, will be evaluated every 12 weeks. Performance status will be assessed at the start of therapy and after 6 months, using subscale and total scores from the KINDL assessments. Multivariate Cox regression will be employed to analyze the influence of various factors on response rate, overall survival, progression-free survival, toxicity, quality of life, and performance status. Descriptive examination of angiogenic factors, such as VEGF, EPC, and prostaglandin E2 levels, will also be conducted.