International Euro Ewing (iEuroEwing) trial for treatment optimisation in patients with Ewing sarcoma

The primary objective of the International Euro Ewing (iEuroEwing) trial is to evaluate the impact of adding a maintenance treatment using VinoCyc to the standard nine cycles of VDC/IE on **event-free survival (EFS)** in patients with Ewing sarcoma. This is assessed in two parts: the iEuroEwing-SR part aims for a 10% increase in 3-year EFS for patients with primary disease, while the iEuroEwing-HR part targets a 17% increase in 2-year EFS for those with primary disseminated disease. Additionally, the iEuroEwing-SR part RT seeks to demonstrate that a higher radiation therapy (RT) dose is not inferior in terms of acute skin toxicity compared to a lower dose, with a non-inferiority margin of 8%.

The secondary objectives include: - Investigating if maintenance therapy with VinoCyc improves overall survival (OS) in both standard and high-risk groups, aiming for a 10% and 15% increase, respectively, compared to historical controls. - Evaluating if a higher dose of radiation improves local control, event-free survival (EFS), and overall survival (OS) since randomisation. - Assessing toxicity and safety profiles. - Analyzing survival outcomes, including EFS and OS, across all patient groups. - Evaluating the quality of life of patients. - Analyzing the time to diagnosis. - Investigating cancer predisposition. - Correlating histopathological response with imaging data. - Studying the biology of Ewing sarcoma.

The clinical trial involves a total of **73 participants** diagnosed with **Ewing Sarcoma**, including both primary localized and metastatic forms. The study population comprises individuals of any gender, aged between **2 and 50 years** at the time of diagnostic biopsy. Participants were selected based on a histological and molecular diagnosis of Ewing Sarcoma or Ewing-like sarcoma, with the pathological diagnosis performed at the investigational site. The trial includes a vulnerable population, indicating the inclusion of potentially at-risk groups. Participants are required to have a white blood cell count greater than 2000/μl, cardiac function with LVEF over 40% and SF over 28%, and serum creatinine levels below 1.5 times the upper limit of normal. Lifestyle considerations such as diet and physical activity are not specified, but participants of childbearing potential must adhere to effective contraception measures during and after the trial. The trial does not specify any particular lifestyle or habitual criteria beyond these medical requirements.

The clinical trial is designed to evaluate the efficacy of a maintenance treatment using VinoCyc in patients with **Ewing Sarcoma**. This is a Phase III confirmatory trial, employing a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The trial aims to improve event-free survival (EFS) in patients with both primary localized and disseminated disease. The trial is expected to run from December 2022 to May 2031, with participant involvement lasting up to 34 months, depending on the treatment arm and individual response.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as histological diagnosis and age range. Following the screening, participants will be randomized into different treatment arms. The trial includes multiple follow-up visits to monitor treatment response, side effects, and overall health status. These visits are crucial for assessing the primary endpoint of EFS and secondary endpoints, including overall survival and quality of life. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, fail to comply with the study protocol, or withdraw consent. The trial involves the administration of several investigational products, including **Filgrastim**, **Mesna**, **Doxorubicin**, **Cyclophosphamide**, **Etoposide**, **Vincristine Sulfate**, **Vinorelbine**, and **Ifosfamide**, delivered through various routes such as intravenous, oral, and subcutaneous. The trial's rigorous design and comprehensive monitoring aim to provide robust data on the potential benefits of the maintenance treatment in improving outcomes for patients with Ewing Sarcoma.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Filgrastim** is utilized in this study as a granulocyte stimulating factor. It is administered in a pharmaceutical form identified as PHF802, with a maximum daily dose of 10 µg/kg and a total maximum dose of 1500 µg/kg. The administration routes include subcutaneous, intramuscular, or intravenous methods, and the treatment period extends up to 34 days.

**Mesna** is employed as a chemical agent in the trial, with a pharmaceutical form designated as PHF00231MIG. The maximum daily dose is set at 4000 mg/m², with a total maximum dose of 42000 mg/m². Mesna is administered intravenously over a treatment period of 34 days.

**Doxorubicin**, another chemical agent, is administered intravenously in the form PHF00231MIG. The maximum daily dose is 37.5 mg/m², with a total maximum dose of 375 mg/m², over a 34-day treatment period.

**Anhydrous Cyclophosphamide** is administered intravenously in the form PHF00231MIG, with a maximum daily dose of 1200 mg/m² and a total maximum dose of 9600 mg/m², over a 34-day treatment period.

**Etoposide** is administered intravenously in the form PHF675, with a maximum daily dose of 100 mg/m² and a total maximum dose of 3000 mg/m², over a 34-day treatment period.

**Vincristine Sulfate** is administered intravenously as a solution for injection, with a maximum daily dose of 2 mg/m² and a total maximum dose of 16 mg/m², over a 34-day treatment period.

**Vinorelbine** is administered in two forms: orally in the form PHF00230MIG, with a maximum daily dose of 60 mg/m² and a total maximum dose of 120 mg/m² over a 24-day treatment period, and intravenously as a solution for infusion, with a maximum daily dose of 25 mg/m² and a total maximum dose of 60 mg/m² over a 24-day treatment period.

**Ifosfamide** is administered intravenously in the form PHF00231MIG, with a maximum daily dose of 1800 mg/m² and a total maximum dose of 54000 mg/m², over a 34-day treatment period.

**Cyclophosphamide** is administered in two forms: intravenously in the form PHF00231MIG, with a maximum daily dose of 25 mg/m² and a total maximum dose of 9600 mg/m² over a 24-day treatment period, and orally as a tablet, with the same dosing parameters.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus is on evaluating the efficacy and safety of the experimental medications in the context of the trial's objectives.

The efficacy of the clinical trial will be assessed primarily through the analysis of **Event-Free Survival (EFS)**. In the iEuroEwing-SR part, the trial aims to determine whether the addition of a maintenance treatment using VinoCyc to nine cycles of VDC/IE improves EFS in patients with primary disease, targeting a 10% increase in 3-year EFS compared to the standard VDC/IE treatment. For the iEuroEwing-HR part, the objective is to evaluate if the same maintenance treatment improves EFS in patients with primary disseminated disease, with a goal of a 17% increase in 2-year EFS compared to the standard treatment.

Secondary endpoints include the investigation of overall survival (OS) improvements, aiming at a 10% increase in the iEuroEwing-SR part and a 15% increase in the iEuroEwing-HR part. Additional secondary endpoints involve the assessment of toxicity/safety, survival outcomes, quality of life, time to diagnosis, cancer predisposition, and the correlation of histopathological and biological characteristics of Ewing sarcoma. The occurrence of acute skin toxicity CTCAE grade ≥3 during radiotherapy will also be analyzed in the iEuroEwing-SR-RT part to determine the non-inferiority of a higher radiation dose.