Evaluation of Regorafenib Addition to VDC/IE Chemotherapy and Maintenance Vinorelbine-Cyclophosphamide in Newly Diagnosed Metastatic Ewing Sarcoma

The primary objectives of the INTER-EWING-1 trial focus on evaluating treatment strategies for newly diagnosed **Ewing Sarcoma**. For chemotherapy, the study aims to determine if the addition of regorafenib to the standard VDC/IE regimen improves outcomes in metastatic patients compared to VDC/IE alone (Randomisation A). Additionally, it seeks to assess whether six cycles of maintenance chemotherapy with vinorelbine and cyclophosphamide enhance patient outcomes (Randomisation C). For radiotherapy, the objectives include evaluating whether dose escalation benefits patients with inoperable disease (Randomisation B1) and determining the optimal post-operative radiotherapy dose following surgical resection of the primary tumor site (Randomisation B2). These objectives are clinically relevant as they aim to improve survival rates and treatment efficacy in Ewing Sarcoma, a rare and aggressive cancer.

The secondary objectives include assessing overall survival, toxicity, cancer quality of life measures, and histological response in patients undergoing induction chemotherapy (Randomisation A). For radiotherapy (Randomisations B1 & B2), the study evaluates local failure-free survival time, overall survival, toxicity, achievement of local control, acute post-radiotherapy toxicity, late toxicity, and cancer quality of life measures. In maintenance therapy (Randomisation C), the focus is on overall survival, toxicity, and cancer quality of life measures. These secondary objectives provide a comprehensive understanding of the treatment's impact on patient health and quality of life.

The clinical trial involves a total of **402 participants** diagnosed with **Ewing Sarcoma**, a rare type of cancer that occurs in bones or soft tissue. The study population includes both male and female subjects, with an age range starting from 2 years and encompassing children, adolescents, and adults. Participants were selected based on specific inclusion criteria, including histologically and genetically confirmed Ewing Sarcoma or similar round cell sarcomas. The trial also considers vulnerable populations, ensuring appropriate ethical considerations. Participants are required to be medically fit to receive treatment, and lifestyle factors such as the use of contraception during and after the trial are considered. The trial does not specify any particular dietary or physical activity requirements for participants. Key inclusion criteria include adequate liver function and a documented negative pregnancy test for females of childbearing potential. The trial aims to evaluate the efficacy of adding regorafenib to standard chemotherapy and the impact of radiotherapy dose escalation on patient outcomes.

The clinical trial is designed to evaluate the efficacy of adding **regorafenib** to standard chemotherapy in patients with newly diagnosed metastatic **Ewing Sarcoma**. This is a randomized, double-blind, controlled trial with a confirmatory phase III classification. The trial will assess multiple treatment regimens, including the addition of maintenance chemotherapy with **vinorelbine** and **cyclophosphamide**, and the impact of radiotherapy dose escalation. The trial is expected to run until November 2032, with recruitment starting in May 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on histological and genetic criteria. The inclusion criteria require participants to have a confirmed diagnosis of Ewing Sarcoma or similar round cell sarcomas, be medically fit for treatment, and provide informed consent. Follow-up visits will occur at regular intervals to monitor treatment response, assess toxicity, and ensure compliance with the study protocol. The end-of-study visit will evaluate the primary endpoint of event-free survival, defined as the time from randomization to the first failure event.

The expected length of participant involvement is up to 24 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. Secondary endpoints include overall survival, quality of life measures, and histological response, with specific assessments for each randomization group. The trial aims to improve outcomes in Ewing Sarcoma by optimizing chemotherapy and radiotherapy strategies.

The clinical trial involves the administration of **Vinorelbine**, a chemotherapeutic agent, in two pharmaceutical forms. The first form is a **concentrate for solution for infusion**, administered via the **intravenous route**. The dosage is calculated based on body surface area, with a maximum daily dose of 25 mg/m² and a cumulative maximum dose of 450 mg/m² over a treatment period of 24 weeks. This formulation is not a paediatric formulation and is classified as a chemical medicinal product.

The second form of **Vinorelbine** is a **soft capsule** intended for **oral use**. The oral formulation allows for a maximum daily dose of 60 mg/m², with a total maximum dose of 1080 mg/m² over the same 24-week treatment period. This form is also not paediatric and is similarly classified as a chemical medicinal product. Both forms of Vinorelbine are used as part of the trial's chemotherapy regimen.

**Cyclophosphamide** is another chemotherapeutic agent used in the trial, available in two forms. The first is a **powder for solution for injection**, which is administered orally. The dosing for Cyclophosphamide is also based on body surface area, with a maximum daily dose of 25 mg/m² and a total maximum dose of 4200 mg/m² over 24 weeks. This formulation is not intended for paediatric use and is classified as a chemical medicinal product.

The second form of **Cyclophosphamide** is a **tablet** for **oral administration**. The dosing parameters are identical to the powder form, with a maximum daily dose of 25 mg/m² and a cumulative maximum dose of 4200 mg/m² over the 24-week treatment period. This form is also not a paediatric formulation and is classified as a chemical medicinal product. Both forms of Cyclophosphamide are utilized in the maintenance chemotherapy phase of the trial.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to evaluate the efficacy of these chemotherapeutic agents in improving outcomes for patients with newly diagnosed Ewing Sarcoma, with specific focus on the addition of maintenance chemotherapy to the standard treatment protocol.

The efficacy of the clinical trial titled "INTER-EWING-1: International Clinical Research Programme to Improve Outcomes in Newly Diagnosed Ewing Sarcoma – Trial 1" will be assessed using several primary and secondary endpoints. The primary endpoint for all randomizations is **Event-free survival**, defined as the time from randomization until the first failure event. This endpoint will be crucial in determining the effectiveness of the interventions being tested.

Secondary endpoints vary depending on the randomization group. For Randomisation A, the secondary endpoints include Induction chemotherapy Overall Survival, Toxicity, Cancer Quality of Life Measures, and Histological response if surgery is performed. For Randomisations B1 and B2, the secondary endpoints are Radiotherapy Local Failure-Free Survival Time, Overall Survival, Toxicity, Achievement of local control, Acute post-radiotherapy toxicity, Late toxicity, and Cancer Quality of Life Measures. Randomisation C will assess Maintenance therapy Overall Survival, Toxicity, and Cancer Quality of Life Measures.

The trial will involve the administration of chemotherapy regimens, including the addition of regorafenib to the standard backbone chemotherapy VDC/IE, and the use of maintenance chemotherapy with vinorelbine and cyclophosphamide. The efficacy assessments will be conducted at various stages of the trial to evaluate the impact of these treatments on patient outcomes. The trial is designed as a confirmatory phase III clinical trial, with an estimated end date of November 30, 2032.