Evaluation of Metformin as Maintenance Therapy in Patients with High-Risk Relapse Bone Sarcomas: A Focus on Osteosarcoma and Ewing's Sarcoma

The primary objective of this study is to evaluate **Event Free Survival (EFS)** in patients with **osteosarcoma** and **Ewing's sarcoma** who are at high risk of relapse. This is compared with historical controls to determine the efficacy of **metformin** as a maintenance therapy. The clinical relevance of this objective lies in its potential to improve survival outcomes in a population with limited treatment options, thereby addressing a significant unmet need in the management of high-risk bone sarcomas.

Secondary objectives include the evaluation of metformin toxicity through blood tests and clinical assessments, as well as therapy compliance using the age-adjusted EORTC QLQ-C30 questionnaire for adults. These assessments are crucial for understanding the safety profile of metformin and ensuring adherence to the therapeutic regimen, which are essential for the successful implementation of maintenance therapy in clinical practice.

The clinical trial involves participants diagnosed with **bone sarcoma**, specifically focusing on individuals with **osteosarcoma** and Ewing's sarcoma at high risk of relapse. The study population includes both male and female subjects, aged 10 years and older, with a body weight of at least 30 kg. Participants are required to have normal renal and liver function, with specific criteria for creatinine, creatinine clearance, serum total bilirubin, AST, and ALT levels. The trial includes individuals who have been rendered disease-free after the first relapse and are not part of other protocols. Participants must be able to swallow and undergo screening within 30 days of chemotherapy termination or relapse surgery, with treatment commencing within 30 days of screening. The sponsor has not provided the total number of participants involved in the study. The trial population selection considers individuals who are part of a vulnerable population, ensuring comprehensive evaluation and monitoring throughout the study period.

The clinical trial is designed to evaluate the **event-free survival** (EFS) in patients with **osteosarcoma** and **Ewing's sarcoma** at high risk of relapse, using **metformin** as maintenance therapy. This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to last until March 15, 2028, with recruitment having started on March 15, 2021. Participants will be involved in the study for a maximum treatment period of 48 months, receiving metformin orally with a maximum daily dose of 250 mg and a total dose of 850 mg.

The study includes several key visits: an inclusion (screening) visit, follow-up visits, and an end-of-study visit. The screening visit must occur within 30 days of chemotherapy termination or relapse surgery, ensuring participants meet the inclusion criteria, such as age ≥ 10 years, body weight ≥ 30 kg, and normal renal and liver function. Treatment must commence within 30 days of the screening. Follow-up visits will monitor primary and secondary endpoints, including unexpected metformin toxicity and patient therapy compliance using the EORTC QLQ-C30 questionnaire. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any adverse events.

Participants may be terminated early from the study if they fail to comply with the protocol, experience significant adverse effects, or withdraw consent. The trial aims to provide valuable insights into the efficacy of metformin in improving EFS in high-risk bone sarcoma patients, contributing to the development of effective maintenance therapies.

The clinical trial involves the use of **Metformin** as an experimental medication, specifically as a maintenance therapy for patients with bone sarcomas at high risk of relapse. **Metformin** is classified under the ATC code A10BA02 and is administered in an oral pharmaceutical form, designated as PHF00245MIG. The maximum daily dose of **Metformin** is 250 mg, with a total maximum dose of 850 mg over the course of the treatment. The treatment period is set for a maximum of 48 weeks. The medication is not a paediatric formulation and is not classified as an orphan drug. The administration of **Metformin** is intended to evaluate event-free survival (EFS) in patients with osteosarcoma and Ewing's sarcoma, comparing outcomes with historical controls.

The efficacy of Metformin as maintenance therapy in patients with bone sarcomas at high risk of relapse will be assessed primarily through **Event Free Survival (EFS)**. This primary endpoint will evaluate the duration in which patients remain free from events such as disease progression or relapse. Secondary endpoints include the assessment of unexpected Metformin toxicity and patient therapy compliance, which will be measured using the EORTC QLQ-C30 questionnaire, a validated tool for evaluating quality of life in cancer patients. Data collection will occur at specified intervals throughout the trial, with the estimated end date set for March 15, 2028. The trial is a Phase II study, indicating its focus on evaluating the efficacy and safety of Metformin in this specific patient population. The study will involve patients with osteosarcoma and Ewing's sarcoma who meet the inclusion criteria, such as being disease-free after the first relapse and having normal renal and liver function. The maximum treatment period for participants is 48 months, during which efficacy and safety data will be systematically collected and analyzed.