Evaluation of Perioperative Doxorubicin, Ifosfamide, and Dacarbazine in CINSARC High-Risk Localized Soft Tissue Sarcoma Patients

The primary objective of this study is to evaluate whether the addition of four cycles of peri-operative **doxorubicin**-based chemotherapy enhances metastasis-free survival compared to standard management in patients with resectable soft tissue sarcoma (STS) identified as high-risk according to the CINSARC signature. This is clinically relevant as improving metastasis-free survival could significantly impact the long-term outcomes and quality of life for these patients.

Secondary objectives include:

• Comparing two therapeutic strategies in high-risk CINSARC patients with resectable STS in terms of disease-free survival, overall survival, and safety profile.
• Prospectively validating the prognostic value of the CINSARC signature in STS patients treated with standard treatment.

The clinical trial involves participants diagnosed with **Soft Tissue Sarcoma**, with a focus on individuals considered high-risk according to the CINSARC signature. The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. Participants are required to have acceptable hematologic, renal, and liver function, as well as a normal left ventricular ejection fraction (LVEF) greater than 50%. The trial does not include a vulnerable population. Lifestyle considerations include the requirement for women to be post-menopausal or to use effective contraception during and after the treatment period, while men must also use effective contraception during and after the study. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of peri-operative **doxorubicin**-based chemotherapy in improving metastasis-free survival in patients with high-risk localized **soft tissue sarcoma**. This is a Phase III, randomized, double-blind, controlled trial. The study will span approximately nine years, with an estimated recruitment start date in February 2020 and an anticipated end date in February 2029. Participants will be randomly assigned to receive either the investigational treatment or standard management. The investigational treatment involves four cycles of chemotherapy, including **ifosfamide**, **doxorubicin**, and **dacarbazine citrate**, administered intravenously.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as histologically confirmed diagnosis, acceptable hematologic, renal, and liver function, and a high-risk CINSARC signature. Following randomization, participants will undergo regular follow-up visits to monitor treatment response and safety, with assessments including metastasis-free survival, disease-free survival, and overall survival. Safety will be evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0).

The expected length of participant involvement is up to 12 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the development of unacceptable toxicity, withdrawal of consent, or any condition that, in the investigator's opinion, warrants discontinuation for the participant's safety. The end-of-study visit will occur after the completion of the treatment period or upon early termination, where final assessments will be conducted to evaluate the primary and secondary endpoints.

The clinical trial involves the administration of **ifosfamide**, marketed as HOLOXAN 2000 mg, in the form of a **solution for infusion**. This experimental medication is provided as a powder for parenteral use, which is reconstituted into a solution for intravenous administration. The dosing regimen for ifosfamide is calculated based on body surface area, with a maximum daily dose of 9 gm/m² and a cumulative maximum dose of 36 gm/m² over a treatment period of up to 12 weeks. The administration is conducted under controlled conditions to ensure participant safety and adherence to the protocol.

Another experimental medication used in the trial is **doxorubicin**, available as DOXORUBICINE TEVA 50 mg/25 ml, in the form of an **injection**. This medication is administered intravenously, with the dosage also determined by body surface area. The maximum daily dose is set at 60 mg/m², with a total maximum dose of 240 mg/m² over the same 12-week treatment period. Doxorubicin is a well-established chemotherapeutic agent, and its administration is closely monitored to manage potential side effects and ensure compliance with the treatment protocol.

The trial also includes the use of **dacarbazine citrate**, marketed as Dacarbazine medac 500 mg, provided as a powder for solution for infusion. This medication is administered intravenously, with a dosing schedule based on body surface area. The maximum daily dose is 900 mg/m², and the total maximum dose is 3600 mg/m² over a 12-week period. As with the other medications, dacarbazine citrate is administered under strict clinical supervision to monitor efficacy and safety, as well as to ensure participant adherence to the treatment regimen.

Throughout the trial, participant compliance with the dosing schedules is monitored through regular assessments and documentation. The trial aims to evaluate the efficacy of these chemotherapeutic agents in improving metastasis-free survival in patients with high-risk localized soft tissue sarcoma, as defined by the CINSARC classification. No non-experimental treatments, such as standard-of-care therapy or placebo, are utilized in this study.

Efficacy in this clinical trial will be assessed primarily through **Metastasis-free survival (MFS)**, which is defined as the time from randomization to the occurrence of metastatic disease or death from any cause. This primary endpoint will provide a direct measure of the treatment's impact on delaying or preventing metastasis in patients with high-risk localized soft tissue sarcoma. Secondary endpoints include **Disease-free survival (DFS)**, which measures the time from randomization to the first relapse (local, regional, or distant) or death from any cause, and **Overall survival (OS)**, which is the time from randomization to death from any cause. Patients who are alive at the time of analysis without relapse will be censored at the last disease assessment date for DFS, and at the last known alive date for OS.

Safety will also be evaluated as part of the efficacy assessment, using the toxicity grading of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. The trial aims to determine whether the addition of four cycles of peri-operative doxorubicin-based chemotherapy improves metastasis-free survival compared to standard management in patients with resectable soft tissue sarcoma, identified as high-risk according to the CINSARC signature. The trial is structured as a Phase III study, with a planned duration extending until February 2029, and it commenced recruitment in February 2020.