Phase 2 Multicentre Randomized Trial of Mifamurtide with Post-Operative Chemotherapy in High-Risk Osteosarcoma Patients

The primary objective of this study is to evaluate the impact on **efficacy** (event-free survival, EFS) of **mifamurtide** administered during 36 weeks as an add-on treatment to post-operative chemotherapy, compared to post-operative chemotherapy alone, in the first-line treatment of patients aged over 2 years and up to 50 years with high-risk **osteosarcoma**. This includes patients with metastatic osteosarcoma at diagnosis or localized disease with poor histological response to pre-operative chemotherapy. The clinical relevance of this objective lies in potentially improving the prognosis and treatment outcomes for patients with this aggressive form of cancer.

Secondary objectives include:

• Evaluating the impact on overall survival and progression-free survival of mifamurtide administered during 36 weeks, in addition to post-operative chemotherapy, compared to chemotherapy alone.
• Assessing the feasibility and safety of mifamurtide administration during and after post-operative chemotherapy for a total duration of 36 weeks.
• Evaluating the effect of mifamurtide on tumor immunity in patients with sequential surgery of lung metastases.
• Investigating biomarkers through an associated translational research program that could serve as surrogates of mifamurtide pharmacological efficacy, and predictive factors of efficacy and/or toxicity.
• Analyzing the tumor microenvironment in osteosarcoma and correlating it to clinical characteristics and outcomes, such as stage at diagnosis, metastatic versus localized disease, response to preoperative chemotherapy, event-free survival, and overall survival.
• Identifying potential new therapeutic targets for future combinations using genomics, transcriptomics, multiplex immunofluorescence, constitutional DNA, circulating tumor DNA, and other techniques depending on the state of the art.

The clinical trial involves a study population of patients aged **greater than 2 years and up to 50 years** diagnosed with high-risk **osteosarcoma**. This includes both male and female participants. The trial focuses on individuals with metastatic osteosarcoma at diagnosis or localized osteosarcoma with a poor histological response to pre-operative chemotherapy. Participants are required to have undergone pre-operative chemotherapy and surgery of the primary tumor and lung metastases, if applicable. The trial population was selected based on specific inclusion criteria, such as having a biopsy-proven, high-grade osteosarcoma and normal hematological, renal, cardiac, and hepatic functions. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, and participants must be affiliated with a social insurance regimen. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **mifamurtide** as an add-on treatment to post-operative chemotherapy in patients with high-risk **osteosarcoma**. This is a multicenter, randomized, open-label, Phase 2 trial. The primary objective is to assess the impact on event-free survival (EFS) when **mifamurtide** is administered over 36 weeks in combination with standard post-operative chemotherapy, compared to chemotherapy alone. The trial is expected to run until September 2033, with recruitment having started in October 2018.

Participants will be randomly assigned to receive either the standard chemotherapy regimen or the chemotherapy regimen with the addition of **mifamurtide**. The chemotherapy regimen includes **doxorubicin hydrochloride**, **ifosfamide**, **cisplatin**, **methotrexate**, and **etoposide**, all administered intravenously. The trial will involve several study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, diagnosis of high-grade osteosarcoma, and normal organ function. Participants must provide informed consent before any study-specific procedures.

Following the screening, participants will undergo randomization and begin the treatment phase, which includes regular follow-up visits to monitor treatment response and adverse events. The primary endpoint is event-free survival, with secondary endpoints including overall survival, progression-free survival, treatment feasibility, safety, long-term toxicity, and biomarker analysis. The expected duration of participant involvement is up to 36 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.

The clinical trial involves the administration of several **experimental medications** for the treatment of high-risk osteosarcoma. **Doxorubicin Hydrochloride** is provided as a solution for infusion, with a maximum daily dose of 60 mg/m² and a total dose not exceeding 300 mg/m². It is administered intravenously over a treatment period of up to 13 weeks. Participant compliance is monitored through regular assessments of infusion adherence and dose adjustments as necessary.

**Ifosfamide** is also administered as a solution for infusion, with a maximum daily dose of 3 g/m² and a total dose limit of 90 g/m². The administration route is intravenous, and the treatment duration can extend up to 26 weeks. Compliance is ensured by tracking infusion schedules and adjusting doses based on patient response and tolerance.

**Cisplatin** is provided in the form of a concentrate for solution for infusion, with a maximum daily dose of 100 mg/m² and a total dose cap of 500 mg/m². It is administered intravenously over a period of up to 13 weeks. Monitoring of participant compliance includes regular evaluations of infusion adherence and dose modifications as required.

**Methotrexate** is administered as a concentrate for solution for infusion, with a maximum daily dose of 12 g/m² and a total dose not exceeding 84 g/m². The intravenous route is used for administration, with a treatment period of up to 13 weeks. Compliance is monitored through scheduled assessments of infusion adherence and necessary dose adjustments.

**Etoposide** is provided as a concentrate for solution for infusion, with a maximum daily dose of 75 mg/m² and a total dose limit of 1500 mg/m². It is administered intravenously over a treatment period of up to 13 weeks. Participant compliance is tracked through regular infusion adherence checks and dose adjustments based on patient response.

**Mifamurtide**, marketed as MEPACT, is administered as a powder for concentrate for dispersion for infusion. The maximum daily dose is 2 mg/m², with a total dose not exceeding 96 mg/m². It is delivered intravenously over a period of up to 36 weeks. Compliance monitoring includes regular assessments of infusion adherence and dose modifications as necessary.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is on evaluating the efficacy of the experimental medications in combination with post-operative chemotherapy for newly diagnosed high-risk osteosarcoma patients. Regular monitoring of participant compliance and adherence to dosing schedules is integral to the study protocol.

The efficacy of the clinical trial will be assessed primarily through the measurement of **event-free survival (EFS)**. EFS will be estimated from the date of randomization to the occurrence of the first event, which may include loco-regional or distant relapse, progression, second malignancy, or death from any cause. For patients who remain in first complete remission, observations will be censored at the date of the last follow-up visit.

Secondary endpoints for efficacy assessment include **overall survival (OS)**, which will be measured from the randomization date to the date of death, regardless of the cause. **Progression-free survival (PFS)** will also be evaluated from the randomization date to the date of disease progression, either radiologically or clinically, or death from any cause, whichever occurs first. Observations for PFS will be censored at the date of the last follow-up visit for patients remaining in first complete remission.

Additional secondary endpoints include the feasibility of the planned treatment, which will be assessed by calculating the cumulative dose and dose intensity of mifamurtide and chemotherapy. Safety will be evaluated by analyzing all adverse events, except those unequivocally related to the underlying disease or its progression/relapse, using the NCI-CTCAE v5 criteria. Long-term toxicity and biomarkers to evaluate the mechanisms of action and resistance of mifamurtide will also be considered as part of the efficacy assessment.