Prospective Evaluation of Personalized Treatment Efficacy and Safety in Young Adults with Poor-Prognosis Non-Seminomatous Germ-Cell Tumors Using Early Tumor Marker Kinetics

The primary objective of this prospective research program is to validate the efficacy and safety of a personalized treatment based on early tumor marker kinetic assessment in real life for patients with poor-prognosis **non-seminomatous germ-cell tumors** (NSGCT). This is clinically relevant as it aims to improve outcomes for young adults with disseminated disease classified as poor prognosis according to IGCCCG criteria, potentially leading to more effective and tailored therapeutic strategies.

Secondary objectives include:

• To prospectively collect tissue samples from patients with poor-prognosis NSGCT.
• To assess the efficacy and safety of early surgery and/or high-dose chemotherapy with transplant in patients with a mediastinal NSGCT and an unfavorable decline.
• To assess whether an early systematic brain magnetic resonance imaging (MRI) can identify and allow better treatment for patients with asymptomatic oligo-brain metastases.

The clinical trial focuses on **non-seminomatous germ-cell tumors** with disseminated disease, classified as poor prognosis according to IGCCCG criteria. The study population comprises male participants older than 16 years, with no upper age limit specified. Participants are required to have a primary site in the testis, retroperitoneal, or mediastinal regions, and must exhibit evidence of disseminated disease at clinical stages II or III as per the AJCC 8th edition. The trial does not include female subjects, and the population is not considered vulnerable. Participants must have adequate renal function and meet specific hematological criteria. Lifestyle considerations such as diet and physical activity are not detailed. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy and safety of a personalized treatment regimen for young adults with poor-prognosis **non-seminomatous germ-cell tumors** (NSGCT). This study is a prospective, randomized, double-blind, controlled trial, with an estimated duration extending until October 2037. The trial aims to validate the treatment approach based on early tumor marker kinetic assessment in real-life settings. Participants will be randomly assigned to receive either the investigational treatment or a comparator, with the primary endpoint being progression-free survival (PFS). Secondary endpoints include overall survival, response criteria, and quality of life assessments.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, medical history, and laboratory results. Following the screening, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments of tumor markers, imaging studies, and evaluations of any adverse events. The end-of-study visit will occur after the completion of the treatment regimen, where final assessments will be conducted to determine the overall efficacy and safety of the treatment.

The expected length of participant involvement in the study is contingent upon the treatment regimen, with the maximum treatment period for individual drugs ranging from 1 to 20 days. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent by the participant. The trial is conducted in compliance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **ETOPOSIDE ACCORD** is provided as a 20 mg/mL solution for infusion. It is administered via **IV injection** or **IV infusion** with a maximum daily dose of 100 mg/m² and a total treatment period of up to 5 days. The active substance, **etoposide**, is of chemical origin.

**GRANOCYTE 34 Millions UI/ml** is a powder and solvent for solution for injection or infusion, containing the active substance **lenograstim**, a protein of other origin. It is administered via **subcutaneous injection** with a maximum daily dose of 263 µg and a treatment period of up to 20 days.

**PACLITAXEL SANDOZ** is a 6 mg/mL solution for infusion, administered via **IV injection** or **IV infusion**. The active substance, **paclitaxel**, is of chemical origin, with a maximum daily dose of 175 mg/m² and a treatment period of 1 day.

**BLEOMYCINE BELLON** is provided as a powder for solution for injection, containing **bleomycin sulfate**. It is administered via **IV injection** or **IV infusion**, with a maximum daily dose of 30 mg and a treatment period of up to 15 days.

**OXALIPLATINE ACCORD** is a 5 mg/mL solution for infusion, administered via **IV injection** or **IV infusion**. The active substance, **oxaliplatin**, is of chemical origin, with a maximum daily dose of 130 mg/m² and a treatment period of up to 10 days.

**CISPLATINE KABI** is a 1 mg/mL solution for infusion, administered via **IV injection** or **IV infusion**. The active substance, **cisplatin**, is of chemical origin, with a maximum daily dose of 25 mg/m² and a treatment period of up to 5 days.

**HOLOXAN** is a powder for solution for injection, containing **ifosfamide**. It is administered via **IV injection** or **IV infusion**, with a maximum daily dose of 2 g/m² and a treatment period of up to 14 days.

**GRANOCYTE 13 Millions UI/ml** is a powder and solvent for solution for injection or infusion, containing **lenograstim**, a protein of other origin. It is administered via **subcutaneous injection** with a maximum daily dose of 263 µg and a treatment period of up to 20 days.

**CARBOPLATINE KABI** is a 10 mg/mL solution for infusion, administered via **IV injection** or **IV infusion**. The active substance, **carboplatin**, is of chemical origin, with a maximum daily dose of 8 dosage forms and a treatment period of up to 5 days.

**MESNA EG** is a 100 mg/mL solution for infusion, administered via **IV injection** or **IV infusion**. The active substance, **mesna**, is of chemical origin, with a maximum daily dose of 500 mg/m² and a treatment period of up to 14 days.

The efficacy of the clinical trial will be assessed using several key endpoints. The primary endpoint is **progression-free survival (PFS)**, which will be measured from the first day of the first cycle of BEP chemotherapy to the date of disease progression or death from any cause, whichever occurs first. Progression is defined by an increase in tumor markers or radiographic progression. Secondary endpoints include the assessment of best tumor response at the end of treatment, overall survival (OS), and quality of life through patient-reported outcomes. The quality of life will be evaluated using the QLQ-C30, QLQ-TC26, FACT-GOG-NTX, and IPQ questionnaires.

Additionally, specific endpoints for the diagnostic study include the proportion of patients initially free of brain metastases who are diagnosed with brain metastases early on a systematic brain MRI performed mid-treatment. This proportion will be calculated with its exact 95% confidence interval. The survival after brain metastases relapse will also be assessed. All toxicities will be evaluated and recorded based on the NCI common toxicity criteria (CTCAE v5.0), described by frequency and grade, by cycle and over all cycles, with the maximum grade over all cycles used as the summary measure for each patient.