Phase II Evaluation of De-escalated Therapy with Etoposide, Cisplatin, and Carboplatin in Stage IIa/IIb Seminoma Less Than 3 cm

The primary objective of this study is to evaluate the **efficacy** of de-escalated therapy in patients with stage IIa/IIb seminoma measuring less than 3 cm. This involves administering one cycle of EP (Etoposide and Cisplatin) followed by either one cycle of carboplatin AUC 7 or a boost of radiotherapy on lymph nodes, contingent upon a negative FDG-PET result at week 3. The clinical relevance of this objective lies in its potential to reduce treatment intensity while maintaining effective disease control, thereby minimizing treatment-related toxicity and improving patient outcomes.

Secondary objectives include:

• The serum level of **miRNA-M371** as a potential biomarker of response.
• The association between FDG-PET results and miRNA M371 rate.
• The overall survival (OS) at 3 years.
• The quality of life (QoL) assessed using the QLQ-C30 questionnaire.
• The safety profile evaluated using NTI-CTCAE v5.0.

The clinical trial involves participants diagnosed with **stage IIa/IIb seminoma** with a tumor size of less than 3 cm. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a primary testicular seminomatous germ cell tumor, confirmed histologically after orchiectomy, and must not have received prior treatment with radiotherapy or chemotherapy. The trial does not include a vulnerable population. Participants must demonstrate good general health, as indicated by adequate bone marrow, hepatic, and renal functions, and a good prognosis according to IGCCCG criteria. The selection process for the trial population is not specified, as the sponsor has not provided the total number of participants. Lifestyle considerations include the requirement for participants to use effective contraceptive measures or abstain from heterosexual activity during the study and for 12 months after the last dose of chemotherapy. Participants must also be willing and able to comply with scheduled visits, treatment plans, and other study procedures. The sponsor has not provided specific information regarding the selection process for the trial population.

The clinical trial is designed to evaluate the efficacy of a **de-escalated therapy** regimen in patients with stage IIa/IIb seminoma measuring less than 3 cm. This Phase II study employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The trial is expected to span from May 2023 to May 2031, with participant involvement lasting approximately 36 months, contingent upon individual response and progression.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease stage, and overall health status. Following the initial screening, participants will receive one cycle of EP (Etoposide and **Cisplatin**) chemotherapy. At week 3, a follow-up visit will include an FDG-PET scan to assess treatment response. If the scan is negative, participants will either receive one cycle of **Carboplatin** or a boost of radiotherapy on lymph nodes. Subsequent follow-up visits will monitor the progression-free rate at 36 months, as well as secondary endpoints such as the association between miRNA-M371 levels and treatment response, overall survival, quality of life, and safety profile.

The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, which may be necessitated by adverse events, disease progression, or withdrawal of consent. Participants are required to comply with scheduled visits, treatment plans, and laboratory tests throughout the study. Conditions for early termination include significant adverse reactions or failure to adhere to the study protocol. The trial aims to provide valuable insights into the management of stage IIa/IIb seminoma, with a focus on minimizing treatment intensity while maintaining efficacy.

The clinical trial involves the administration of **Carboplatin**, a chemotherapeutic agent classified under the ATC code L01XA02. The pharmaceutical form of Carboplatin is denoted as PHF00230MIG, and it is administered via **intravenous use**. The maximum daily dose is 1015 mg, with a total dose not exceeding 1015 mg over a treatment period of one day. This compound is of chemical origin and is not formulated for pediatric use. Compliance with the dosing schedule is monitored to ensure adherence to the protocol.

**Cisplatin**, marketed as Cisplatin Teva® 1 mg/ml, is another chemotherapeutic agent used in this study. It is provided as a solution for infusion and is also administered intravenously. The dosing regimen for Cisplatin is calculated based on body surface area, with a maximum daily dose of 20 mg/m² and a total dose of 100 mg/m² over a five-day treatment period. This product is of chemical origin and is not intended for pediatric patients. Participant compliance is closely monitored to maintain the integrity of the trial.

The study also includes **Etoposide**, classified under the ATC code L01CB01. Etoposide is administered in a pharmaceutical form identified as PHF675, and like the other agents, it is delivered intravenously. The dosing is based on body surface area, with a maximum daily dose of 100 mg/m² and a total dose of 500 mg/m² over a five-day treatment period. This chemical-origin compound is not designed for pediatric use. Adherence to the dosing schedule is essential and is monitored throughout the trial.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the progression-free rate at 36 months (PFR-36m), defined as the proportion of patients with a complete response (CR), partial response (PR), or stable disease (SD) at 36 months according to RECIST v1.1 criteria. This endpoint will help determine the effectiveness of the de-escalated therapy in preventing disease progression or relapse in patients with stage IIa/IIb seminoma.

Secondary endpoints include the association between serum levels of **miRNA-M371** and response to treatment, as well as the correlation between these serum levels and FDG-PET results indicating a complete metabolic response. Overall survival (OS) will be measured from the date of inclusion to the date of death from any cause, with patients whose death is not known at the time of analysis being censored based on the last recorded date they were known to be alive. Quality of life (QoL) will be assessed using the EORTC QLQ-C30 at baseline and at the end of treatment. The safety profile will be determined using the NCI-CTC AE grading scale version 5, with adverse events described by their intensity and severity.