Randomized Multicenter Trial Comparing Carboplatin and Cisplatin in Intermediate to Very High-Risk Malignant Extracranial Germ Cell Tumors

The primary objective of this multicentre prospective trial is to assess whether the efficacy of **Carboplatin** (600 mg/m² per cycle / AUC 7.9 mg/ml/min) is not inferior to **Cisplatin** (100 mg/m² per cycle) in patients with malignant extracranial germ cell tumours (MGCT) of intermediate, high, and very high risk, with regard to event-free survival (EFS). This comparison is clinically relevant as it may offer an alternative treatment option with potentially different toxicity profiles, impacting patient management and outcomes.

Secondary objectives include:

• Evaluation of event-free survival (EFS) and overall survival (OS) rates in defined risk groups compared to results of the MAKEI 96 study and published data.
• Assessment of toxicity under treatment with Carboplatin or Cisplatin, focusing on hospitalization duration and the number of platelet and red blood cell transfusions.
• Evaluation of toxicity concerning ototoxicity, nephrotoxicity, cardiotoxicity, and fertility-relevant endocrine outcomes.
• Assessment of patient-reported outcomes (PROs), including health-related quality of life (HRQoL) and fatigue, and in adult patients, sexual function and fertility outcomes.
• Implementation of standardized documentation of surgical procedures and evaluation of potential impact of variations in procedures on EFS.
• Evaluation of risk stratification for therapy implemented in MAKEI V based on standardized staging and pathological evaluation in comparison to MAKEI 96, including specific evaluations for low, intermediate, and very high-risk MGCT.
• Assessment of radiological response after two (and if applicable four) cycles of either Carboplatin or Cisplatin chemotherapy.
• Evaluation of standard tumour marker kinetics after every cycle of either Carboplatin or Cisplatin chemotherapy.

The clinical trial involves a total of **10 participants** diagnosed with **Malignant Extracranial Germ Cell Tumours (MGCT)**. The study population includes both male and female subjects, with an age range extending up to 17 years and 11 months for general cases, and up to 29 years and 11 months for patients with ovarian primaries. Participants were selected based on specific criteria, including a confirmed diagnosis of chemotherapy-naïve extracranial MGCT and a **Karnofsky Index** greater than 70% or an ECOG status of 0-II. The trial population is considered vulnerable, and written informed consent was obtained from patients and/or their parents according to national law. Female participants of childbearing potential were required to have a negative pregnancy test within seven days prior to starting treatment. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the efficacy of **Carboplatin** compared to **Cisplatin** in patients with **Malignant Extracranial Germ Cell Tumours (MGCT)**. The primary objective is to determine if Carboplatin is not inferior to Cisplatin in terms of event-free survival (EFSr) in patients with intermediate, high, and very high-risk MGCT. The trial is expected to run from December 2019 to December 2028, with participant involvement lasting up to 20 weeks, depending on the treatment arm and response.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and health status. Following randomization, participants will receive either Carboplatin or Cisplatin, administered via **intravenous use** or **intravenous infusion**. The treatment period will include regular follow-up visits to monitor health status, adverse events, and treatment efficacy, with assessments of tumor markers and radiological response after every cycle. The end-of-study visit will evaluate overall survival, health economic parameters, and any short or late toxicities according to CTCAE v4.03.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will also assess secondary endpoints, including overall survival, health economic parameters, and patient-reported outcomes such as health-related quality of life (HRQoL) and fertility outcomes. The study aims to provide comprehensive data on the safety and efficacy of Carboplatin versus Cisplatin in treating MGCT, contributing valuable insights into the management of this condition.

The clinical trial involves the administration of **Cisplatin**, an antineoplastic agent with the active substance name cisplatin. The pharmaceutical form is coded as PHF00230MIG, and it is administered via **intravenous use**. The dosage is set at a maximum of 20 mg/m² per day, with a total maximum dose of 400 mg/m² over a treatment period of 20 days. Cisplatin is a chemical substance, and its synonyms include Cis-diamminedichloroplatinum and CDDP. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Ifosfamide** is another experimental medication used in this trial. It is also an antineoplastic agent, with the pharmaceutical form coded as PHF00231MIG. Ifosfamide is administered through **intravenous infusion**. The maximum daily dose is 2000 mg/m², with a total maximum dose of 40,000 mg/m² over a treatment period of 4 weeks. This chemical substance will be administered according to the specified dosing schedule, and participant adherence will be closely monitored.

The trial also includes the administration of **Etoposide**, an antineoplastic agent with the pharmaceutical form coded as PHF675. Etoposide is administered via **intravenous use**. The maximum daily dose is 300 mg/m², with a total maximum dose of 6000 mg/m² over a treatment period of 4 weeks. As a chemical substance, etoposide will be administered according to the trial protocol, with participant compliance being monitored.

**Carboplatin** is used as a comparator treatment in this trial. It is an antineoplastic agent with the pharmaceutical form coded as PHF00230MIG, administered via **intravenous use**. The maximum daily dose is 600 mg/m², with a total maximum dose of 2400 mg/m² over a treatment period of 4 weeks. Carboplatin, a chemical substance, will be administered according to the trial's dosing schedule, and participant adherence will be monitored to ensure compliance.

The efficacy of the clinical trial will be assessed primarily through **Event-free survival (EFSr)**, which is defined as the minimum time from the date of randomization to the occurrence of specific events. These events include death from any cause, progressive disease indicated by an increase in standard tumor markers with or without tumor mass/metastases expansion, viable tumor cells at the time of final surgery, relapse, second malignancy, or the date of the last follow-up. This primary endpoint is specifically related to patients randomized to receive either Carboplatin or Cisplatin.

Secondary endpoints for efficacy assessment include overall survival (OS), defined as the minimum time from the date of diagnosis to death from any cause or to the last follow-up. Additional secondary endpoints involve health economic parameters such as hospitalization days and the number of blood transfusions, short and late toxicities according to CTCAE v4.03, and safety assessments including adverse events and laboratory abnormalities. Fertility-relevant endocrine outcomes, patient-reported outcomes like HRQoL, fatigue, sexual function, and fertility outcomes in adult patients will also be evaluated. The determination of relapse risk concerning surgical intervention, radiological response rate after two or four cycles of chemotherapy, and standard tumor marker levels after each chemotherapy cycle will further contribute to the efficacy assessment.