Phase 3 Non-Inferiority Trial of Vincristine, Actinomycin-D, and Doxorubicin Versus Vincristine, Carboplatin, and Etoposide in Stage IV Pediatric Renal Tumors

The primary objective of this study is to determine the **non-inferiority** of preoperative 6 weeks of Vincristine, Carboplatin, and Etoposide (VCE) compared to Vincristine, Actinomycin-D, and Doxorubicin (VAD) in the overall metastatic rapid response rate (MetRR) in newly diagnosed stage IV childhood renal tumors. This includes evaluating the pulmonary response rate (PRR) and the response rate on non-pulmonary metastasis (NPRR). Establishing non-inferiority is clinically relevant as it may offer an alternative treatment regimen with potentially different side effect profiles or logistical advantages.

Secondary objectives include:

• Investigating acute toxicity (grade and duration) of preoperative chemotherapy of 6 weeks of VAD compared to VCE in stage IV renal tumors.
• Examining the histological composition and local stage distribution of the primary tumor after 6 weeks of VAD compared to VCE in stage IV Wilms' tumor (WT).
• Assessing the primary tumor volume reduction after 6 weeks of VAD compared to VCE in stage IV renal tumors.
• Determining the number of patients needing radiotherapy (local and/or metastatic site) in both randomized arms.
• Evaluating the 2-year and 5-year event-free survival (EFS) and overall survival (OS) of upfront 6 weeks of VAD versus VCE.
• Investigating short-term (hematological, mucositis, hepatic) and long-term side effects (auditive, cardiac, hepatic) of upfront 6 weeks of VAD versus VCE followed by a response-, histology-, and stage-based adjuvant therapy in stage IV renal tumors.
• Exploring the role of molecular markers, specifically the gain of 1q.
• Prospectively assessing and reviewing the standard imaging criteria in use for pulmonary metastases to better define what is considered a lung metastasis.
• Investigating the imaging characteristics of lung metastasis (maximum size, number, lungs (lobes) involved) in routine chest imaging in correlation with outcome (EFS/OS after two years).

The clinical trial involves a total of **56 participants** diagnosed with **Stage IV childhood renal tumour** with pulmonary and/or non-pulmonary metastasis. The study population includes both male and female subjects, aged between 3 months and 18 years. Participants were selected based on specific criteria, including the presence of at least one circumscript, non-calcified pulmonary nodule or other lesions highly suspicious of metastasis, as determined by chest CT-scan and abdominal CT-scan/MRI, with confirmation of metastatic disease by central review. The trial population is characterized by the absence of pre-existing and ongoing cardiac malfunction disease and liver function deficiency that is not controllable by substitution. Participants are required to understand and voluntarily provide permission to the informed consent form, adhere to the study visit schedule, and meet other protocol requirements. The study includes a vulnerable population, given the age range and health condition of the participants.

The clinical trial is a **randomized**, multi-center, open-label, non-inferiority phase 3 study designed to evaluate the efficacy of two chemotherapy regimens in patients with stage IV childhood renal tumors. The trial compares the standard treatment regimen of Vincristine, Actinomycin-D, and Doxorubicin (VAD) with an experimental regimen of Vincristine, **Carboplatin**, and **Etoposide** (VCE). The primary objective is to determine the non-inferiority of the VCE regimen in terms of the overall metastatic rapid response rate (MetRR), which includes both pulmonary and non-pulmonary response rates.

The trial is expected to last until November 2025, with recruitment having started in March 2020. Participants will be involved in the study for a maximum of 6 weeks of preoperative chemotherapy, followed by 9 weeks of adjuvant chemotherapy, depending on their response to treatment. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and side effects, and an end-of-study visit to assess the final outcomes. The inclusion criteria require participants to be under 18 years of age, have a confirmed diagnosis of metastatic renal tumor, and meet specific health criteria. Exclusion criteria include pre-existing cardiac or liver conditions that are not manageable.

Participants may be withdrawn from the study if they experience severe adverse effects, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial's primary endpoint is the percentage of patients achieving a radiologic complete response or a very good partial response of lung metastasis after 6 weeks of preoperative chemotherapy. Secondary endpoints include the percentage of patients achieving complete response after surgery, the response rate after adjuvant chemotherapy, and overall survival rates at 2 and 5 years. The study aims to provide valuable insights into the treatment of stage IV childhood renal tumors, potentially improving therapeutic strategies for this condition.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Carboplatin** is utilized in the trial as a cytostatic agent. It is administered in a pharmaceutical form identified as PHF00230MIG. The dosage is calculated based on body surface area, with a maximum daily dose of 200 mg/m² and a total maximum dose of 1200 mg/m² over a treatment period of up to 6 weeks. The route of administration is **intravenous**.

**Doxorubicin Hydrochloride** is another cytostatic agent used in the study. It is provided in the pharmaceutical form PHF00231MIG. The dosing is also based on body surface area, with a maximum daily dose of 50 mg/m² and a total maximum dose of 100 mg/m², administered over a maximum treatment period of 2 weeks. The administration route is **intravenous use**.

**Etoposide** is included in the trial as a cytostatic agent, with a pharmaceutical form designated as PHF675. The dosing follows a body surface area calculation, with a maximum daily dose of 100 mg/m² and a total maximum dose of 600 mg/m² over a treatment period of up to 6 weeks. The route of administration is **intravenous use**.

**Dactinomycin** is administered as a cytostatic agent in the trial, with a pharmaceutical form identified as PHF00231MIG. The dosage is calculated based on body weight, with a maximum daily dose of 45 µg/kg and a total maximum dose of 135 µg/kg over a treatment period of up to 3 weeks. The administration route is **intravenous**.

**Vincristine Sulfate** is used as a cytotoxic agent in the trial. It is provided as a solution for injection or infusion, with a concentration of 1 mg/ml. The dosage is based on body surface area, with a maximum daily dose of 1.5 mg/m² and a total maximum dose of 9 mg/m² over a treatment period of up to 6 weeks. The route of administration is **intravenous**.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to compare the efficacy of the experimental arm, consisting of Vincristine, Carboplatin, and Etoposide (VCE), with the standard arm, consisting of Vincristine, Actinomycin-D, and Doxorubicin (VAD), in patients with stage IV childhood renal tumors.

Efficacy in this clinical trial will be assessed by evaluating the overall metastatic rapid response rate (MetRR) in patients with newly diagnosed stage IV childhood renal tumors. The primary endpoint is the percentage of patients achieving a radiologic complete response (CR) of any metastasis and/or a Very Good Partial Response (VGPR) of lung metastasis after 6 weeks of preoperative chemotherapy. Secondary endpoints include the percentage of patients achieving a CR after surgery of metastasis at the time of nephrectomy, and the percentage of patients with CR or VGPR of pulmonary metastasis after preoperative chemotherapy followed by 9 weeks of adjuvant chemotherapy, with or without metastasectomy.

Additional secondary endpoints involve the assessment of primary tumor volume shrinkage, the number and maximum diameters of metastases at diagnosis and after preoperative treatment, and the histologic subtype distribution of local tumors and resected nodules/metastasis. The trial will also evaluate the percentage of patients with complete necrosis in resected nodules and the percentage of patients requiring pulmonary radiotherapy in the first line. Event-free survival and overall survival at 2 and 5 years will be measured for the entire cohort and according to study arm (VAD/VCE) and 1qGain status.