Phase II Evaluation of Electrochemotherapy with Bleomycin and Cisplatin in High-Grade Vulvar Squamous Lesions and Non-Invasive Paget's Disease

The primary objective of this single-center phase II study is the evaluation of the **activity** of electrochemotherapy in the treatment of vulvar lesions and non-invasive Paget's disease. This is clinically relevant as it aims to assess the efficacy of electrochemotherapy, a treatment modality that combines chemotherapy with electrical pulses, in managing these specific conditions, potentially offering a less invasive alternative to traditional surgical methods.

Secondary objectives include:

• Evaluation of the safety of electrochemotherapy, which is crucial for determining the risk-benefit profile of this treatment approach.
• Evaluation of the control of the presence of **HPV**, as this virus is often associated with vulvar lesions and its management is important for long-term disease control.
• Follow-up evaluation of vulvar VIN 2-3 and non-invasive Paget's disease, to monitor disease progression or regression post-treatment.
• Evaluation of the symptoms reported by the patient, providing insight into the treatment's impact on patient quality of life and symptom management.

The clinical trial involves **female** participants diagnosed with newly diagnosed or recurrent high-grade or initially invasive precancerous squamous lesions of the vulva and non-invasive vulvar Paget's disease. The study population is exclusively adult women, with an age range starting from 18 years and above. Participants are required to have a **Karnofsky performance status** greater than 70%, indicating a relatively stable general health status. The trial does not include male subjects or vulnerable populations. The selection criteria emphasize histological confirmation of the disease, positivity for cervical and/or vaginal high-risk human papillomavirus (HR HPV), and the absence of surgical treatment indications due to various reasons, including patient refusal or medical contraindications. Participants must provide informed consent and have negative pregnancy test results. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is a **phase II** study designed to evaluate the activity of electrochemotherapy in the treatment of patients with newly diagnosed or recurrent high-grade or initially invasive precancerous squamous lesions of the vulva and non-invasive vulvar Paget's disease. The trial employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The study is expected to commence on March 1, 2023, and conclude by May 31, 2025, with an estimated duration of 27 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histological diagnosis, age, and performance status. Following the screening, eligible participants will be randomized to receive either **bleomycin** or **cisplatin** as part of the electrochemotherapy regimen. The treatment phase will involve administration of the investigational products via **intravenous** or **intratumoral use**, depending on the specific protocol requirements.

Subsequent follow-up visits will be scheduled at one, three, six, and twelve months post-treatment to assess the primary endpoint, which is the histological pathological response of vulvar lesions and non-invasive Paget's disease according to RECIST criteria. Secondary endpoints include safety evaluation using CTCAE criteria v. 5.0, assessment of HPV persistence, duration of disease control, and symptomatology assessment through specific questionnaires. The end-of-study visit will occur at the 12-month mark, where final evaluations will be conducted.

Participant involvement is expected to last approximately 12 months, with conditions for early termination including withdrawal of consent, adverse events, or any other medical reasons deemed necessary by the investigator. The trial aims to provide valuable insights into the efficacy and safety of electrochemotherapy for the specified medical conditions, contributing to the advancement of treatment options for these patients.

The clinical trial involves the administration of **BLEOMYCIN**, a cytotoxic antibiotic and related substance, utilized in the treatment of vulvar lesions and non-invasive Paget's disease. **BLEOMYCIN** is provided in the pharmaceutical form of a solution for injection/infusion. The active substance, **bleomycin**, is a mixture, and the medication is administered intravenously. The maximum daily dose is 15 mg/m², with a total dose not exceeding 15 mg/m² over a treatment period of one day. The administration of **BLEOMYCIN** is monitored to ensure compliance with the dosing schedule and to assess any potential adverse effects.

Additionally, the trial includes the use of **CISPLATIN**, classified under other antineoplastic agents, specifically platinum compounds. **CISPLATIN** is provided as a concentrate for solution for infusion, with the active substance being a chemical compound known as **cisplatin**. The administration route for **CISPLATIN** is intratumoral, with a maximum daily and total dose of 2 mg/ml. The treatment period is limited to one day. Compliance with the dosing regimen is closely monitored to ensure participant safety and to evaluate the therapeutic efficacy of the treatment.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint involves the evaluation of the histological pathological response of vulvar lesions and non-invasive **Paget's disease** on surgical specimens 30 days post-electrochemotherapy, utilizing the RECIST criteria. This will provide a measure of the treatment's impact on the targeted lesions.

Secondary endpoints include several parameters to further evaluate the treatment's efficacy and safety. The safety of the method will be assessed using the CTCAE criteria version 5.0. Additionally, the persistence of HPV will be evaluated through an HPV test conducted at the 6-month follow-up visit. The duration of disease control will be monitored during follow-up periods. Symptomatology will be assessed using specific patient-reported outcome measures, including the VAS, EQ-5D, and FSFI questionnaires, which will be completed by patients before treatment and at one, three, six, and twelve months after treatment. These assessments will provide comprehensive data on the treatment's efficacy and its impact on patient quality of life.