Primary chemoradiation versus neoadjuvant chemotherapy followed by surgery as treatment strategy for locally advanced vulvar carcinoma (VULCANize2)

The primary objective of this clinical trial is to compare the **efficacy** and safety of primary chemoradiation with neoadjuvant chemotherapy (NACT) followed by surgery in patients with locally advanced vulvar carcinoma (LAVC). This comparison is clinically relevant as it aims to determine the most effective treatment strategy for LAVC, potentially improving patient outcomes and minimizing treatment-related morbidity.

Secondary objectives include:

• Comparing the quality of life (QoL) of patients with LAVC after primary chemoradiation with those treated with NACT followed by surgery.
• Determining the effect of human papillomavirus (HPV) status on treatment response.

The clinical trial involves a **study population** of female patients aged 18 years and older, diagnosed with locally advanced vulvar cancer (LAVC) requiring primary chemoradiation or extensive surgery. The trial does not include male participants, and no vulnerable populations are selected. The sponsor has not provided the total number of participants. Participants are selected based on specific criteria, including a histologically-confirmed diagnosis of primary or recurrent squamous cell carcinoma of the vulva, FIGO stage Ib to IVa, T1b or higher, with any N, M0. The trial requires participants to have a World Health Organization performance status of 0 to 2 and adequate hematological, hepatic, and renal function. Lifestyle considerations such as diet and physical activity are not specified. The trial excludes individuals with a beta HCG level above 14 mIU/mL and requires the use of highly effective contraception for those at risk of conception. Participants must provide signed and written informed consent to be included in the study.

The clinical trial is designed to evaluate the efficacy and safety of **primary chemoradiation** compared to neoadjuvant chemotherapy followed by surgery in patients with locally advanced vulvar carcinoma (LAVC). This study employs a randomized, controlled, and double-blind methodology to ensure unbiased results. The trial is expected to run from July 2023 to June 2029, with participants involved for a maximum treatment period of 12 months, depending on the treatment arm they are assigned to.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of squamous cell carcinoma, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments of loco-regional control, morbidity, and quality of life, among other secondary endpoints. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Early termination from the study may occur if participants experience unacceptable toxicity, withdraw consent, or if the investigator deems it in the participant's best interest. The primary endpoint is the assessment of loco-regional control at two years, with secondary endpoints including disease-free survival and treatment-related morbidity. The trial involves the administration of **paclitaxel**, **carboplatin**, and **cisplatin** via intravenous infusion, with specific dosing regimens tailored to each participant's treatment plan. The study aims to provide valuable insights into the optimal treatment strategy for LAVC, potentially influencing future clinical practice.

The clinical trial involves the administration of **Paclitaxel**, a cytostatic agent, as part of the treatment regimen. **Paclitaxel** is administered in the form of an intravenous infusion. The pharmaceutical form is identified as PHF00016MIG. The dosage is calculated based on body surface area, with a maximum daily dose of 175 mg/m² and a total maximum dose of 700 mg/m² over the treatment period. The treatment duration is set for a maximum of 12 weeks. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Carboplatin** is also utilized in this study as a cytostatic agent. It is administered via intravenous infusion, with the pharmaceutical form designated as PHF00230MIG. The maximum daily dose is 6 units, with a total maximum dose of 24 units over the course of the treatment. The treatment period for **Carboplatin** is also set for a maximum of 12 weeks. Compliance with the administration schedule will be closely monitored to ensure adherence to the protocol.

Additionally, **Cisplatin** is included as a comparator treatment in the trial. It is administered through intravenous infusion, with the pharmaceutical form identified as PHF00230MIG. The dosage is determined based on body surface area, with a maximum daily dose of 40 mg/m² and a total maximum dose of 240 mg/m². The treatment period for **Cisplatin** is limited to a maximum of 6 weeks. Monitoring of participant compliance with the dosing regimen will be conducted to maintain protocol integrity.

The efficacy of the clinical trial comparing primary chemoradiation with neoadjuvant chemotherapy followed by surgery in patients with locally advanced vulvar carcinoma will be assessed using specific endpoints. The primary endpoint is **loco-regional control** at 2 years per arm, which includes any salvage or adjuvant treatments. Secondary endpoints include morbidity, disease-related treatment failure, disease-free survival, prevention of trimodal treatment (surgery, chemotherapy, and radiotherapy), functional organ preservation, quality of life, treatment-related morbidity, death, complications, and the influence of HPV status on treatment outcomes.