Evaluation of Nivolumab and Autologous Dendritic Cell Therapy in Combination with Cytoreductive Surgery and HIPEC for Peritoneal Mesothelioma

The primary objective of this study is to evaluate the **efficacy** of (neo-)adjuvant checkpoint inhibition (CPI) using nivolumab and dendritic cell therapy (DCT) with MesoPher in conjunction with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) in patients diagnosed with **Peritoneal Mesothelioma**. This is clinically relevant as it aims to enhance treatment outcomes by integrating immunotherapy with surgical and chemotherapeutic interventions, potentially improving patient prognosis and quality of life.

Secondary objectives include assessing the safety profile, radiological response, immunological outcomes, and survival outcomes associated with the treatment regimen. These evaluations are crucial for understanding the broader impact of the therapy on patient health and for identifying any potential adverse effects or benefits beyond the primary efficacy endpoint.

The clinical trial involves participants diagnosed with **Peritoneal Mesothelioma**, specifically those with a histologically confirmed diagnosis of epithelioid peritoneal mesothelioma. The study population includes both male and female subjects, aged 18 years and older, who are in a general health status fit to undergo CRS-HIPEC, as per the standard of care of the treating physician or institution. The trial does not include a vulnerable population. Participants must be able to return to the study center for adequate follow-up and vaccinations. Lifestyle considerations such as the use of effective contraceptive methods are required for both men and women during the study and for at least 12 months after the last study drug administration. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of **nivolumab** and a personalized cellular product, **autologous dendritic cells loaded with allogenic lysate of mesothelioma cell lines**, in patients with **peritoneal mesothelioma**. This is a Phase II, randomized, double-blind, controlled trial. The trial will involve a combination of neo-adjuvant checkpoint inhibition and dendritic cell therapy with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. The estimated duration of the trial is from February 2025 to August 2030.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of epithelioid peritoneal mesothelioma, age of at least 18 years, and the ability to provide informed consent. Follow-up visits will be scheduled to monitor the progression-free survival, lymphocyte infiltration and activity, safety, radiological response, and overall survival. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 12 months after the last administration of the study drug.

Participants may be terminated early from the study if they experience adverse events that compromise their safety, fail to comply with study procedures, or withdraw consent. The primary endpoint is the progression-free survival in patients receiving the treatment regimen. Secondary endpoints include lymphocyte activity, safety assessments, radiological response, and overall survival. The trial aims to provide valuable insights into the treatment efficacy and safety profile of the investigational products in this patient population.

The clinical trial involves the administration of **nivolumab**, an experimental medication classified under the ATC code L01FF01. Nivolumab is a monoclonal antibody used as an immune checkpoint inhibitor. It is administered in the form of an intravenous infusion. The pharmaceutical form is designated as PHF00230MIG. The maximum daily dose of nivolumab is 480 mg, with a total maximum dose of 1440 mg over the treatment period. The treatment duration for nivolumab is set at a maximum of 8 weeks. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to nivolumab, the trial includes the use of a **personalized cellular product** known as MesoPher. This product consists of autologous dendritic cells loaded with allogeneic lysate of mesothelioma cell lines. MesoPher is classified under the ATC code L03, indicating its role as an immunostimulant. The administration route for MesoPher is also via intravenous infusion. The maximum daily dose is 50,000,000 units, with a total maximum dose of 350,000,000 units over the treatment period. The treatment duration for MesoPher is set at a maximum of 12 weeks. Compliance with the administration schedule will be closely monitored to ensure adherence to the protocol.

The clinical trial aims to assess the efficacy of a combination therapy involving **nivolumab** and dendritic cell therapy (DCT) known as MesoPher, in conjunction with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for patients with peritoneal mesothelioma. The primary endpoint for evaluating efficacy is progression-free survival in patients who have received both neo-adjuvant and adjuvant treatments with anti-PD-1 and DCT vaccinations, alongside cytoreduction. Secondary endpoints include lymphocyte infiltration and activity, which will be measured through TCR repertoire analysis and immune phenotyping, with lymphocyte activity assessed via apoptosis and proliferation markers using flow cytometry. Safety will be evaluated by recording adverse events (AEs) and serious adverse events (SAEs). Radiological response will be assessed using CT scans following RECIST 1.1 criteria, categorizing outcomes as progressive or stable disease, and partial or complete response. The Peritoneal Cancer Index (PCI) will be evaluated during diagnostic laparoscopy and compared to the PCI observed at CRS-HIPEC. Overall survival will also be a secondary objective.