Evaluation of Atezolizumab and WT1 LAMP mRNA DC Vaccine in Combination with Platinum/Pemetrexed for Epithelioid Malignant Pleural Mesothelioma

The primary objective of this study is to investigate the **feasibility** and safety of adding **atezolizumab** and WT1/DC vaccination to first-line platinum/pemetrexed-based chemotherapy in patients with epithelioid malignant pleural mesothelioma (MPM). This is clinically relevant as it aims to enhance the therapeutic efficacy and safety profile of the current standard treatment for epithelioid MPM, potentially improving patient outcomes.

Secondary objectives include:

• Assessing indicators of clinical activity of first-line platinum/pemetrexed-based chemotherapy when combined with atezolizumab and WT1/DC vaccination in epithelioid MPM patients.
• Determining the immunogenicity of atezolizumab and WT1/DC vaccination when added to first-line platinum/pemetrexed-based chemotherapy in epithelioid MPM patients.

The clinical trial involves participants diagnosed with **malignant pleural mesothelioma**, specifically the epithelioid subtype, ranging from stage I to IV. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a World Health Organization performance status of grade 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on their diagnosis of histologically proven epithelioid unresectable mesothelioma and their ability to comply with the study protocol. Participants must have adequate hematologic and end-organ function and test negative for viral serology, including HIV, HBV, and HCV. Women of childbearing potential are required to have a negative pregnancy test at screening. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, emphasizing the need for careful monitoring and ethical considerations throughout the study.

The clinical trial is designed to evaluate the **feasibility** and **safety** of integrating the PD-L1 inhibitor **atezolizumab** and WT1/DC vaccination into the first-line platinum/pemetrexed-based chemotherapy for patients with epithelioid malignant pleural mesothelioma. This is a Phase I/II trial, characterized by a randomized, double-blind, controlled design, ensuring the reliability and validity of the results. The trial is expected to span approximately four years, with an estimated end date in February 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically proven diagnosis of epithelioid unresectable malignant pleural mesothelioma, adequate hematologic and end-organ function, and a negative viral serology for HIV, HBV, or HCV. Following successful screening, participants will be randomized to receive the investigational treatment, which includes four cycles of platinum/pemetrexed-based chemotherapy in combination with four treatments of atezolizumab and four WT1/DC vaccinations.

Throughout the trial, participants will attend regular follow-up visits to monitor the occurrence of adverse events (AEs) and serious adverse events (SAEs), as well as to assess clinical efficacy endpoints such as best overall response, duration of response, disease control rate, objective response rate, progression-free survival, and overall survival. The immunogenicity of the treatment will also be evaluated by measuring functional WT1-specific T cell responses.

The expected length of participant involvement is determined by the completion of the treatment schedule, with conditions for early termination including the occurrence of unacceptable toxicity, withdrawal of consent, or any other reason deemed necessary by the treating physician. The trial aims to provide valuable insights into the potential benefits and risks of this novel treatment approach for patients with this rare and aggressive form of cancer.

The clinical trial involves the administration of **WT1 LAMP mRNA DC**, a **suspension for injection**. This experimental medication is a structurally diverse substance used in cell therapy, specifically involving monocyte-derived dendritic cells electroporated with Wilms' Tumor 1 LAMP mRNA. The medication is administered via **intradermal injection**. The maximum daily and total dose is 10,000,000 units, with a treatment period extending up to 40 weeks. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

In addition to the experimental treatment, the trial includes the administration of **Tecentriq 840 mg concentrate for solution for infusion**, which contains the active substance **atezolizumab**. This medication is a protein-based therapy administered through **intravenous infusion**. The maximum daily and total dose is 1,680 mg, with a treatment period of up to 168 weeks. Compliance is monitored through infusion records and participant follow-up visits.

Another non-experimental treatment used in the study is **Tecentriq 1,200 mg concentrate for solution for infusion**, also containing **atezolizumab**. This formulation is similarly administered via **intravenous infusion**. The maximum daily and total dose is 1,200 mg, with a treatment period of up to 12 weeks. Participant adherence to the dosing schedule is ensured through detailed infusion logs and regular clinical evaluations.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoints focus on feasibility and safety, specifically evaluating the proportion of patients who complete the study treatment schedule, which includes the administration of four cycles of platinum/pemetrexed-based chemotherapy in combination with four treatments of **atezolizumab** and four **WT1/DC** vaccinations. Safety will be assessed by monitoring the occurrence of adverse events (AEs) and serious adverse events (SAEs) during the investigational treatment administration and follow-up. This includes evaluating the proportions of patients experiencing AEs and SAEs that are possibly, probably, or definitely related to the treatments, as well as the number and grade of these events.

Secondary endpoints will assess clinical efficacy and immunogenicity. Clinical efficacy will be measured by parameters such as best overall response (BOR), duration of response (DOR), disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Immunogenicity will be evaluated by assessing functional WT1-specific T cell responses. These endpoints will provide a comprehensive evaluation of the treatment's impact on patients with epithelioid malignant pleural mesothelioma.