Evaluation of Diagnostic Accuracy and Clinical Utility of 68Ga-FAPI-46 and Fludeoxyglucose (18F) PET in Malignant Pleural Mesothelioma Staging and Response Assessment

The primary objective of this study is to investigate the **diagnostic accuracy** of FAPI PET in malignant **pleural mesothelioma** (PM) for primary staging. This is clinically relevant as accurate staging is crucial for determining the appropriate treatment strategy and prognosis for patients with PM.

Secondary objectives include:

• Investigating the FAPI PET uptake parameters in suspicious PM lesions.
• Exploring the clinical role of FAPI PET in determining biopsy procedures of suspicious pleural PM lesions.
• Exploring potential limitations of FAPI PET in PM.
• Exploring the feasibility of FAPI PET for response assessment in PM.
• Investigating FDG PET-based response assessment in PM.
• Evaluating the prognostic value of FAPI PET/CT and FDG PET/CT in PM.
• Investigating the level of FAP expression in different PM subtypes and its correlation with FAPI uptake in the PET images.
• Correlating the FAPI and FDG uptake parameters in different PM subtypes.
• Analyzing changes in FAPI and FDG uptake parameters from before to after anticancer treatment.
• Calculating the FAPI PET/CT interobserver agreement.

The clinical trial focuses on individuals diagnosed with **Pleural Mesothelioma**, aiming to assess the diagnostic accuracy of FAPI for primary staging. The study population includes both male and female participants aged 18 years and older. Participants are required to have pleural lesions suspicious of pleural mesothelioma and must have undergone or be undergoing FDG PET/CT as part of their diagnostic workup. The trial does not involve a vulnerable population. Participants are expected to be physically and mentally capable of participating in the research and must understand the study information to provide informed consent. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **diagnostic accuracy** of FAPI PET in patients with **pleural mesothelioma**. This is a Phase 4, randomized, double-blind, controlled trial, which aims to compare the efficacy of FAPI PET/CT against FDG PET/CT in primary tumor staging, regional lymph nodes, and distant metastases. The trial is expected to commence recruitment on November 1, 2024, and conclude by March 1, 2027. Participants will be involved in the study for a maximum treatment period of one day, with the primary endpoint being the comparison of FAPI PET/CT and FDG PET/CT findings against a histopathological reference standard.

The study will include several visits, starting with a screening visit to confirm eligibility based on criteria such as age (18 years or older), ability to consent, and previous or ongoing FDG PET/CT as part of the diagnostic workup. Follow-up visits will be scheduled to assess the primary and secondary endpoints, including changes in cancer staging and treatment decisions influenced by FAPI PET/CT findings. The end-of-study visit will involve a comprehensive evaluation of the diagnostic outcomes and any adverse events related to the administration of 68Ga-FAPI-46.

Participants may be withdrawn from the study if they experience significant adverse events, are unable to comply with study procedures, or withdraw consent. The trial will utilize intravenous infusion of the investigational product, 68Ga-FAPI-46, and the comparator, Fluor-18-FDG, both administered as solutions for injection. The trial will also explore secondary endpoints such as changes in standardized uptake value (SUV) and tumor to background ratio (TBR) values, as well as the impact of FAPI PET/CT on biopsy location decisions and treatment modifications. A 10-year follow-up will be conducted to assess overall survival, recurrence-free survival, and progression-free survival, comparing FAPI PET/CT-based markers with conventional clinical practice markers.

The clinical trial involves the use of **68Ga-FAPI-46**, an experimental medication formulated as a **solution for injection**. The active substance is chemically derived and identified as (S)-2,2',2''-(10-(2-(4-(3-((4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)-quinolin-6-yl)(methyl)amino)-propyl)piperazin-1-yl)-2-oxoethyl)-68Ga-[1,4,7,10]-tetraazacyclododecane-1,4,7-triyl)triacetate. The medication is administered via **intravenous infusion**. The maximum daily dose is 250 MBq, with a total maximum dose of 500 MBq over a treatment period of one day. The product is not a pediatric formulation and is not classified as an orphan drug.

The comparator treatment in the study is **Fluor-18-FDG**, also provided as a **solution for injection**. The active substance, **Fludeoxyglucose (18F)**, is chemically synthesized and is administered through **intravenous infusion**. The maximum daily dose for this comparator is 400 MBq, with a total maximum dose of 800 MBq, also over a one-day treatment period. This product is similarly not a pediatric formulation and is not designated as an orphan drug. Both treatments are monitored for participant compliance, ensuring adherence to the dosing schedules and administration routes as specified in the trial protocol.

The efficacy of the clinical trial titled "FAPI PET in Pleural Mesothelioma: The Diagnostic Accuracy and Clinical Value of FAPI PET at Diagnosis, Primary Staging, and the Feasibility of FAPI PET for Response Evaluation" will be assessed through a series of primary and secondary endpoints. The primary endpoint involves comparing the **FAPI PET/CT** and **FDG PET/CT** findings in primary tumors, regional lymph nodes, and distant metastases against a histopathological reference standard. This comparison will determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the PET/CTs at primary staging.

Secondary endpoints include evaluating the impact of FAPI PET/CT on the location of intended pleural biopsies and its role in guiding these procedures. The trial will also compare cancer staging as determined by FAPI PET/CT with conventional imaging, including FDG PET/CT, using the IASCL 8th edition TNM-classification. The study will assess changes in treatment plans following the hypothetical addition of FAPI PET/CT at primary staging. Quantitative measures such as standardized uptake value (SUV) and tumor to background ratio (TBR) for pleural lesions, regional lymph nodes, and distant metastases will be calculated and compared between FAPI PET/CT and FDG PET. These measurements will be taken both at primary staging and after 2-3 series of anticancer treatment.

Further assessments will include measuring Molecular Imaging Tumor Volume (MITV) and Volume Intensity Product (VIP) for both FAPI PET/CT and FDG PET/CT, and comparing these values before and after neoadjuvant chemotherapy. The trial will also correlate FAPI PET and FDG PET uptake parameters (SUV, TBR, MITV, VIP) with the subtype of pleural mesothelioma (epithelioid, biphasic, sarcomatoid). A 10-year follow-up will be conducted to determine overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS), comparing FAPI PET/CT-based markers with other clinical practice-derived markers. Additionally, the study will compare conventional CT-based response assessments to PET-based assessments and conduct an interobserver study of FAPI PET/CTs. Potential adverse events and adverse reactions related to the [68Ga]Ga-FAPI-46 injection will also be reported.