Evaluation of [18F]-AlF-FAPI-74 PET/CT and Laparoscopy for Staging in Advanced Gastric Cancer: A Multicenter Prospective Study

The primary objective of this study is to evaluate the applicability and impact of **[18F]AlF-FAPI-74 PET/CT** as a non-invasive imaging biomarker for optimizing whole-body staging in patients with locally advanced gastric cancer. This approach aims to reduce the necessity for staging laparoscopy, which is clinically significant as it may decrease the invasiveness and associated risks of the staging process, potentially improving patient outcomes and resource utilization.

Secondary objectives include:

• Assessing the diagnostic performance of **[18F]AlF-FAPI-74 PET/CT** compared to CT and staging laparoscopy in detecting M1 disease.
• Determining the occurrence and impact of incidental and/or non-specific findings on **[18F]AlF-FAPI-74 PET/CT**.
• Evaluating the diagnostic time delay due to the additional investigation with **[18F]AlF-FAPI-74 PET/CT**.
• Contributing to safety data regarding the clinical use of **[18F]AlF-FAPI-74 PET/CT**.
• Evaluating the region-based accuracy (sensitivity and specificity) between **[18F]AlF-FAPI-74 PET**-based PCI scores and staging laparoscopy-based PCI scores.
• Establishing a quantitative correlation between PCI-regional FAPI uptake and PCI-regional histopathological tumor scores to develop a standardized, non-invasive method for PCI evaluation in the future.
• Assessing the agreement between TSR and CAF-specific FAP expression determined on diagnostic pre-operative tumor biopsies.
• Assessing the correlation between TSR/FAP expression and uptake on **[18F]AlF-FAPI-74 PET/CT** in tissue specimens.
• Assessing the characteristics of FAP-expressing CAF subsets.
• Conducting a trial-based cost-effectiveness analysis to calculate the incremental cost-effectiveness ratio (ICER) of **[18F]AlF-FAPI-74 PET/CT** compared with staging laparoscopy in the Dutch context, contingent on sufficient diagnostic performance.

The clinical trial focuses on individuals diagnosed with **advanced gastric cancer**, specifically targeting those with histologically confirmed adenocarcinoma of the stomach or the esophagogastric junction (Siewert type III). The study population includes both male and female participants aged 18 years and older, with no specific mention of vulnerable populations being included. Participants are required to have surgically resectable, advanced tumors, as determined by gastroscopy and contrast-enhanced CT scans, and must have the intention to undergo gastrectomy. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants' general health status is not detailed, but they must have given written informed consent and should not have interactions with study procedures if they have recently participated in another interventional study. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the applicability and impact of **[18F]AlF-FAPI-74 PET/CT** as a non-invasive imaging biomarker for optimizing whole-body staging in patients with **advanced gastric cancer**. This is a multicenter, prospective study with a randomized, double-blind, controlled design. The trial is expected to commence recruitment on May 1, 2025, and conclude by July 1, 2029. Participants will be involved in the study for a maximum treatment period of one day, with the primary endpoint being the proportion of patients in whom the imaging leads to detection of M1-disease, resulting in a change in treatment intent.

The study will include several visits, starting with an inclusion (screening) visit where eligibility criteria are assessed. Key inclusion criteria include histologically proven adenocarcinoma of the stomach or esophagogastric junction, age 18 years or older, and surgically resectable advanced tumors. Participants must provide written informed consent. Follow-up visits will be scheduled to monitor the diagnostic performance and any changes in treatment plans. The end-of-study visit will assess the primary and secondary endpoints, including diagnostic performance metrics and patient-reported outcomes.

Participants may be terminated early from the study if they experience serious adverse events or if they withdraw consent. The trial will utilize **[18F]-AlF-FAPI-74** administered via intravenous injection, with a maximum total dose of 370 MBq/kg. The study aims to limit the need for staging laparoscopy by providing accurate non-invasive imaging, thereby potentially reducing unnecessary surgeries and altering treatment plans from curative to palliative when appropriate. The trial will also assess the diagnostic accuracy, sensitivity, specificity, and the impact on patients' quality of life and healthcare costs.

The clinical trial involves the use of the experimental medication **[18F]-AlF-FAPI-74**, which is a **solution for injection**. The active substance in this medication is **[AL[18F]F]FAPI-74**, a chemically synthesized compound. The pharmaceutical form of the medication is a solution intended for intravenous injection. The dosage is measured in megabecquerels per kilogram (MBq/kg), with a maximum daily dose of 3.0 MBq/kg and a total maximum dose of 370 MBq/kg. The treatment period is limited to a single day. The administration of the medication is conducted via intravenous injection, ensuring direct delivery into the bloodstream for optimal imaging results.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the application of **[18F]-AlF-FAPI-74** to assess its efficacy as a non-invasive imaging biomarker for staging advanced gastric cancer. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol and to maintain the integrity of the trial data. The trial aims to evaluate the potential of this imaging agent to optimize whole-body staging, potentially reducing the need for invasive procedures like staging laparoscopy.

Efficacy in the clinical trial titled "[18F]FAPI-PET/CT and Laparoscopy in Staging Advanced Gastric Cancer – a multicenter prospective study (PLASTIC-3-study)" will be assessed using both primary and secondary endpoints. The primary endpoints focus on the proportion of patients in whom **[18F]AlF-FAPI-74 PET/CT** leads to the detection of M1-disease, resulting in a change in treatment intent as determined by local multidisciplinary team (MDT) meetings. This includes the number of prevented unnecessary surgeries, such as staging laparoscopies and gastrectomies, and changes from curative to palliative treatment. Additionally, the primary endpoints will evaluate the proportion of patients in whom the PET/CT scan leads to changes in diagnostic work-up, including additional biopsies or longitudinal imaging and changes in the extent of surgery.

Secondary endpoints will include diagnostic performance metrics such as sensitivity, specificity, diagnostic accuracy, positive predictive value, and negative predictive value, using histopathologic tumor tissue collected during biopsy, staging laparoscopy, and follow-up imaging as reference tests. Other secondary endpoints will assess the proportion of patients with relevant incidental findings, the extra burden on patients due to additional diagnostics, and the time between pre-diagnostic and post-diagnostic MDT meetings. The study will also evaluate the occurrence, type, and severity of adverse events, correlations between PET-based and laparoscopy-based Peritoneal Cancer Index (PCI) scores, and the expression of CAF content as measured by tumor-stroma ratio (TSR) on tissue samples. Patient-reported outcomes will be measured using EORTC-QLQ-C30, EQ-5D-5L, and a developed patient-reported experience measure (PREM) questionnaire. The quality of life and costs associated with **[18F]AlF-FAPI-74 PET/CT** compared to staging laparoscopy will also be analyzed.