Diagnostic Accuracy of 68Ga-FAPI-46 PET/CT Versus 18F-Fludeoxyglucose PET/CT in Staging and Restaging of Gastric and Gastroesophageal Junction Cancer

The primary objective of this study is to compare the **diagnostic accuracy** of **FAPI PET/CT** to **FDG PET/CT** on a lesion basis during primary staging and restaging after neoadjuvant chemotherapy in patients with gastric and gastroesophageal junction cancer. This comparison is clinically relevant as it may enhance the precision of cancer staging, potentially leading to improved treatment planning and outcomes. Additionally, the study aims to compare the tentative staging capabilities of FAPI PET/CT to FDG PET/CT at these critical stages, investigate the feasibility of FAPI PET/CT at restaging, and explore any potential limitations of FAPI PET/CT in detecting tumor deposits.

The secondary objectives include: - Investigating the **FAPI uptake** in tumor deposits. - Assessing the feasibility of FAPI PET/CT in chemotherapy response evaluation compared to FDG PET/CT. - Evaluating the prognostic value of FAPI PET/CT compared to FDG PET/CT at primary staging and restaging. - Identifying potential unexpected findings with FAPI PET/CT. - Estimating interobserver agreement. - Investigating the safety of **[68Ga]Ga-FAPI-46** injection. - Evaluating the impact of FAPI PET/CT on patient management.

The clinical trial involves participants diagnosed with **gastroesophageal junction cancer** or **gastric cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to be physically and mentally capable of participating in the research and must be able to read and understand Danish. The trial does not include a vulnerable population. Participants were selected based on their recent diagnosis, with biopsy verification of gastric or GEJ cancer, and their referral for primary staging FDG PET/CT. They must be deemed resectable and operable, with or without neoadjuvant chemotherapy. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **diagnostic accuracy** of 68Ga-FAPI PET/CT compared to FDG PET/CT in patients with **gastric cancer** and **gastroesophageal junction cancer**. This is a Phase 4, randomized, double-blind, controlled trial. The trial aims to assess the diagnostic performance of FAPI PET/CT at both primary staging and restaging after neoadjuvant chemotherapy. The study will involve a series of visits, starting with an inclusion visit where participants will be screened based on specific criteria, including a confirmed diagnosis of gastric or gastroesophageal junction cancer, and the ability to consent and understand Danish. The trial is expected to last until December 31, 2025, with recruitment starting on December 1, 2023.

Participants will undergo a series of study visits, including initial screening, baseline assessments, and follow-up visits to monitor the effects of the investigational product. The inclusion visit will confirm eligibility based on criteria such as age, diagnosis, and physical and mental capacity to participate. Follow-up visits will be scheduled to assess the primary and secondary endpoints, including the comparison of FAPI PET/CT and FDG PET/CT findings in primary tumors, regional lymph nodes, and distant metastases. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any adverse events are addressed.

The expected length of participant involvement is determined by the trial's duration, with conditions for early termination including withdrawal of consent, adverse events, or any situation where continued participation is deemed unsafe. The trial will adhere to rigorous scientific standards, ensuring the collection of reliable and valid data to support the study's objectives. The primary endpoints focus on comparing the sensitivity, specificity, and predictive values of the imaging modalities, while secondary endpoints include SUV and TBR values, changes in these parameters, and the correlation of imaging results with clinical outcomes.

The clinical trial involves the use of **68Ga-FAPI-46**, an experimental medication formulated as a **solution for injection**. The active substance in this formulation is (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 administration of this compound is monitored to ensure compliance with the dosing schedule.

The comparator treatment in this study is **Fluor-18-FDG**, also provided as a **solution for injection**. The active substance is Fludeoxyglucose (18F), and it is administered as an **injectable solution**. 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. As with the experimental medication, administration and dosing compliance are closely monitored to ensure adherence to the study protocol.

Efficacy in this clinical trial will be assessed by comparing the diagnostic accuracy of **FAPI PET/CT** to **FDG PET/CT** on a lesion basis during primary staging and restaging after neoadjuvant chemotherapy in patients with gastric and gastro-esophageal junctional cancer. The primary endpoints include determining the sensitivity, specificity, positive predictive value, and negative predictive value of the PET/CT scans, using a histopathological reference standard. Additionally, the cancer stage will be compared according to the AJCC 8th edition TNM-classification, with the proportion of patients downstaged, unchanged, or upstaged due to the added FAPI PET/CT being determined.

Secondary endpoints involve comparing SUV and TBR values for primary tumors, regional lymph nodes, and distant metastases between FAPI PET/CT and FDG PET/CT, both at primary staging and restaging. Changes in these values from before to after neoadjuvant chemotherapy will also be analyzed. Furthermore, MTV and TLG values will be compared between the two imaging modalities. The study will also investigate the correlation between FAPI PET/CT SUV values and the extent of FAP-expressing CAFs in tumor deposits through volume-density estimation and immunohistochemical assessment of surgical specimens. Additional analyses will include correlating FAPI PET/CT results with actual clinical outcomes, determining RFS and OS, and conducting an interobserver study of FAPI PET/CTs.