Evaluation of 68Ga-FAPI-46 PET Imaging for Non-Invasive Diagnosis of Desmoplastic Tumors in Pancreatic, Biliary, Gastric, and Ovarian Cancers

The primary objective of this study is to enhance the **non-invasive diagnostics** of malignancy in tumors of the pancreas, stomach, and bile ducts, as well as in epithelial ovarian cancer (EOC). This is clinically relevant as it aims to improve the accuracy and efficiency of diagnosing these cancers, potentially leading to better patient outcomes through earlier and more precise treatment interventions.

Secondary objectives include:

• Evaluating **FAPI-PET/CT** as a staging tool for pancreatic, gastric, and bile duct cancers, as well as for primary and recurrent EOC.
• Investigating the correlation between in-vivo uptake of FAPI and ex-vivo immunohistochemically determined biomarker expression, including FAP, PDGFR-α, PDGFR-β, and α-SMA, in the stroma of these tumors.
• Assessing FAPI-PET/CT and stroma markers as prognostic factors in patients with these cancer entities.
• Exploring the correlation between FAPI-PET/CT imaging results and those of conventional radiology, such as CT and MRT imaging, as well as gastroscopy including biopsy for gastric cancer patients.
• Evaluating the safety and tolerability of the investigational product, **68Ga-FAPI-46**.

The clinical trial focuses on improving non-invasive diagnostics of malignancy in tumors of the **pancreas**, stomach, and bile ducts, as well as in epithelial ovarian cancer. The study population includes both male and female participants, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. The trial does not specifically target a vulnerable population. Participants were selected based on a multimodal strategy that includes blood markers, tissue markers, and imaging diagnostics, with a requirement for scheduled surgical removal of the lesion and histopathological confirmation of diagnosis. 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 efficacy of **68Ga-FAPI-46**, a novel tracer, in improving non-invasive diagnostics of malignancy in tumors of the pancreas, stomach, bile ducts, and epithelial ovarian cancer. This is a Phase 4, diagnostic exploratory trial, employing a randomized, double-blind, controlled design. The trial is expected to run from June 1, 2021, to May 31, 2029, with participant involvement lasting up to the point of surgical intervention and histopathological confirmation of diagnosis.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as suspected cancer diagnosis and consent to participate. The primary endpoint is the surgical removal of the tumor with histopathological confirmation. Secondary endpoints include evaluating **FAPI-PET/CT** as a staging tool, investigating the correlation between in-vivo uptake of FAPI and ex-vivo biomarker expression, and assessing prognostic factors such as disease-free survival and overall survival at 1, 2, and 5 years. Follow-up visits will be conducted to monitor these outcomes and assess the frequency of adverse events.

The expected length of participant involvement is until the surgical procedure and subsequent histopathological analysis. Conditions that may lead to early termination from the study include withdrawal of consent or the occurrence of serious adverse events. The trial aims to provide a comprehensive assessment of the diagnostic accuracy and prognostic value of **FAPI-PET/CT** in comparison to conventional radiology, using histopathological confirmation as the reference standard.

The clinical trial involves the use of an experimental medication, **68Ga-FAPI-46**, which is a **solution for injection**. This investigational product is designed for **intravenous use** and is classified under the ATC code V09X, indicating it as an "Other Diagnostic Radiopharmaceutical." The active substance in 68Ga-FAPI-46 is chemically synthesized and is 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 maximum daily and total dose of 68Ga-FAPI-46 is 370 MBq, with a treatment period limited to a single day. The administration of this radiopharmaceutical is conducted under the supervision of nuclear medicine specialists to ensure precise dosing and participant safety.

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 diagnostic capabilities of 68Ga-FAPI-46 in imaging tumors with a strong desmoplastic reaction, particularly in the pancreas, bile ducts, stomach, and ovaries. Participant compliance with the dosing schedule is monitored through standard clinical trial procedures, ensuring adherence to the protocol and accurate data collection. The trial aims to enhance non-invasive diagnostics of malignancies in the specified tumor types, leveraging the novel tracer properties of 68Ga-FAPI-46.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint involves surgery with histopathological confirmation of diagnosis, which serves as a definitive measure for confirming the presence and type of malignancy in tumors of the pancreas, stomach, bile ducts, and epithelial ovarian cancer. Secondary endpoints include evaluating the efficacy of **FAPI-PET/CT** as a staging tool, with histopathological diagnosis used as a reference standard for assessing regional or distant lymph nodes and metastatic tumor tissue. Additionally, the trial will investigate the correlation between in-vivo uptake of **FAPI** and ex-vivo immunohistochemically determined biomarkers such as FAP, PDGFR-α, PDGFR-β, and α-SMA in the tumor stroma. This will be confirmed through postsurgical histopathological analysis.

Further assessments will include the evaluation of **FAPI-PET/CT** and stroma markers as prognostic factors by recording disease-free survival (DFS) and overall survival (OS) at 1-year, 2-year, and 5-year intervals during the follow-up period. The trial will also compare the diagnostic accuracy of **FAPI-PET/CT** against conventional radiology, using histopathological or cytological confirmation as a reference standard for differentiating between malignant and benign lesions, as well as for N and M staging. The frequency of adverse events, adverse reactions, serious adverse events, and suspected unexpected serious adverse reactions will also be monitored as part of the efficacy assessment.