Evaluation of 68Ga-FAPI-46 PET/CT in Initial Staging of Pancreatic Adenocarcinoma and Cholangiocarcinoma for Curative Treatment Eligibility

The primary objective of this study is to estimate the proportion of patients who exhibit an appropriate change in **TNM classification** following the addition of **68Ga-FAPI-46 PET-CT** to the reference examinations during the initial staging of pancreatic and bile duct cancers eligible for curative treatment. This objective is clinically relevant as it aims to enhance the accuracy of cancer staging, which is crucial for determining the most effective treatment strategy and improving patient outcomes.

Secondary objectives include:

• Estimating the proportion of patients who present an appropriate change in the M status of the TNM classification following the addition of 68Ga-FAPI-46 PET-CT.
• Estimating the proportion of patients who experience a change in therapeutic management due to the addition of 68Ga-FAPI-46 PET-CT.
• Estimating the number of additional tumor lesions detected by the addition of 68Ga-FAPI-46 PET-CT.
• Estimating the inter-observer reproducibility of 68Ga-FAPI-46 PET-CT interpretation.
• Estimating the diagnostic performance of 68Ga-FAPI-46 PET-CT for baseline staging, including sensitivity, specificity, and predictive values.

The clinical trial involves participants diagnosed with **cholangiocarcinoma** and **pancreatic adenocarcinoma**. The study population includes both male and female subjects, aged over 18 years, who are eligible for curative treatment and are non-metastatic according to reference staging. Participants are required to be affiliated with a social security system and must provide free and informed consent. The trial population was selected based on pathological evidence or strong suspicion of de novo pancreatic adenocarcinoma or cholangiocarcinoma on imaging, with conditions being immediately resectable, borderline, or locally advanced. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, and lifestyle considerations such as diet, physical activity, or habits have not been specified. Key inclusion criteria focus on the eligibility for curative treatment and the non-metastatic status of the participants.

The clinical trial is designed to evaluate the **diagnostic** value of 68Ga-FAPI-46 PET/CT in the initial work-up of pancreatic and biliary cancers eligible for curative treatment. This study is a Phase IV, randomized, double-blind, controlled trial. The trial aims to assess the proportion of patients who experience a change in TNM classification following the addition of 68Ga-FAPI-46 PET-CT to standard reference examinations. The trial is expected to commence recruitment in September 2025 and conclude by September 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of **pancreatic adenocarcinoma** or **cholangiocarcinoma**, and non-metastatic status. Following the screening, participants will be randomized to receive either the investigational product or a control. The investigational product, 68GA-FAPI-46, is administered via intravenous injection. The primary endpoint is the proportion of patients with a change in TNM classification, while secondary endpoints include changes in M status, therapeutic management, and diagnostic parameters.

Study visits will include baseline assessments, administration of the investigational product, and follow-up evaluations to monitor changes in disease classification and management. The end-of-study visit will assess the final outcomes and gather data on the primary and secondary endpoints. The expected length of participant involvement is approximately one month, with conditions for early termination including withdrawal of consent or adverse events that compromise participant safety.

The clinical trial involves the administration of three experimental medications, each formulated as a **solution for injection** and administered via **intravenous injection**. The first experimental medication is GalliaPharm, a radiopharmaceutical generator containing **gallium (68Ga) chloride** as the active substance. This product is manufactured by Eckert & Ziegler Radiopharma GmbH and is authorized in France. The dosage of GalliaPharm ranges from 0.74 to 1.85 GBq, with a maximum daily dose of 350 MBq. The treatment period is limited to one day, ensuring that the total dose does not exceed 350 MBq.

The second experimental medication is Galliad, another radiopharmaceutical generator, which contains **germanium (68Ge) chloride** as its active substance. Produced by IRE ELIT, Galliad is also authorized in France. Similar to GalliaPharm, the dosage of Galliad ranges from 0.74 to 1.85 GBq, with a maximum daily and total dose of 350 MBq, administered over a single day.

The third experimental medication is 68GA-FAPI-46, a solution for injection containing the active substance **(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**. This product is developed by the Centre Hospitalier Universitaire de Bordeaux. The maximum daily and total dose for 68GA-FAPI-46 is also 350 MBq, administered within a single day.

All three medications are used in the trial to evaluate their diagnostic value in the initial work-up of pancreatic and biliary cancers eligible for curative treatment. Participant compliance is monitored to ensure adherence to the dosing schedule and administration route. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial.

The efficacy of the clinical trial will be assessed by evaluating the impact of **68Ga-FAPI-46 PET-CT** on the initial staging of pancreatic and bile duct cancers eligible for curative treatment. The primary endpoint is the proportion of patients who exhibit an appropriate change in TNM classification following the addition of **68Ga-FAPI-46 PET-CT** to the reference examinations. This will be determined by comparing the initial staging results with those obtained after the inclusion of the PET-CT scan.

Secondary endpoints include several parameters: the proportion of patients with an appropriate change in the M status of the TNM classification, the proportion of patients with changes in therapeutic management (such as surgical treatment or chemotherapy), and the average number of tumor lesions detected by **68Ga-FAPI-46 PET-CT** compared to reference staging. Additionally, the inter-observer reliability of the PET-CT interpretation will be measured using Cohen's kappa coefficient, and diagnostic parameters such as sensitivity, specificity, and predictive values for detecting loco-regional lymph node and distant metastatic lesions will be evaluated.