Diagnostic Accuracy of 68Ga-FAPI-46 PET/CT Versus 18F-Fludeoxyglucose PET/CT in Primary Staging and Restaging of Ovarian Cancer Patients

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 in patients with **ovarian cancer**. This comparison is clinically relevant as it may enhance the precision of staging and restaging, potentially leading to improved patient management and treatment outcomes. Additionally, the study aims to explore how the inclusion of FAPI PET/CT influences patient management at these stages, assess the feasibility of FAPI PET/CT at restaging post-chemotherapy, identify potential limitations of FAPI PET/CT in detecting tumor deposits, and evaluate the safety of the **68Ga-FAPI-46** injection.

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. - Determining the prognostic value of FAPI PET/CT versus FDG PET/CT at primary staging and restaging. - Evaluating potential unexpected findings from FAPI PET/CT. - Estimating the interobserver agreement.

The clinical trial focuses on participants diagnosed with **ovarian cancer**, specifically targeting a female-only population. The study includes individuals aged 18 years and older, who are physically and mentally capable of participating in the research. Participants must be able to read and understand Danish, as this is a requirement for informed consent. The trial does not include vulnerable populations, and the sponsor has not provided the total number of participants. The selection criteria emphasize individuals who are newly diagnosed with biopsy-verified ovarian cancer or those highly suspected of having the condition, as determined by a multidisciplinary team. Participants are required to be deemed resectable and operable, with or without neoadjuvant chemotherapy. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the **diagnostic accuracy** of 68Ga-FAPI-46 PET/CT compared to FDG PET/CT in patients with **ovarian 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 is expected to run from October 20, 2023, to December 31, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a biopsy-verified diagnosis of ovarian cancer, operability, and the ability to consent. The trial will include follow-up visits to monitor the diagnostic outcomes and safety of the 68Ga-FAPI-46 injection. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted.

The expected length of participant involvement is determined by the trial's duration, with conditions for early termination including withdrawal of consent or adverse events. The primary endpoints focus on comparing the sensitivity, specificity, and predictive values of FAPI PET/CT and FDG PET/CT. Secondary endpoints include evaluating changes in SUV and TBR values, as well as correlating imaging results with clinical outcomes. The trial will also explore the feasibility and potential limitations of FAPI PET/CT in detecting tumor deposits.

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 and safety, as part of the trial's objective to evaluate its diagnostic accuracy and safety in patients with ovarian cancer.

In addition to the experimental treatment, the study utilizes **Fluor-18-FDG** as a comparator treatment. This compound is also provided as a **solution for injection** and contains the active substance **fludeoxyglucose (18F)**. The administration route is via injectable solution, with a maximum daily dose of 400 MBq and a total maximum dose of 800 MBq over a one-day treatment period. The use of Fluor-18-FDG serves as a standard-of-care comparator to assess the diagnostic accuracy of 68Ga-FAPI-46 in the context of primary staging and re-staging of ovarian cancer. Compliance with the dosing schedule is monitored to ensure the integrity of the trial results.

The efficacy of the clinical trial titled "68Ga-FAPI PET/CT: The Diagnostic Accuracy for Primary Staging and Re-staging of Patients with Ovarian Cancer" will be assessed through a series of primary and secondary endpoints. The primary endpoints include 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, and negative predictive value of the PET/CTs at both primary staging and restaging. Additionally, the trial will evaluate the cancer stage as determined by FAPI PET/CT compared to conventional imaging, including FDG PET/CT, and assess the proportion of patients whose cancer stage is downstaged, unchanged, or upstaged due to the added FAPI PET/CT. The trial will also explore the hypothetical impact of FAPI PET/CT on patient management decisions at primary staging and restaging, and investigate the feasibility of FAPI PET/CT at restaging by comparing its signal to a histopathological reference standard. Furthermore, the correlation between FAPI PET/CT standardized uptake value (SUV) and the extent of fibroblast activation protein (FAP) expressing cancer-associated fibroblasts (CAFs) in tumor deposits will be examined through volume-density estimation and immunohistochemical assessment of surgical specimens. Patient-reported discomfort, heart rate, and blood pressure will be monitored before and after FAPI infusion.

Secondary endpoints will focus on the SUV and tumor-to-background ratio (TBR) values for primary tumors, regional lymph nodes, and distant metastases for both FAPI PET/CT and FDG PET/CT, comparing these values at primary staging and restaging. Changes in SUV and TBR from before to after neoadjuvant chemotherapy will also be analyzed. Additionally, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) for both FAPI PET/CT and FDG PET/CT will be compared at primary and restaging, with changes in these parameters assessed from before to after neoadjuvant chemotherapy. The trial will seek supplementary information from medical records, biochemistry, pathology, or other imaging modalities for final diagnosis in cases of unexpected FAPI PET/CT findings not related to the known cancer. The correlation of FAPI PET/CT results and staging with actual clinical outcomes will be compared to FDG PET/CT results, with recurrence-free survival (RFS) and overall survival (OS) determined. An interobserver study of FAPI PET/CTs will also be conducted to assess consistency in interpretation.