Evaluation of [68Ga]Ga-FAPI-46 and Gadobutrol in Multimodal PET/MRI Imaging for Detection of Occult Invasive Cancer in Ductal Carcinoma In Situ

The primary objective of this study is the **evaluation** of the feasibility of detecting occult invasive cancer in patients diagnosed with ductal carcinoma in situ (DCIS) using [68Ga]Ga-FAPI-46 breast PET/MRI. This is clinically relevant as it may enhance early detection and treatment planning for breast cancer, potentially improving patient outcomes.

Secondary objectives include:

• Evaluation of the feasibility of detecting occult invasive cancer in diagnosed DCIS using [68Ga]Ga-FAPI-46 breast PET/MRI.
• Evaluating the possible superiority of PET/MRI visual assessment over breast MRI alone.
• Assessing the added value for diagnostic performance of MRI measures of diffusibility, perfusion, and permeability.
• Evaluating the diagnostic performance of the PET parameter SUVmax (60-75min) and PET pharmacokinetic modeling parameters.
• Assessing the impact of PET/MRI and MRI on follow-up minimal invasive diagnostic procedures.
• Evaluating the correspondence of FAP-expression determined by immunohistochemistry and PET.
• Assessing the safety of [68Ga]Ga-FAPI-46.

The clinical trial focuses on individuals diagnosed with **breast cancer**, specifically ductal carcinoma in situ (DCIS). The study population includes both male and female participants aged 18 years and older. Participants are required to be in general good health, with no vulnerable populations being selected for this trial. The total number of participants has not been disclosed by the sponsor. Selection criteria include newly diagnosed DCIS with an extent suspected to be greater than 4 cm, and participants must have a planned DCIS resection, either breast-conserving or mastectomy, as per guideline recommendations. Lifestyle considerations such as the use of highly effective contraception are required for women of childbearing potential and fertile male patients with partners of childbearing potential. The trial does not include any vulnerable populations, ensuring a focus on individuals who can provide informed consent and comply with the study requirements.

The clinical trial is designed to evaluate the feasibility of detecting occult invasive cancer in patients diagnosed with **ductal carcinoma in situ** (DCIS) using [68Ga]Ga-FAPI-46 breast PET/MRI. This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on July 1, 2024, and conclude by July 20, 2026. Participants will be involved in the study for a maximum treatment period of one day, with the primary endpoint being the sensitivity and specificity based on blinded readers' PET/MRI visual assessment scores.

The trial will include several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as newly diagnosed DCIS with an extent suspected to be greater than 4 cm, planned DCIS resection, age of 18 years or older, and written informed consent. Women of childbearing potential must have a confirmed menstrual period and a negative pregnancy test, and both women and men with partners of childbearing potential must agree to use highly effective contraception.

Following the screening visit, participants will undergo the investigational procedure involving the administration of [68Ga]FAPI-46 via **intravenous injection**. The study will assess primary and secondary endpoints, including optimal threshold and area-under-the-curve of the receiver-operating-characteristics curve, diagnostic odds ratio, and various sensitivity and specificity measures related to MRI and PET imaging features. Adverse events following the application of [68Ga]Ga-FAPI-46 will also be monitored.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial aims to provide valuable insights into the diagnostic capabilities of FAPI-PET/MRI in detecting invasive cancer in patients with DCIS.

The clinical trial involves the administration of two experimental medications. The first medication is **Gadovist® 1.0 mmol/ml**, a **solution for injection** containing the active substance **gadobutrol**. This pharmaceutical product is manufactured by Bayer Vital GmbH and is authorized under the marketing authorization number 40252.00.00 in Germany. Gadobutrol is a chemical substance classified under the ATC code V08CA09. The medication is administered via **intravenous injection** with a maximum daily and total dose of 0.3 mmol/kg. The treatment period is limited to a single day, and the formulation is not specifically designed for pediatric use. Participant compliance with the dosing schedule is monitored throughout the trial.

The second experimental medication is **[68Ga]FAPI-46**, an **infusion** 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 compound is produced by Universitaet Muenster and is identified by the sponsor product code [68Ga]Ga-FAPI-46. The medication is administered through **intravenous injection** with a maximum daily and total dose of 2.5 MBq/kg. Similar to Gadovist®, the treatment period is restricted to one day, and the formulation is not intended for pediatric use. Compliance with the administration protocol is ensured by monitoring participants during the trial.

Efficacy in the clinical trial titled "Multimodal Imaging with FAPI-PET/MRI in Breast Carcinoma-In-Situ for Detection of occult Invasive cancer (MI-CISDIR)" will be assessed using both primary and secondary endpoints. The primary endpoints include the **sensitivity** and **specificity** based on blinded readers' PET/MRI visual assessment scores. These scores will be used to evaluate the ability of the imaging technique to accurately detect occult invasive cancer in patients diagnosed with ductal carcinoma in situ (DCIS).

Secondary endpoints will further explore the diagnostic performance of the imaging modalities. These include the optimal threshold and area-under-the-curve of the receiver-operating-characteristics curve based on the tumor-to-background ratio of SUVmax (60-75 minutes), and the Diagnostic Odds Ratio (DOR) comparing blinded readers' PET/MRI versus MRI-only visual assessment scores. Additional secondary endpoints involve the sensitivity and specificity of various MRI and PET parameters, such as the lesion MRI diffusion-weighted MRI apparent diffusion coefficient (ADC), dynamic contrast-enhanced MRI (DCE-MRI) features like "Maximal Slope" and "Bolus arrival time," and pharmacokinetic modeling parameters like Volume transfer constant (KTrans) and Fractional plasma volume (Vp).

Furthermore, the trial will assess the number of additional biopsies triggered by PET/MRI and MRI visual assessments, and the correlation of immunohistopathology FAP visual staining scores with SUVmax (60-75 minutes). Adverse events following the application of [68Ga]Ga-FAPI-46 will also be monitored. These efficacy parameters will be collected and analyzed at specified timepoints to ensure a comprehensive evaluation of the imaging technique's performance in detecting occult invasive cancer in the study population.