Assessment of T Cell Activation in Breast, Esophageal, Melanoma, and NSCLC Using [18F]F-AraG and [89Zr]Zr-Df-Crefmirlimab PET Tracers

The primary objectives of this study are to evaluate the **spatial correlation** of PET uptake of [18F]F-AraG and [89Zr]Zr-Df-Crefmirlimab in tumors and T-cell rich organs, such as lymph nodes, prior to resection. Additionally, the study aims to assess the strength of correlation between the presence of **CD8+ cells** and T cell activation features in the resected tumor and lymph nodes with preoperative uptake of [89Zr]Zr-Df-Crefmirlimab and [18F]F-AraG, respectively. These objectives are clinically relevant as they may provide insights into the effectiveness of these PET tracers in identifying T-cell activity and tumor characteristics, which could enhance diagnostic precision and treatment planning in cancers such as breast cancer, esophageal cancer, melanoma, and non-small cell lung carcinoma.

The secondary objective is to measure the strength of correlation of pathological response, specifically the percentage of residual viable tumor cells in the resected tumor, with preoperative uptake of [89Zr]Zr-Df-Crefmirlimab and [18F]F-AraG, respectively. This could further elucidate the potential of these tracers in predicting treatment outcomes and guiding therapeutic decisions.

The clinical trial involves a study population comprising both **male** and **female** participants, with an age range that includes adults and older adults. The trial focuses on individuals diagnosed with **breast cancer**, **esophageal cancer**, **melanoma**, and **non-small cell lung carcinoma**. Participants are required to have a histologically confirmed diagnosis of one of these conditions, with a lesion size of at least 2 cm at the time of (re)staging FDG PET/CT. The study does not include vulnerable populations. Participants must be planned for resection according to routine treatment guidelines and may have undergone neoadjuvant chemotherapy and immuno-oncology treatments. They must be above 18 years of age, have measurable disease based on RECIST 1.1, and possess an ECOG performance status of 0-1, indicating they are operable based on pulmonary function and/or exercise testing. The sponsor has not provided information regarding the total number of participants in the trial. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of two PET imaging tracers, [18F]F-AraG and [89Zr]Zr-Df-Crefmirlimab, in patients with **breast cancer**, **esophageal cancer**, **melanoma**, and **non-small cell lung carcinoma**. The trial aims to measure the spatial correlation of PET uptake in tumors and T-cell rich organs, such as lymph nodes, prior to resection. The study will assess the correlation between the presence of CD8+ cells and T cell activation features in resected tumors and lymph nodes with preoperative uptake of the tracers. The trial is expected to commence on November 1, 2024, and conclude by November 1, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed cancer, lesion size, and planned resection. Following the screening, participants will receive the investigational tracers via **intravenous administration**. Subsequent follow-up visits will monitor tracer uptake and assess the correlation with T cell features. The end-of-study visit will involve a comprehensive evaluation of the primary and secondary endpoints, including the spatial overlap of tracer uptake and the correlation with residual viable tumor cells.

The expected length of participant involvement is approximately one year, with the possibility of early termination if adverse events occur or if the participant withdraws consent. The study will utilize the **Dice Similarity Coefficient** and **Pearson correlation coefficient** to analyze the primary and secondary endpoints, respectively. Participants must be above 18 years of age, have measurable disease based on RECIST 1.1, and an ECOG performance status of 0-1. The trial is categorized as a Phase II study, focusing on the safety and efficacy of the investigational tracers, which have been evaluated in earlier studies.

The clinical trial involves the administration of **Zirconium (89Zr) crefmirlimab berdoxam**, an experimental medication provided as an **aqueous solution for intravenous (IV) administration**. This radiopharmaceutical tracer is administered via **intravenous infusion**. The maximum daily dose is 33 MBq, with a total maximum dose of 41 MBq over a treatment period of one day. The active substance, zirconium (89Zr) crefmirlimab berdoxam, is a protein-based compound designed to target CD8+ cells, facilitating the imaging of T-cell activity in cancer patients. The administration of this tracer is monitored to ensure compliance with the dosing schedule and to evaluate its uptake in tumors and T-cell rich organs such as lymph nodes.

In addition to the experimental medication, the study utilizes **Nelarabine**, a non-experimental treatment provided as a **solution for injection**. Nelarabine is administered through **intravenous administration**. The maximum daily dose is 166 MBq, with a total maximum dose of 204 MBq over a treatment period of one day. Nelarabine, known chemically as arabinofuranosylguanine (AraG), is used as a comparator treatment to assess the correlation of PET uptake with T-cell activation features. The administration of Nelarabine is also monitored to ensure adherence to the dosing regimen and to evaluate its role in the study's primary objectives.

Efficacy in this clinical trial will be assessed through the evaluation of the spatial correlation and uptake of two PET tracers, [18F]F-AraG and **[89Zr]Zr-Df-Crefmirlimab**, in tumors and T-cell rich organs such as lymph nodes. The primary endpoints include measuring the spatial overlap of the regions of uptake for both PET tracers using the Dice Similarity Coefficient (DSC) and assessing the Pearson correlation coefficient between each tracer's tumor uptake and T cell features in regions of concordance and discordance. Secondary endpoints involve analyzing the Pearson correlation coefficient between each tracer's tumor uptake and the percentage of residual viable tumor cells (VTC) in regions of concordance and discordance, as well as the maximal VTC of the entire tumor. Additionally, the correlation between each tracer uptake and T cell features in resected lymph nodes will be evaluated if present.