Phase II Evaluation of 68GaNOTA-Anti-MMR VHH2 PET Imaging in MMR-Expressing Macrophages in Non-Small Cell Lung Cancer Patients

The primary objective of this phase II study is to **correlate** the uptake of 68GaNOTA-AntiMMR-VHH2 in a lesion of **non-small cell lung cancer** (NSCLC) before surgical intervention with the immunohistological MMR-staining of the excised lesion. This objective is clinically relevant as it aims to evaluate the potential of 68GaNOTA-AntiMMR-VHH2 as a diagnostic imaging agent for identifying MMR-expressing macrophages in vivo using Positron Emission Tomography (PET). Such correlation could enhance the precision of NSCLC diagnosis and potentially guide therapeutic decisions by providing detailed insights into the tumor microenvironment.

The clinical trial involves **patients with non-small cell lung cancer** (NSCLC) and aims to correlate the uptake of 68GaNOTA-AntiMMR-VHH2 in a NSCLC lesion before surgery with the immunohistological MMR-staining of the excised lesion. The study population includes both male and female participants, aged 18 years and older, who have given informed consent. Participants are required to have local, locally advanced, or metastatic lung cancer and be scheduled for resection or surgical biopsy of at least one lesion, with specific size criteria for the tumor to be resected or biopsied. The trial does not include a vulnerable population. 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 as a **randomized**, **double-blind**, and controlled study to evaluate the imaging potential of 68GaNOTA-Anti-MMR VHH2 in patients with non-small cell lung cancer (NSCLC). The trial aims to correlate the uptake of the investigational product in NSCLC lesions with the immunohistological MMR-staining of excised tissue. The study is expected to run from February 15, 2023, to April 1, 2027, with recruitment having commenced on June 7, 2023. Participants will be involved in the study for a period that includes an initial screening visit, multiple follow-up visits, and an end-of-study visit.

The sequence of study visits begins with the inclusion (screening) visit, where eligibility is confirmed based on criteria such as age (at least 18 years), informed consent, and the presence of a resectable or biopsiable lung lesion. Follow-up visits will be scheduled to monitor the uptake of the investigational product and assess any adverse events. The end-of-study visit will conclude the participant's involvement, during which final assessments and data collection will occur. The expected length of participant involvement is contingent upon the individual's treatment schedule and response to the investigational product.

Participants may be subject to early termination from the study if they experience significant adverse effects, withdraw consent, or fail to comply with study protocols. The investigational product, 68Ga-UZBRU-VHH2, is administered intravenously as a solution for injection, with a maximum daily dose of 370 MBq. The trial's primary endpoint is the immunohistological MMR score on excised tissue, which will provide insights into the imaging potential of the investigational product. The study is not classified as a low-intervention trial and is conducted under the authorization of relevant regulatory bodies.

The clinical trial involves the administration of the experimental medication **68Ga-UZBRU-VHH2**, which is a **solution for injection**. This investigational product is designed for **intravenous administration**. The active substance in this formulation is a **nanobody against macrophage mannose receptor**, conjugated with **1,4,7-triazacyclononane-N,N',N''-triacetic acid**, and labelled with **gallium Ga-68**. The maximum daily dose and total dose for this trial is set at 370 MBq (megabecquerels), with a treatment period limited to a single day. The product is not a pediatric formulation and is not classified as an orphan drug.

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 investigational product, 68Ga-UZBRU-VHH2, to evaluate its imaging potential in patients with non-small cell lung cancer (NSCLC). The trial aims to correlate the uptake of the investigational product in NSCLC lesions with immunohistological staining results. Participant compliance with the dosing schedule will be monitored to ensure adherence to the protocol.

The efficacy of the investigational product, **68Ga-UZBRU-VHH2**, will be assessed in a clinical trial involving patients with non-small cell lung cancer (NSCLC). The primary endpoint for evaluating efficacy is the **immunohistological MMR score** on excised tissue. This endpoint aims to correlate the uptake of **68GaNOTA-AntiMMR-VHH2** in a NSCLC lesion before surgery with the immunohistological MMR-staining of the excised lesion. The trial will utilize Positron Emission Tomography (PET) imaging to evaluate the in vivo imaging potential of the investigational product in MMR-expressing macrophages.