A pivotal phase 3 clinical trial to assess the diagnostic performance and safety of [68Ga]Ga-PentixaFor ([68Ga]Ga-PTF), a positron emission tomography (PET) imaging agent, versus [18F]FDG PET/CT imaging, for staging of patients with confirmed marginal zone lymphoma (MZL) exemplary for CXCR4-positive malignant lymphomas: a prospective, international, multi-center, comparative, randomized, cross-over, open-label lymphoma diagnostic trial (LYMFOR).

The primary objective of this pivotal phase 3 clinical trial is to evaluate the **superiority** in terms of sensitivity and non-inferiority in terms of specificity of [68Ga]Ga-PentixaFor PET/CT imaging compared to [18F]FDG PET/CT imaging for tumor detection on a lesion-basis in patients with confirmed **Marginal Zone Lymphoma**. This assessment is confirmed by a Standard of Truth (SoT), which involves centrally histopathological confirmation of tumor tissue, or a surrogate SoT, which includes central evaluation through clinical and imaging follow-up. The clinical relevance of this objective lies in potentially improving diagnostic accuracy and patient management in CXCR4-positive malignant lymphomas.

Secondary objectives include: - Assessing the impact on staging of each PET/CT imaging agent on a patient-basis both locally by referring physicians and centrally by an Independent Committee. - Evaluating the impact on the intended treatment plan and patient management of each PET/CT imaging agent. - Assessing inter-observer agreement of local and central assessment in terms of staging. - Evaluating the diagnostic performance, including sensitivity and specificity, of each PET/CT imaging agent in tumor detection across various anatomical regions. - Determining the positive and negative predictive values, diagnostic accuracy, and detection rate of each PET/CT imaging agent. - Assessing the inter-reader and intra-reader agreement for tumor detection. - Evaluating the reproducibility and image quality of [68Ga]Ga-PentixaFor PET/CT imaging. - Assessing the safety and tolerability of each PET/CT imaging agent.

The clinical trial involves participants diagnosed with **Marginal Zone Lymphoma** (MZL), a type of lymphoid neoplasm. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of MZL, with a biopsy-proven nodal, extranodal, or splenic MZL. The trial is open to treatment-naïve individuals with acceptable organ function and a life expectancy of at least 12 weeks. Participants must not have undergone any curative or palliative interventions between diagnostic measures and the imaging scans. The trial includes a vulnerable population, and all participants must provide informed consent. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized**, cross-over, open-label study to evaluate the diagnostic performance and safety of **[68Ga]Ga-PentixaFor** compared to **[18F]FDG** in patients with confirmed **marginal zone lymphoma**. The trial aims to assess the superiority in sensitivity and non-inferiority in specificity of [68Ga]Ga-PentixaFor PET/CT imaging versus [18F]FDG PET/CT imaging for tumor detection. The study is expected to run until August 31, 2026, with recruitment starting on December 1, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and treatment history. The trial will include multiple follow-up visits to monitor the diagnostic performance of the imaging agents and assess any impact on patient management and treatment plans. The end-of-study visit will conclude the participant's involvement, evaluating the overall safety and efficacy of the imaging agents.

The expected duration of participant involvement is approximately 12 weeks, with conditions for early termination including withdrawal of consent, adverse events, or any protocol violations. The trial will utilize a centrally confirmed Standard of Truth (SoT) or surrogate SoT for lesion-based tumor detection, ensuring rigorous assessment of the primary and secondary endpoints. The study will also evaluate the impact on staging, inter-observer agreement, and the safety and tolerability of the imaging agents.

The clinical trial involves the use of **[68Ga]Ga-PentixaFor**, a **solution for injection** designed for **intravenous administration**. This experimental medication is utilized as a positron emission tomography (PET) imaging agent. The active substances in [68Ga]Ga-PentixaFor are **gallium (68Ga)** and **pentixafor**, both of which are of chemical origin. The maximum daily dose is set at 200 megabecquerels (MBq), with a total maximum dose of 400 MBq over a treatment period of up to 2 days. The administration of this agent is intended to assess its diagnostic performance in detecting tumors in patients with confirmed marginal zone lymphoma (MZL), particularly those with CXCR4-positive malignant lymphomas.

The comparator treatment in this trial is **Fludeoxyglucose (18F)**, also administered as a **solution for injection** via **intravenous injection**. This agent is commonly used in PET/CT imaging and serves as a standard-of-care therapy for tumor detection. The active substance, **fludeoxyglucose (18F)**, is also of chemical origin. The dosing for Fludeoxyglucose (18F) is calculated based on body weight, with a maximum daily and total dose of 3 MBq per kilogram. The treatment period for this comparator is limited to 1 day. This agent is used to evaluate its performance against [68Ga]Ga-PentixaFor in terms of sensitivity and specificity in tumor detection.

The efficacy of the clinical trial will be assessed by evaluating the diagnostic performance of **[68Ga]Ga-PentixaFor** PET/CT imaging compared to **[18F]FDG** PET/CT imaging in patients with confirmed marginal zone lymphoma (MZL). The primary endpoint focuses on demonstrating the superiority of **[68Ga]Ga-PentixaFor** in terms of sensitivity and non-inferiority in terms of specificity for tumor detection on a lesion-basis. This will be confirmed by a Standard of Truth (SoT), which involves central histopathological confirmation of tumor tissue, or a surrogate SoT, which includes central evaluation of clinical and imaging follow-up.

Secondary endpoints include assessing the impact of each PET/CT imaging agent on staging, intended treatment plans, and patient management. The trial will also evaluate the percentage of inter-observer agreement, diagnostic performance on a region-basis, and sensitivity on a patient-basis. Additional assessments will determine the positive predictive value (PPV) and negative predictive value (NPV) of each imaging agent, as well as the tumor detection rate on both patient-basis and lesion-basis. The trial will further explore the proportion of patients with additional or fewer lesions detected by **[68Ga]Ga-PentixaFor** compared to **[18F]FDG**, and the percentage of intra- and inter-reader agreement for tumor detection. Reproducibility of **[68Ga]Ga-PentixaFor** imaging will be evaluated by comparing two successive scans in a subpopulation of patients, and the image quality of each agent in PET-positive lesions will be assessed. Safety and tolerability of each PET/CT imaging agent will also be evaluated.