Efficacy and Safety of Lutetium (177Lu) Oxodotreotide as Adjuvant Therapy in Stage III Small Intestinal Neuroendocrine Neoplasms

The primary objective of this study is to evaluate the **efficacy** of adjuvant peptide receptor radionuclide therapy (PRRT) in the experimental group (Arm A) compared to standard care involving close surveillance in the control group (Arm B) in terms of **relapse-free survival** (RFS) at 60 months. This is clinically relevant as it aims to determine the potential benefit of PRRT in preventing disease recurrence in patients with locoregionally restricted (stage III) small intestinal neuroendocrine neoplasms (SI-NEN) following curative surgery.

Secondary objectives include: - Evaluating the **efficacy** of Arm A compared to Arm B in terms of overall survival (OS) and cancer-specific overall survival (OS). - Assessing the **safety** and tolerability of Arm A compared to Arm B. - Evaluating health-related quality of life (HRQOL) associated with Arm A compared to Arm B.

The clinical trial involves participants diagnosed with **locoregionally restricted (stage III) small intestinal neuroendocrine neoplasms (SI-NEN)**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically confirmed resected locoregionally limited SI-NEN, with specific preoperative and postoperative imaging criteria. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize the necessity for participants to have undergone specific surgical interventions and imaging assessments. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include the requirement for written informed consent and adherence to contraception guidelines for participants of childbearing potential. The trial aims to evaluate the efficacy of adjuvant treatment with PRRT compared to standard care in terms of relapse-free survival over 60 months.

The clinical trial is designed to evaluate the **efficacy** and safety of adjuvant peptide receptor radionuclide therapy (PRRT) using **Lutathera** in patients with locoregionally restricted (stage III) small intestinal neuroendocrine neoplasms (SI-NEN) following curative surgery. This is a multi-center, prospective, open-label, two-arm parallel group, randomized, controlled, phase III study. The primary objective is to assess relapse-free survival (RFS) over a period of 60 months, comparing the experimental arm receiving PRRT with the control arm under standard care and close surveillance. The trial is expected to conclude by December 31, 2033, with recruitment starting on October 15, 2025.

Participants will be randomly assigned to either the experimental or control group. The study will involve several key visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of resected SI-NEN, and preoperative and postoperative imaging results. Follow-up visits will be scheduled to monitor the participants' health status, adherence to the treatment protocol, and to collect data on primary and secondary endpoints, including overall survival and health-related quality of life (HRQOL) using EORTC QLQ-C30/GINET21 questionnaires. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted.

The expected length of participant involvement is up to 60 months, with the possibility of early termination if criteria such as significant adverse events or withdrawal of consent are met. The study will administer **Lutathera** via intravenous infusion, with a maximum total dose of 14.8 GBq over a treatment period of up to 9 months. Participants must adhere to contraception guidelines to prevent pregnancy during and after the study treatment. The trial will follow strict ethical guidelines, ensuring informed consent and the safety of all participants throughout the study duration.

The clinical trial involves the administration of **Lutathera 370 MBq/mL solution for infusion**, which contains the active substance **lutetium (177Lu) oxodotreotide**. This experimental medication is provided in the form of a solution for infusion and is administered via **intravenous (IV) infusion**. The dosing regimen for this trial specifies a maximum daily dose of 7.4 GBq, with a total maximum dose of 14.8 GBq over the course of the treatment. The treatment period is limited to a maximum of 9 months, with only two cycles of administration instead of the standard four cycles. The pharmaceutical product is manufactured by Advanced Accelerator Applications and is classified as a chemical substance. It is important to note that this formulation is not intended for pediatric use.

In the control arm of the study, participants will receive standard-of-care therapy, which involves close surveillance without the administration of the experimental medication. This approach serves as the comparator treatment to evaluate the efficacy of the adjuvant peptide receptor radionuclide therapy (PRRT) in the experimental arm. The primary objective of the trial is to assess the efficacy of PRRT in terms of relapse-free survival at 60 months, comparing the outcomes between the experimental and control groups. Participant compliance with the dosing schedule and administration protocol will be closely monitored throughout the study to ensure adherence to the trial's guidelines.

The efficacy of the clinical trial will be assessed primarily through the measurement of **relapse-free survival (RFS)** at 60 months. RFS is defined as the time from randomization to the first relapse or death, whichever occurs earlier, in accordance with ENETS guidelines. Relapse is characterized by the detection of a new lesion with somatostatin receptor (SSTR) uptake in PET-CT imaging. This endpoint will be used to compare the efficacy of adjuvant peptide receptor radionuclide therapy (PRRT) in the experimental arm (Arm A) against standard care based on close surveillance in the control arm (Arm B).

Secondary efficacy endpoints include overall survival (OS) and cancer-specific OS, which are defined as the time from randomization to death or cancer-specific death. Additionally, health-related quality of life (HRQOL) will be evaluated using the EORTC QLQ-C30 and GINET21 questionnaires. Adverse events (AEs) and serious adverse events (SAEs) will also be monitored as part of the secondary endpoints. These assessments will provide a comprehensive evaluation of the treatment's impact on patient outcomes.