Evaluation of Absorbed Tumor Dose in Peptide Receptor Radionuclide Therapy with Octreotide, Lanreotide, and Lutetium (177Lu) Oxodotreotide in Neuroendocrine Tumors

The primary objective of the study is to evaluate the effect of continued use of long-acting **somatostatin analogues** (LA-SSA) on the absorbed dose in tumor lesions during peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine tumors. This is clinically relevant as optimizing the absorbed dose in tumor lesions can potentially enhance the therapeutic efficacy of PRRT, leading to improved patient outcomes.

Secondary objectives include assessing the effect of continued LA-SSA use on:

• The absorbed dose in normal tissues during PRRT, which is crucial for minimizing potential adverse effects and ensuring patient safety.
• The tumor-to-background ratio, which can provide insights into the specificity and effectiveness of the treatment in targeting tumor cells.
• The population pharmacokinetic parameters of [177Lu]Lu-HA-DOTATATE, which can help in understanding the drug's distribution and clearance, thereby aiding in dose optimization.

The clinical trial involves a **study population** of patients aged 18 years and older diagnosed with a **neuroendocrine tumor** of grade I or II, who have a clinical indication for peptide receptor radionuclide therapy (PRRT). The trial includes both male and female participants, with no vulnerable populations selected. The sponsor has not provided information regarding the total number of participants. Participants were selected based on their ability to provide informed consent and meet specific clinical criteria, including having at least one soft tissue lesion greater than 2 cm and an Eastern Cooperative Oncology Group (ECOG) performance status score between 0 and 2. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The inclusion criteria ensure that participants have a histopathologically confirmed neuroendocrine tumor and are eligible for PRRT, with an aimed administered activity of 7400 MBq.

The clinical trial is designed to evaluate the effect of continued use of long-acting somatostatin analogues (LA-SSA) on the absorbed dose in tumor lesions during **Peptide Receptor Radionuclide Therapy (PRRT)** in patients with neuroendocrine tumors. This trial is a low-intervention study, adhering to standard care protocols, and is structured as a randomized, double-blind, controlled trial. The trial is expected to commence recruitment in May 2024 and conclude by November 2026, with an estimated duration of 40 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), confirmed diagnosis of a neuroendocrine tumor, and clinical indication for PRRT. The trial will include follow-up visits to monitor the absorbed dose in target lesions and normal tissues using SPECT/CT imaging. The primary endpoint is the absorbed dose in target lesions, while secondary endpoints include the absorbed dose in normal tissues and the effect of LA-SSA on pharmacokinetic parameters. The end-of-study visit will assess the overall outcomes and any adverse events.

Participant involvement is expected to last up to 40 weeks, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with the study protocol. The trial will utilize **octreotide**, **lutetium (177Lu) oxodotreotide**, and **lanreotide** as investigational products, administered via intramuscular, intravenous, and subcutaneous routes, respectively. The maximum treatment period for octreotide and lanreotide is 4 weeks, while lutetium (177Lu) oxodotreotide is administered over a maximum of 40 weeks. The trial aims to provide valuable insights into the dosimetric effects of LA-SSA in PRRT, contributing to optimized treatment strategies for neuroendocrine tumors.

The clinical trial involves the administration of **octreotide**, a somatostatin analog, as part of the treatment regimen. Octreotide is provided in a pharmaceutical form identified as PHF675 and is administered via **intramuscular injection**. The maximum daily dose is 40 mg, with a total dose not exceeding 40 mg over a treatment period of 4 weeks. This medication is not a pediatric formulation and is classified under the ATC code H01CB02. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another experimental medication used in the trial is **lutetium (177Lu) oxodotreotide**, also known by synonyms such as 177LU-DOTATATE. This compound is a radiopharmaceutical administered **intravenously**. The pharmaceutical form is designated as PHF00230MIG. The maximum daily dose is 7400 MBq, with a total dose limit of 29600 MBq over a 40-week treatment period. A magistral formula of the product will be used, employing a licensed radionuclide for labeling instead of the licensed final preparation. This medication is also not a pediatric formulation and is classified under the ATC code V10XX04.

**Lanreotide**, another somatostatin analog, is included as an auxiliary treatment in the study. It is administered **subcutaneously** in a pharmaceutical form identified as PHF1103MIG. The maximum daily dose is 120 mg, with a total dose not exceeding 120 mg over a 4-week treatment period. Lanreotide is not a pediatric formulation and is classified under the ATC code H01CB03. As with the other medications, participant adherence to the dosing schedule will be closely monitored.

Efficacy in the clinical trial titled "Absorbed Tumor Dose in Peptide Receptor Radionuclide Therapy with long-acting Somatostatin Analogues – ATSA trial" will be assessed through a series of primary and secondary endpoints. The primary endpoint is the **absorbed dose** in target lesions, which will be measured using SPECT/CT imaging. Secondary endpoints include the absorbed dose in normal tissues such as kidneys, liver, and spleen, also measured via SPECT/CT imaging. Additionally, the bone marrow dose will be determined using blood withdrawals and SPECT/CT imaging. The uptake on SPECT/CT between target lesions and the liver and spleen will be measured at the 24-hour time point. Furthermore, the effect of continued long-acting somatostatin analogues (LA-SSA) use on specific population pharmacokinetic parameters will be evaluated using population pharmacokinetic modeling, which will incorporate data from SPECT/CT scans and blood samples for dosimetry.