Phase III Study on the Efficacy and Safety of 177Lu-Edotreotide PRRT Versus Everolimus in Inoperable, Progressive SSTR+ GEP-NET Patients

The primary objective of this study is to demonstrate the efficacy of **Peptide Receptor Radionuclide Therapy (PRRT)** with 177Lu-edotreotide in prolonging progression-free survival (PFS) in patients with inoperable, progressive, somatostatin receptor-positive (SSTR+) neuroendocrine tumors of gastroenteric or pancreatic origin (GEP-NET), compared to everolimus. This is clinically relevant as it aims to provide an alternative treatment option that could potentially improve the management and outcomes for patients with these types of tumors, which are often challenging to treat due to their inoperable and progressive nature.

Secondary objectives include:

• Assessing objective response rates (ORR), defined as the proportion of patients achieving partial response (PR) or complete response (CR) as the best outcome, after treatment with 177Lu-edotreotide compared to everolimus.
• Evaluating overall survival (OS), defined as the time from the date of randomization until death.

The clinical trial involves a total of **56 participants** diagnosed with **neuroendocrine tumours** of gastroenteric or pancreatic origin. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of well-differentiated neuroendocrine tumours, either of non-functional gastroenteric origin or both functional and non-functional pancreatic origin. All participants have measurable disease per RECIST 1.1 and exhibit somatostatin receptor-positive (SSTR+) disease. The trial specifically targets individuals with progressive disease as evidenced by two morphological imaging examinations using the same method, either CT or MRI. The study population is characterized by a vulnerable group, indicating the inclusion of individuals who may require additional considerations during the trial. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is a **randomized**, controlled, open-label, multicenter Phase III study designed to evaluate the efficacy and safety of Peptide Receptor Radionuclide Therapy (PRRT) with **177Lu-Edotreotide** compared to targeted molecular therapy with **Everolimus** in patients with inoperable, progressive, somatostatin receptor-positive (SSTR+) neuroendocrine tumors of gastroenteric or pancreatic origin (GEP-NET). The primary objective is to demonstrate the efficacy of PRRT with 177Lu-Edotreotide in prolonging progression-free survival (PFS) compared to Everolimus. The trial is expected to run from March 29, 2018, to March 12, 2029, with an estimated participant involvement of up to 270 days for those receiving Everolimus and up to 9 days for those receiving 177Lu-Edotreotide.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of well-differentiated neuroendocrine tumors, measurable disease per RECIST 1.1, and SSTR+ status. Following randomization, participants will receive either 177Lu-Edotreotide or Everolimus, with the treatment regimen tailored to the specific therapeutic agent. Follow-up visits will be scheduled to monitor safety, tolerability, and efficacy, including assessments of progression-free survival, objective response rate, overall survival, and health-related quality of life. The end-of-study visit will conclude the participant's involvement, with comprehensive evaluations to assess the primary and secondary endpoints.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will also include sub-studies focusing on dosimetry and pharmacokinetics to further understand the treatment's impact on target organs and tumor lesions. The study aims to provide robust data on the comparative effectiveness of PRRT with 177Lu-Edotreotide versus Everolimus, contributing valuable insights into the management of GEP-NET.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. The **Arginine-Lysine solution for infusion** is utilized as an auxiliary treatment. This solution is composed of **L-Lysine Hydrochloride** and **L-Arginine Hydrochloride**, both of which are chemically derived substances. The pharmaceutical form is a solution for infusion, administered intravenously. The maximum daily dose is 2000 ml, with a total treatment period of up to 270 days. This solution serves as a nephroprotective amino acid solution, supporting the primary treatment regimen.

The primary experimental medication in this trial is **177Lu-Edotreotide**, a solution for injection/infusion, also administered intravenously. The active substance, **Lutetium (177Lu) Edotreotide**, is chemically synthesized. The maximum daily dose is 7.5 GBq, with a total dose not exceeding 30 GBq over a treatment period of 9 months. This medication is designated as an orphan drug, indicating its use in treating rare conditions, specifically targeting somatostatin receptor-positive neuroendocrine tumors.

As a comparator treatment, **Afinitor** is used in two dosages: 5 mg and 10 mg tablets. The active substance in both formulations is **Everolimus**, a chemically derived compound. These tablets are administered orally, with a maximum daily dose of 10 mg. The treatment period for Afinitor is up to 270 days. Everolimus functions as an antineoplastic agent and protein kinase inhibitor, providing a standard-of-care therapy against which the efficacy of 177Lu-Edotreotide is evaluated.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**. This endpoint is designed to evaluate the duration during which patients with inoperable, progressive, somatostatin receptor-positive gastroenteric or pancreatic neuroendocrine tumors (GEP-NET) remain free from disease progression. The trial will compare the efficacy of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide against targeted molecular therapy with Everolimus.

Secondary endpoints include the **Objective Response Rate (ORR)**, which measures the percentage of patients achieving partial or complete response as the best outcome, and **Overall Survival (OS)**. Additional assessments will focus on safety and tolerability, including changes in Total Effective Radiation (TER), Glomerular Filtration Rate (GFR), and renal volume, as well as the frequency and severity of abnormal findings in safety investigations such as vital signs, ECG, clinical laboratory results, and adverse events.

Health-related quality of life (HRQL) will be evaluated using the EORTC QLQ-C30 and GI.NET21 questionnaires, focusing on maximum improvement, duration of improvement, and time to deterioration. Dosimetry assessments will be conducted to determine the cumulative absorbed dose from 177Lu-Edotreotide to target tumor lesions and other organs. Pharmacokinetic studies will analyze urine and blood radioactivity to assess excretion and clearance patterns, with radiochemical purity evaluated through HPLC of urine samples.