Evaluation of Lutetium (177Lu) Edotreotide Versus Standard Care in Aggressive Grade 2/3 SSTR+ Gastroenteropancreatic Neuroendocrine Tumors

The primary objective of this study is to demonstrate the **efficacy** of Peptide Receptor Radionuclide Therapy (PRRT) with lutetium (177Lu) edotreotide in the treatment of well-differentiated aggressive Grade 2 (G2; Ki67 between 15 and 20, inclusive) and Grade 3 (G3; Ki-67 above 20 up to 55, inclusive) somatostatin receptor-positive (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This is compared to the best standard of care as determined by the investigator's choice from a protocol comparator list. The clinical relevance of this objective lies in potentially offering a more effective treatment option for patients with these specific types of neuroendocrine tumors, which are characterized by their aggressive nature and limited treatment options.

Secondary objectives include:

• To further demonstrate the efficacy of PRRT with lutetium (177Lu) edotreotide.
• To assess the impact of PRRT on patients' health-related quality of life (HRQL) and neuroendocrine functional tumor symptoms during and after therapy, in comparison to the best standard of care.
• To assess the safety and tolerability of PRRT with lutetium (177Lu) edotreotide in trial patients compared to control treatment options.

The clinical trial involves a total of **71 participants** diagnosed with **well-differentiated aggressive Grade 2 and Grade 3, somatostatin receptor-positive (SSTR+) neuroendocrine tumors of gastroenteric or pancreatic origin (GEP-NET)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on a histologically confirmed diagnosis of unresectable, well-differentiated GEP-NETs, with measurable disease as per RECIST v1.1 criteria, and confirmed SSTR+ status. The trial does not specify particular lifestyle considerations such as diet or physical activity. The population includes vulnerable groups, although specific details on the nature of vulnerability are not provided. The selection criteria ensure that the study population is representative of the target patient group for the investigational treatment.

The clinical trial is designed as a **randomized**, controlled, open-label, multicenter study to evaluate the efficacy, safety, and patient-reported outcomes of Peptide Receptor Radionuclide Therapy (PRRT) with **lutetium (177Lu) edotreotide** compared to the best standard of care in patients with well-differentiated aggressive Grade 2 and Grade 3, somatostatin receptor-positive (SSTR+), neuroendocrine tumors of gastroenteric or pancreatic origin. The trial aims to demonstrate the efficacy of PRRT in treating these specific neuroendocrine tumors compared to the investigator's choice from a protocol comparator list. The primary endpoint is progression-free survival, with secondary endpoints including objective response rate, overall survival, duration of response, disease control rate, and quality of life assessments.

The trial is expected to run from December 21, 2021, to December 31, 2027. Participants will be involved for a maximum treatment period of 44 weeks, with the possibility of early termination if they experience disease progression, unacceptable toxicity, or withdrawal of consent. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, histological diagnosis, and SSTR+ status; regular follow-up visits to monitor treatment response and safety; and an end-of-study visit to assess final outcomes and collect data on adverse events and quality of life.

Participants will receive the investigational product, **177Lu-Edotreotide**, administered via **intravenous use**. The maximum daily dose is 7.5 GBq, with a total dose not exceeding 45 GBq over the treatment period. The trial also involves the use of a nephroprotective amino acid solution, **arginine-lysine**, to mitigate potential renal toxicity. The study will adhere to rigorous scientific standards, with blinded central assessments for endpoints based on RECIST v1.1 criteria, ensuring the reliability and validity of the trial results.

The clinical trial involves the administration of **177Lu-Edotreotide**, a **solution for injection/infusion**. This experimental medication is administered via **intravenous use**. The maximum daily dose is 7.5 GBq, with a total maximum dose of 45 GBq over a treatment period of 44 days. The active substance, **lutetium (177Lu) edotreotide**, is of chemical origin and is provided by ITM Solucin GmbH. This treatment is designated as an orphan drug and is intended for use in patients with well-differentiated aggressive Grade 2 and Grade 3 somatostatin receptor-positive neuroendocrine tumors of gastroenteric or pancreatic origin.

In addition to the experimental treatment, the trial includes the use of an **Arginine-Lysine solution for infusion** as a nephroprotective amino acid solution. This solution is also administered intravenously, with a maximum daily dose of 2000 ml and a total maximum dose of 12000 ml over the same 44-day treatment period. The active substances in this solution are **L-lysine hydrochloride** and **L-arginine hydrochloride**, both of chemical origin, and are also provided by ITM Solucin GmbH.

The trial also involves several comparator treatments, including **Temozolomide**, which is administered orally. The pharmaceutical form is not specified beyond the code PHF00005MIG, and the dosing details are not provided. **Everolimus** is another comparator, also administered orally, with similar unspecified dosing details and pharmaceutical form code PHF00170MIG.

Additional comparator treatments include **Calcium Folinate** and **Sodium Folinate**, both administered intravenously. The pharmaceutical forms are indicated by the codes PHF00190MIG and PHF00231MIG, respectively, with no specific dosing details provided. **Fluorouracil** and **Oxaliplatin** are also administered intravenously, with pharmaceutical form codes PHF00231MIG and PHF00230MIG, respectively, and unspecified dosing details.

Lastly, **Capecitabine** is included as a comparator treatment, administered orally, with a pharmaceutical form code PHF00009MIG. As with the other comparator treatments, specific dosing details are not provided. All comparator treatments are of chemical origin and are intended to provide a standard-of-care comparison to the experimental treatment.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-free survival (PFS)**, which will be measured to evaluate the time from randomization until disease progression or death. Secondary endpoints include the **Objective response rate (ORR)**, defined as the proportion of patients achieving complete or partial response according to RECIST v1.1 criteria, and **Overall survival (OS)**, which measures the time from randomization until death. Additional secondary endpoints are the **Duration of response (DoR)**, **Disease control rate (DCR)**, and **Duration of disease control (DDC)**, all based on RECIST v1.1 criteria.

Quality of life will be assessed using two HRQL questionnaires from the European Organization for Research and Treatment of Cancer (EORTC), specifically the QLQ-C30 and GI.NET21. These will evaluate the maximum improvement in HRQL scores relative to baseline, the duration of maximum HRQL improvement, and the time to HRQL deterioration. Efficacy assessments will be conducted through blinded, central assessments, with local assessments serving as sensitivity analyses. The trial will also monitor safety and tolerability through adverse events, laboratory data, and vital signs. The trial is designed to compare the efficacy of Peptide Receptor Radionuclide Therapy (PRRT) with lutetium (177Lu) edotreotide against the best standard of care in patients with well-differentiated aggressive Grade 2 and Grade 3, somatostatin receptor-positive neuroendocrine tumors of gastroenteric or pancreatic origin.