Efficacy and Safety Evaluation of Lutetium (177Lu) Oxodotreotide in Advanced GEP-NETs with High Proliferation: A Phase III Randomized Study

The primary objective of this phase III study is to demonstrate that **Lutathera** is superior to an active comparator in delaying the time-to-first occurrence of progression or death (progression-free survival, PFS) as a first-line treatment in patients with somatostatin receptor-positive, well-differentiated Grade 2 and Grade 3 advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This is clinically relevant as it aims to improve the management of GEP-NETs by potentially extending the time patients remain progression-free, thereby enhancing their quality of life and treatment outcomes.

Secondary objectives include:

• Demonstrating the superiority of Lutathera compared to the active comparator in terms of objective response.
• Assessing the superiority of Lutathera in delaying the time to deterioration in selected quality of life (QoL) items/scales.
• Evaluating the efficacy of Lutathera in maintaining disease control.
• Assessing the efficacy of Lutathera in terms of duration of response.
• Evaluating the safety and tolerability of Lutathera.
• Assessing the effect of Lutathera on overall survival.

The clinical trial involves a total of **132 participants** diagnosed with somatostatin receptor positive, well-differentiated G2 and G3, advanced gastroenteropancreatic neuroendocrine tumors (**GEP NETs**). The study population includes both male and female subjects, aged 15 years and older, with a body weight exceeding 40 kg. Participants were selected based on the presence of metastasized or locally advanced, inoperable GEP-NETs, diagnosed within six months prior to screening. The trial includes individuals with a Karnofsky Performance Score of 60 or higher, indicating a requirement for a certain level of general health. The study population is characterized by the expression of somatostatin receptors on all target lesions, as confirmed by specific imaging modalities. The trial does not exclude vulnerable populations, and participants have provided informed consent prior to any study-related activities. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, open-label, phase III study designed to evaluate the efficacy and safety of **Lutathera** in patients with Grade 2 and Grade 3 advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The primary objective is to demonstrate that Lutathera is superior to the active comparator in delaying the time-to-first occurrence of progression or death, known as progression-free survival (PFS). The trial involves a comparison between Lutathera combined with best supportive care, including **octreotide** long-acting, and a high dose of octreotide long-acting alone. The study is expected to conclude by October 31, 2027, with recruitment having commenced on September 30, 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as the presence of metastasized or locally advanced, inoperable, well-differentiated GEP-NETs, and a **Ki67 index** between 10% and 55%. The screening will also ensure the expression of somatostatin receptors on all target lesions. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments conducted according to **RECIST 1.1** criteria. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement is up to 136 weeks for those receiving octreotide and up to 48 weeks for those receiving Lutathera, depending on the treatment arm. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or any other reason deemed appropriate by the investigator. The trial will adhere to rigorous scientific standards to ensure the validity and reliability of the results, contributing valuable insights into the management of advanced GEP-NETs.

The clinical trial involves the administration of several treatments, including **SANDOSTATIN LAR** in three different dosages: 10 mg, 20 mg, and 30 mg. Each formulation is provided as a **powder and solvent for suspension for injection**. The active substance in these formulations is **octreotide**, a protein-based compound. The suspension is administered via **intramuscular use**. The maximum daily dose for each formulation is 60 mg, with a total maximum dose of 1950 mg over a treatment period of up to 136 days. The product is relabeled with a clinical trial sticker for identification purposes.

Another treatment used in the trial is **LysaKare 25 g/25 g solution for infusion**, which contains the active substances **L-lysine hydrochloride** and **L-arginine hydrochloride**, both of which are chemical compounds. This solution is administered **intravenously**. The maximum daily dose is one dosage form, with a total maximum of eight dosage forms over a treatment period of up to 48 days. The product is also relabeled with a clinical trial sticker.

The primary experimental medication in the trial is **Lutathera 370 MBq/mL solution for infusion**, containing the active substance **lutetium (177Lu) oxodotreotide**, a chemical compound. This solution is administered via **intravenous use**. The maximum daily dose is 7.4 GBq, with a total maximum dose of 59.2 GBq over a treatment period of up to 48 days. Lutathera is designated as an orphan drug and is relabeled with a clinical trial label for the study.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression Free Survival (PFS)**. This endpoint is defined as the time from randomization to the first line progression or death due to any cause, as centrally assessed according to RECIST 1.1 criteria. Secondary endpoints include the Overall Response Rate (ORR), which is the rate of patients achieving a best overall response of partial response (PR) or complete response (CR), also assessed according to RECIST 1.1. Additionally, the trial will evaluate the Time to Decline (TTD) by 10 points from baseline in scores measured by the EORTC QLQ-C30 questionnaire, specifically focusing on global health status, diarrhea, fatigue, and pain.

The trial is designed to demonstrate the superiority of Lutathera over an active comparator in delaying the time-to-first occurrence of progression or death as a first-line treatment for patients with Grade 2 and Grade 3 advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET). The efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration, with the estimated end date set for October 31, 2027. The trial will employ validated scales and imaging modalities to ensure accurate and reliable assessment of the endpoints.