Efficacy and Safety Evaluation of [177Lu]Lu-DOTA-TATE and Octreotide LAR in Grade 1 and 2 Advanced Gastroenteropancreatic Neuroendocrine Tumors

The primary objective of this study is to demonstrate that **[177Lu]Lu-DOTA-TATE** plus octreotide LAR is superior to an active comparator in delaying the time-to-first occurrence of progression or death (PFS) as a first-line treatment in patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET). This is clinically relevant as it aims to improve progression-free survival, a critical endpoint in the management of advanced GEP-NET, potentially offering a more effective therapeutic option for patients.

Secondary objectives include:

• To demonstrate the superiority of [177Lu]Lu-DOTA-TATE plus octreotide LAR over the active comparator in delaying time to deterioration (TTD) of Quality of Life (QoL).
• To evaluate the efficacy of [177Lu]Lu-DOTA-TATE plus octreotide LAR compared to the active comparator in terms of progression-free survival (PFS), objective response, disease control, and duration of response (DOR).
• To assess the safety and tolerability of [177Lu]Lu-DOTA-TATE plus octreotide LAR compared to the active comparator.
• To evaluate the effect of [177Lu]Lu-DOTA-TATE plus octreotide LAR on overall survival (OS) and quality of life (QoL) as assessed by EORTC QLQ-G.I.NET21, EORTC QLQ-C30, and EQ-5D-5L.
• To evaluate the dosimetry and pharmacokinetics (PK) of [177Lu]Lu-DOTA-TATE at selected cycles in a subset of participants.

The clinical trial involves a total of **141 participants** diagnosed with **gastroenteropancreatic neuroendocrine tumors (GEP-NET)**. The study population includes both male and female subjects, with an age range starting from 12 years, although in certain countries such as Germany, Hungary, The Netherlands, and Poland, only adults aged 18 and above are enrolled. Participants were selected based on the presence of metastasized or locally advanced, unresectable, well-differentiated G1 or G2 GEP-NET, diagnosed within six months prior to screening. The trial includes individuals with a high disease burden, as determined by the investigator, and requires adequate bone marrow and organ function. The study population is characterized by a diverse range of ages and includes vulnerable populations. Participants' general health status is assessed through criteria such as ECOG performance status of 0-1 and the presence of at least one measurable site of disease. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, open-label, phase III study to evaluate the efficacy and safety of **[177Lu]Lu-DOTA-TATE** in patients with advanced **gastroenteropancreatic neuroendocrine tumors (GEP-NET)**. The primary objective is to demonstrate the superiority of [177Lu]Lu-DOTA-TATE plus **octreotide** LAR over an active comparator in delaying progression-free survival (PFS). The trial is expected to commence recruitment on July 29, 2025, and conclude by January 5, 2035.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as the presence of metastasized or locally advanced, unresectable GEP-NET, and adequate bone marrow and organ function. The trial will include multiple follow-up visits to monitor the participants' response to treatment and assess any adverse events. The end-of-study visit will evaluate the overall outcomes and safety of the treatment.

The expected duration of participant involvement is up to 149 weeks, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will employ a **double-blind** methodology for the assessment of primary and secondary endpoints, ensuring unbiased evaluation of treatment efficacy and safety.

Key secondary endpoints include time to deterioration, objective response rate, disease control rate, duration of response, overall survival, and the incidence and severity of adverse events. The study will also assess pharmacokinetic parameters and absorbed radiation dose in selected organs and tumor lesions. Participants will be monitored closely throughout the trial to ensure adherence to protocol and timely identification of any safety concerns.

The clinical trial involves the administration of several treatments, including **SANDOSTATIN LAR** in varying dosages. **SANDOSTATIN LAR** is available in 10 mg, 20 mg, and 30 mg formulations, each provided as a **powder and solvent for suspension for injection**. The active substance in these formulations is **octreotide**, a protein-based compound. The pharmaceutical form is a **suspension for injection**, administered via **intramuscular injection**. The maximum daily dose is 30 mg, with a total dose limit of 1110 mg over a treatment period of up to 149 days. This medication is manufactured by Novartis Ireland Limited.

Another experimental treatment in the trial is **Lutathera**, a **370 MBq/mL solution for infusion**. The active substance is **lutetium (177Lu) oxodotreotide**, a chemical compound. This solution is administered through **intravenous infusion**. The maximum daily dose is 200 mCi, with a total dose limit of 800 mCi over a 24-day treatment period. Lutathera is produced by Advanced Accelerator Applications and is designated as an orphan drug.

**LysaKare** is also used in the trial as a **25 g/25 g solution for infusion**. It contains **arginine hydrochloride** and **lysine hydrochloride** as active substances, both of which are chemical compounds. This solution is administered via **intravenous infusion**. The maximum daily dose is 25 g, with a total dose limit of 100 g over a 24-day treatment period. LysaKare is manufactured by Advanced Accelerator Applications and is relabeled with a clinical trial label by Fisher.

Additionally, the trial includes a non-experimental treatment involving **metoclopramide**, which is a combination of **dimeticone, metoclopramide hydrochloride, sodium hydrogen carbonate, tartaric acid, potassium citrate,** and **citric acid**. The pharmaceutical form and route of administration for this treatment are not specified. This treatment is categorized under the ATC code A03FA01, indicating its use in gastrointestinal disorders.

Lastly, the trial utilizes **octreotide acetate** as an auxiliary treatment. This substance is a protein-based compound administered via **subcutaneous injection**. The pharmaceutical form is not specified, and the treatment period can extend up to 149 days. This treatment is categorized under the ATC code H01CB02, similar to other octreotide formulations used in the trial.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from randomization to the first occurrence of disease progression or death from any cause, as assessed by a Blinded Independent Review Committee (BIRC) according to RECIST v1.1 criteria. Secondary endpoints include time to deterioration in specific domains of the EORTC QLQ-GI.NET21 and EORTC QLQ-C30 questionnaires, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and the incidence and severity of adverse events (AEs) and serious adverse events (SAEs).

Data collection will involve both investigator and central assessments, with specific timepoints for evaluation not explicitly detailed. The trial will utilize validated scales and questionnaires, such as the EORTC QLQ-GI.NET21 and EORTC QLQ-C30, to measure patient-reported outcomes related to gastrointestinal symptoms, fatigue, diarrhea, and global health. Additionally, pharmacokinetic parameters, including area under the curve (AUC), clearance, distribution volume, and half-life, will be derived from [177Lu]Lu-DOTA-TATE blood radioactivity data. The absorbed radiation dose in selected organs, tumor lesions, and the total body will also be measured to assess treatment impact.