Continuing Somatostatin Analogues Upon progression in Neuroendocrine tumour pAtients (SAUNA trial)

The primary objectives of the SAUNA trial are to evaluate the difference in **progression-free survival (PFS)** per substudy between patients continuing or stopping somatostatin analogues (SSA), as assessed by blinded local radiologists using the Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 framework, after initiating second-line therapy with peptide receptor radionuclide therapy (PRRT) in substudy 1 or targeted therapy in substudy 2. Additionally, the trial aims to assess the difference in time to deterioration (TTD) after initiating second-line therapy per substudy, defined as the time from randomization to the first decrease from baseline on the Global Health component of the EORTC QLQ-C30 questionnaire by at least 10 points, with no further increase above this threshold, or death. These objectives are clinically relevant as they provide insights into the efficacy of continuing SSA in patients with **neuroendocrine tumours** undergoing second-line treatments.

The secondary objectives include:

• Assessing PFS according to RECIST 1.1 at 18 months per substudy.
• Evaluating the difference in pooled PFS and TTD of both substudies.
• Assessing overall survival (OS) per substudy and pooled over both substudies.
• Evaluating response rates per substudy and pooled over both substudies.
• Assessing quality of life.
• Evaluating cost-effectiveness.
• Assessing toxicity.
• Analyzing relevant biomarkers in a subset of subjects as an exploratory objective.

The clinical trial involves participants diagnosed with **neuroendocrine tumours**, specifically focusing on those with a histologically-proven diagnosis of locally advanced or metastatic, non-functional, well-differentiated WHO 2019 grade 1–2 gastroenteropancreatic neuroendocrine tumors (GEP NET). The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Participants must have documented radiological disease progression on first-line somatostatin analog (SSA) treatment. The trial does not include vulnerable populations. The selection criteria require participants to have an indication to start second-line therapy, either with peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE or targeted therapy with sunitinib or everolimus, as determined by local investigators. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations.

The clinical trial is designed to evaluate the efficacy of continuing somatostatin analogues in patients with **neuroendocrine tumours** who have shown progression on first-line treatment. This is a phase 4, randomized, double-blind, controlled trial with an estimated duration extending until April 2034. The trial is divided into two substudies: one focusing on peptide receptor radionuclide therapy (PRRT) and the other on targeted therapy. The primary objectives are to assess progression-free survival (PFS) and time to deterioration (TTD) in patients continuing or stopping somatostatin analogues, evaluated through blinded local radiologists using the RECIST 1.1 framework.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age (≥18 years), ECOG performance status (≤2), and documented disease progression. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and collecting data on overall survival, quality of life, and cost-effectiveness.

The expected length of participant involvement is up to 24 months, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or investigator decision based on clinical judgment. The trial employs a robust methodology to ensure the reliability and validity of the findings, contributing valuable insights into the management of neuroendocrine tumours.

The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in patients with neuroendocrine tumors. **Octreotide** is administered as a prolonged-release suspension for injection. The active substance, octreotide, is a protein-based compound. The medication is delivered via **intramuscular injection** with a maximum daily dose of 30 mg. The treatment period for octreotide is up to 18 months, and participant compliance is monitored through regular assessments.

**Lanreotide** is provided as a solution for injection, with the active substance being lanreotide. This medication is administered through **subcutaneous injection**. The maximum daily dose is 120 mg, and the treatment duration is also up to 18 months. Compliance is ensured by scheduled follow-ups and dose adjustments as necessary.

**Everolimus** is administered in tablet form, with the active substance being a chemical compound known as everolimus. The route of administration is **oral**, with a maximum daily dose of 10 mg. The treatment period extends to 18 months, and adherence is monitored through pill counts and patient diaries.

**Sunitinib** is provided as a hard capsule, containing the chemical active substance sunitinib. This medication is also administered **orally**, with a maximum daily dose of 37.5 mg. The treatment duration is up to 18 months, with compliance monitored through regular clinical visits and patient self-reports.

**Lutetium (177Lu) oxodotreotide** is administered as a solution for infusion, with the active substance being a chemical compound. The route of administration is **intravenous infusion**, with a maximum dose of 370 MBq/ml. The treatment period for this medication is up to 24 months. Compliance is monitored through infusion records and patient follow-up appointments.

In addition to the experimental medications, standard-of-care therapies may be used as comparator treatments, depending on the specific substudy within the trial. Participant adherence to dosing schedules is critical and is closely monitored through various compliance measures, including patient logs and clinical assessments.

The efficacy of the clinical trial titled "Continuing Somatostatin Analogues Upon progression in Neuroendocrine tumour pAtients (SAUNA trial)" will be assessed using several primary and secondary endpoints. The primary endpoints include the difference in **progression-free survival (PFS)** between patients continuing or stopping somatostatin analogues (SSA) after initiating peptide receptor radionuclide therapy (PRRT) or targeted therapy. This will be evaluated by blinded local radiologists using cross-sectional imaging, with progression defined according to the Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 standardized framework. Additionally, the difference in time to deterioration (TTD) will be assessed, defined as the time from randomization to the first decrease from baseline on the Global Health component of the EORTC QLQ-C30 questionnaire by at least 10 points, with no further increase above this threshold, or death.

Secondary endpoints include the PFS rate according to RECIST 1.1 at 18 months per substudy, the difference in pooled PFS and TTD of both substudies, overall survival per substudy and pooled over both substudies, response rates per substudy and pooled over both substudies, quality of life (QoL), cost-effectiveness, and toxicity. These efficacy parameters will be measured and collected at specified timepoints throughout the trial, with the primary focus on the 18-month mark for PFS rate evaluation. The trial is designed to provide comprehensive data on the efficacy of continuing SSA treatment in patients with neuroendocrine tumors, with a planned completion date in 2034.