Evaluation of Cabozantinib and Avelumab Combination Therapy in Advanced Neuroendocrine Neoplasias G3 Refractory to Standard Chemotherapy

The primary objective of this phase II, open-label, multicenter trial is to assess the **clinical activity** of the combination therapy of **Cabozantinib** with **Avelumab** in comparison to monotherapy with Avelumab in patients with progressive **Neuroendocrine Neoplasias G3 (NEN G3)** after standard chemotherapy. The primary endpoint is the disease control rate (DCR) according to iRECIST after 16 weeks from the start of treatment until documented disease progression. This evaluation is clinically relevant as it aims to determine the efficacy of the combination therapy in controlling disease progression in a patient population that is refractory to standard treatments.

Secondary objectives include evaluating the following:

• Objective response rate (ORR)
• Duration of disease control (DDC)
• Best overall response (BOR)
• Progression-free survival time (PFS)
• Overall survival (OS)
• Quality of life (QoL)
• Safety and tolerability
• Correlation of subclassification of the NEN G3 (NET G3 vs NEC) and tumor immune microenvironment with tumor response
• Comparison of the efficacy and tolerability of the combination therapy to monotherapy in the AveNEC trial and evaluation of tumor growth rate (TGR)

The clinical trial involves participants diagnosed with **advanced neuroendocrine neoplasias G3** (NEN G3), excluding small cell lung cancer (SCLC) and Merkel cell carcinomas. The study population includes both male and female subjects aged 18 years and older. Participants are required to have histologically confirmed NEN G3, with progression after at least one chemotherapy regimen. The trial population was selected based on the presence of measurable disease according to RECIST1.1 criteria, adequate organ and bone marrow function, and an ECOG Performance Status of 0 to 1. The study does not provide specific information on the total number of participants, as this data was not disclosed by the sponsor. Participants must have no curative options available and must provide written informed consent. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **phase II**, open-label, multicenter study to evaluate the clinical activity and safety of the combination therapy of **cabozantinib** and **avelumab** in patients with advanced neuroendocrine neoplasias G3 (NEN G3) who are refractory to standard chemotherapy. The trial aims to compare the combination therapy to monotherapy with avelumab, with the primary endpoint being the disease control rate (DCR) according to iRECIST after 16 weeks from the start of treatment until documented disease progression. The trial is expected to run from February 28, 2022, to February 28, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of NEN G3, progression after chemotherapy, and adequate organ function. Following the screening, participants will receive treatment and attend follow-up visits every 8 weeks for the first 6 months, and every 12 weeks thereafter, to assess tumor response and monitor safety. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 12 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The study will utilize **oral** administration of cabozantinib in the form of film-coated tablets and **intravenous** administration of avelumab as a solution for infusion. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the results, contributing valuable data to the understanding of treatment options for advanced NEN G3.

The clinical trial involves the administration of **CABOMETYX** in two different dosages as part of the experimental treatment. **CABOMETYX 20 mg film-coated tablets** contain the active substance **cabozantinib**, a chemical compound also known by the synonyms XL-184 and Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide. The pharmaceutical form is a film-coated tablet, and the medication is administered orally. The maximum daily dose is 20 mg, with a total maximum dose of 7300 mg over a treatment period of up to 12 months. The product is manufactured by IPSEN PHARMA and is authorized for use in the European Union.

Another dosage form used in the trial is **CABOMETYX 40 mg film-coated tablets**, which also contain **cabozantinib** as the active ingredient. This formulation is similarly administered orally, with a maximum daily dose of 40 mg and a total maximum dose of 14600 mg over a 12-month period. Like the 20 mg tablets, this product is produced by IPSEN PHARMA and holds authorization in the European Union.

The trial also includes the administration of **Avelumab**, a **solution for infusion** containing the active substance **avelumab**, a protein-based compound. The solution is administered intravenously, with a maximum daily dose of 800 mg and a total maximum dose of 19200 mg over a 12-month period. Avelumab is manufactured by MERCK HEALTHCARE KGAA and is identified by the sponsor product code MSB0010718C. This product is also authorized for use in the trial.

Throughout the trial, participant compliance with the dosing schedule is monitored to ensure adherence to the prescribed treatment regimen. The trial aims to assess the clinical activity and safety of the combination therapy of **cabozantinib** with **avelumab** in patients with advanced neuroendocrine neoplasias G3 (NEN G3) who are refractory to standard chemotherapy.

The efficacy of the combination therapy of Cabozantinib and Avelumab in patients with advanced **Neuroendocrine Neoplasias G3 (NEN G3)** will be assessed primarily through the **disease control rate (DCR)** according to iRECIST criteria. This primary endpoint will be evaluated after 16 weeks from the start of treatment until documented disease progression. Tumor assessments will be conducted every 8 weeks for the first 6 months and every 12 weeks thereafter.

Secondary endpoints include the DCR at weeks 8, 24, and 48, objective response rate (ORR), best overall response (BOR), duration of disease control (DDC), time to response (TTR), progression-free survival (PFS), and overall survival (OS). Additionally, tumor response will be evaluated according to RECIST 1.1 criteria. Quality of life (QoL) will be assessed using the EORTC QLQ-C30 questionnaire. The number, severity, and duration of treatment-emergent adverse events (AEs) will be recorded according to NCI-CTCAE v5.0, along with any dose reductions or treatment interruptions due to AEs.