Phase II Evaluation of Cabozantinib in Advanced Low Proliferative Grade 3 Neuroendocrine Neoplasms

The primary objective of this phase II trial is to evaluate the **efficacy** of Cabozantinib treatment in patients with advanced, low proliferative neuroendocrine neoplasia (NEN) G3. This is clinically relevant as it aims to determine the therapeutic potential of Cabozantinib in managing this specific type of neuroendocrine tumor, which could lead to improved treatment strategies and outcomes for affected patients.

Secondary objectives include: - Evaluating the short- and long-term efficacy of Cabozantinib treatment, which will provide insights into the duration and sustainability of the treatment's effects. - Evaluating exposure time to understand the pharmacokinetics and optimal dosing schedules. - Assessing quality-of-life during and after Cabozantinib treatment to determine the impact on patient well-being. - Assessing the general safety of Cabozantinib treatment to ensure that the benefits outweigh any potential risks associated with its use.

The clinical trial focuses on evaluating the efficacy of Cabozantinib treatment in patients diagnosed with **neuroendocrine neoplasia**. The study population includes male, female, and diverse patients aged 18 years and older, with no upper age limit specified. Participants are required to have a histologically confirmed diagnosis of neuroendocrine neoplasia and must meet specific health criteria, such as adequate platelet and white blood cell counts, liver and kidney function, and a performance status of ECOG 0-2. The trial does not include a vulnerable population. Participants must have a life expectancy of more than three months and at least one measurable tumor lesion as determined by CT or MRI scans. The sponsor has not provided information regarding the total number of participants in the trial. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial population was selected based on their ability to understand and comply with trial procedures, and all participants provided written informed consent according to international guidelines and local laws.

The clinical trial is designed to evaluate the efficacy of **cabozantinib** in patients with advanced, low proliferative neuroendocrine neoplasia (NEN) G3. This is a phase II, randomized, double-blind, controlled trial. The trial is expected to last until March 31, 2026, with recruitment having commenced on December 29, 2021. Participants will be administered **cabozantinib** in the form of film-coated tablets, with dosages of 20 mg, 40 mg, or 60 mg, taken orally. The maximum treatment period is 27 weeks.

The sequence of study visits includes an initial screening visit to confirm eligibility based on specific inclusion criteria, such as a histologically confirmed diagnosis of neuroendocrine neoplasia, adequate organ function, and a performance status of ECOG 0-2. Following the screening, participants will undergo regular follow-up visits to monitor treatment response and safety. These visits will assess primary endpoints, including the disease control rate at 6 months, and secondary endpoints, such as progression-free survival and overall survival. The end-of-study visit will conclude the participant's involvement, evaluating the overall treatment efficacy and safety profile.

Participant involvement is expected to last for the duration of the treatment period, with additional follow-up assessments extending up to 15 months post-treatment. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial aims to provide comprehensive data on the therapeutic potential of **cabozantinib** in this patient population, contributing to the understanding of its efficacy and safety in treating advanced neuroendocrine neoplasia.

The clinical trial involves the administration of **CABOMETYX** in three different dosages: 20 mg, 40 mg, and 60 mg, all in the form of film-coated tablets. The active substance in these tablets is **cabozantinib**, a chemical compound also known by its synonyms XL-184 and Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide. The tablets are manufactured by IPSEN PHARMA and are authorized for use in the European Union. The administration route for all dosages is oral, with a maximum daily dose corresponding to the tablet strength: 20 mg, 40 mg, or 60 mg. The treatment period for each dosage is up to 27 days.

In this trial, the 20 mg film-coated tablet of CABOMETYX is administered orally with a maximum daily dose of 20 mg. The pharmaceutical form is a film-coated tablet, ensuring ease of administration and patient compliance. The treatment duration is set for a maximum of 27 days, during which participant compliance will be monitored through regular assessments.

The 40 mg film-coated tablet of CABOMETYX is similarly administered orally, with a maximum daily dose of 40 mg. The treatment period remains consistent at 27 days. The pharmaceutical form and administration route are designed to optimize the therapeutic efficacy of **cabozantinib** while maintaining patient adherence to the dosing schedule.

The 60 mg film-coated tablet of CABOMETYX is also administered orally, with a maximum daily dose of 60 mg. The treatment duration is up to 27 days, aligning with the other dosages in the study. The consistent pharmaceutical form and administration route across all dosages facilitate a standardized approach to evaluating the efficacy of **cabozantinib** in patients with advanced, low proliferative neuroendocrine neoplasms (NEN) G3.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial. The focus remains on assessing the efficacy of CABOMETYX in its various dosages. Participant compliance will be monitored through scheduled visits and assessments to ensure adherence to the dosing regimen and to evaluate the therapeutic outcomes effectively.

The efficacy of Cabozantinib in the treatment of advanced, low proliferative neuroendocrine neoplasia (NEN) G3 will be assessed in this phase II clinical trial. The primary endpoint for evaluating efficacy is the **Disease Control Rate (DCR)**, which will be measured 6 months after the start of treatment. This includes the sum of Complete Response (CR), Partial Response (PR), and Stable Disease (SD) rates. Secondary endpoints include the DCR at 3 and 12 months, Objective Response Rate (ORR) at 3 months and the best ORR, Progression-Free Survival (PFS), Overall Survival (OS), and Time on Drug (TOD). Additionally, the EORTC QLQ-C30 Quality of Life Questionnaire will be administered monthly for 12 months and again after 15 months to assess patient-reported outcomes.

Data collection will occur at specified intervals, with efficacy parameters being measured through imaging techniques such as CT or MRI scans, in accordance with RECIST criteria 1.1. The trial will also monitor serious adverse events and adverse events, with oversight by a Data Safety Monitoring Board (DSMB). The trial is expected to conclude by March 31, 2026, with recruitment having started on December 29, 2021. The maximum treatment period for participants is set at 27 weeks.