Phase II Multicenter Study of Metronomic Temozolomide in Clinically Frail Patients with Advanced Well-Differentiated Neuroendocrine Neoplasms

The primary objective of this study is to evaluate **progression-free survival (PFS)** in patients with well-differentiated neuroendocrine neoplasms (NENs) who are not eligible for active antitumoral treatments due to their clinical conditions. This is clinically relevant as it aims to determine the efficacy of metronomic Temozolomide in prolonging the time patients live without disease progression, which is crucial for improving patient management and treatment outcomes in this population.

Secondary objectives include: - **Objective response rate (ORR)**, defined as the sum of complete response (CR) and partial response (PR) in progressive, metastatic, low-grade NENs. - **Duration of response**, which assesses the length of time the tumor remains responsive to treatment. - **Overall survival (OS)**, measuring the time from treatment initiation to death from any cause. - **Safety**, evaluating the adverse effects associated with the treatment. - **Quality of life (QoL)**, assessing the impact of treatment on patients' overall well-being. - Centralized evaluation of **O6-methylguanine-DNA-methyltransferase (MGMT) status** in tumor tissue to correlate clinical outcomes with MGMT status and validate the method of MGMT determination.

The clinical trial involves **patients** diagnosed with well-differentiated neuroendocrine neoplasia (NENs) who are not eligible for active antitumoral treatments due to their clinical conditions. The study population includes both male and female participants, aged over 18 years, with a histologically proven diagnosis of low-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), bronchial carcinoids, or low-grade NENs of unknown primary sites. Participants exhibit advanced disease, either unresectable locally advanced or metastatic, and have an Eastern Cooperative Oncology Group (ECOG) performance status of 2, alongside moderate medullary impairment, renal failure, moderate liver failure, severe comorbidities, or a history of more than three prior systemic antitumor therapies. The trial includes individuals with both functioning and non-functioning tumors, who demonstrate clinical and/or radiological progressive disease. Participants must have recovered from toxicities related to any prior treatments and have an adequate wash-out period from previous treatments. The ability to swallow pills is required, and fertile men must agree to use effective contraceptive methods up to six months after the last temozolomide intake. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy and safety of **temozolomide** in patients with well-differentiated neuroendocrine neoplasia (NENs) who are not eligible for active antitumoral treatments due to their clinical conditions. The primary objective is to assess progression-free survival (PFS), with secondary endpoints including objective response rate (ORR), duration of response, overall survival (OS), safety, quality of life (QoL), and the correlation of clinical outcomes with O6-methylguanine-DNA-methyltransferase (MGMT) status in tumor tissue. The trial is expected to last until June 2025, with recruitment having commenced in January 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18 years, histologically proven diagnosis of low-grade NENs, advanced disease status, and ability to swallow pills. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse effects. The end-of-study visit will conclude the trial for each participant, assessing the final outcomes and collecting data for analysis.

The expected length of participant involvement is up to 12 months, corresponding to the maximum treatment period with **temozolomide**. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent by the participant. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **temozolomide**, an experimental medication, to evaluate its efficacy in patients with advanced neuroendocrine neoplasms. **Temozolomide** is provided in the form of a hard capsule, intended for **oral use**. The active substance, **temozolomide**, is of chemical origin. The dosing regimen for this trial specifies a maximum daily dose of 60 mg, with a cumulative maximum total dose of 21,900 mg over the course of the treatment period. The treatment duration is set for a maximum of 12 months. Participants are required to adhere to the dosing schedule as prescribed, and compliance will be monitored throughout the study.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on the administration of **temozolomide** to assess its impact on progression-free survival in the target patient population. The trial does not include any pediatric formulations, and the medication is not classified as an orphan drug. Participants' adherence to the dosing schedule will be closely monitored to ensure the integrity of the study data.

Efficacy in the clinical trial titled "An Italian multicenter phase II trial of Metronomic Temozolomide in unfit patients with advanced neuroendocrine neoplasms (NENs): MeTe study" will be primarily assessed through **Progression Free Survival (PFS)**. This endpoint will measure the length of time during and after the treatment that a patient lives with the disease without it getting worse. Secondary endpoints include the **Objective Response Rate (ORR)**, which encompasses complete response (CR) and partial response (PR) in progressive, metastatic, low-grade NENs, as well as the **Duration of Response**, **Overall Survival (OS)**, **Safety**, and **Quality of Life (QoL)**. Additionally, a centralized evaluation of **O6-methylguanine-DNA-methyltransferase (MGMT)** status in tumor tissue will be conducted to correlate clinical outcomes with MGMT status and validate the method of MGMT determination.