Metronomic Temozolomide in Unfit NENs Patients Metronomic Temozolomide in Unfit Patients With Advanced Neuroendocrine Neoplasms (NENs): MeTe Study

Study design and trial duration This is an italian multicenter phase II trial of metronomic temozolomide in unfit patients with advanced NENs. The accrual will last 1-year and the follow up 2-year for a global 3-year period.

Objectives Primary endpoint Progression free survival (PFS).

Secondary endpoint Overall response rate (ORR) Duration of response (DOR) Overall survival (OS) Safety Quality of life (QoL)

Exploratory endpoint To evaluate O6 methylguanine DNA methyltransferase (MGMT) status in tumor tissue to validate the methods of MGMT determining and correlation with clinical outcomes

Overview on the study design Prospective analyses of consecutively NEN patients treated at Istituto Europeo di Oncologia IRCCS and participant centers between the end of 2021 and 2024 will be conducted. All patients who potentially benefit by these therapies will be proposed to participate to the study. The patient notes will then be assessed for eligibility as defined in the next section.

Treatment drug and schedule The regimen consists of oral temozolomide 60 mg once daily fasting continuously (28-day cycles)

Inclusion criteria

• Age > 18 years.
• Histologically proven diagnosis of low grade GEP-NENs (including morphology and ki67 in accordance with WHO 2019 classification), bronchial carcinoids (in accordance with the Travis classification), low grade of unknown primary sites NENs.
• Advanced disease (unresectable locally advanced or metastatic).
• ECOG performance status 2 and/or moderate medullary impairment (at least one of the following criteria: Hb concentration <10-8 gr/dl; WBC <3000-2000/mm3; platelets <75000-50000/mm3; neutrophil count <1500-1000/mm3); renal failure (eGFR o CrCl 30-59 ml/min - G2) and/or moderate liver failure (Child B 7-9) and/or severe comorbidities and/or > 3 prior systemic antitumor therapies (apart from SSA).

For all the parameters other than the above mentioned criteria n° 4 consider the following criteria (that must be associated with at least one of those above): absolute neutrophil count of ≥1.5×109/L, platelet count of ≥100×109/L, haemoglobin ≥9 g/dL, serum total bilirubin <1.5 times the upper limit of normal (ULN) alanine aminotransferase (ALT), AST, or alkaline phosphatase levels ≤2.5 times the ULN (if known liver metastases ALT, AST, and ALP ≤3× the ULN), serum creatinine <1.5 times ULN or creatinine clearance ≥60 mL/min as estimated by the Cockcroft-Gault formula

• Functioning/non functioning.
• Morphological progressive disease (CT scan or MRI).
• Recovery from toxicities related to any prior treatments, adequate wash-out period from previous treatments.
• Ability to swallow pills.
• Fertile men should agree to use effective contraceptive methods up to 6 months after the last temozolomide intake and should be informed about the possible irreversible infertility related to temozolomide intake.

Exclusion criteria

• Patients pretreated with temozolomide.
• Are Women of Child-Bearing Potential (WOCBP) and men who are able to father a child, unwilling to use adequate contraception prior to trial entry, for the duration of trial participation and for at least 28 days 2 weeks after treatment has ended. Adequate methods of contraception and Women of Child-Bearing Potential; WOCBP childbearing potential who are nursing or are pregnant or do not agree to submit to pregnancy testing required by this protocol
• Patients that did not sign written informed consent prior to admission into the trial that is consistent with International Conference on Harmonisation (ICH)- Good Clinical Practice (GCP) guidelines and local law
• Knowed active hepatitis B infection (defined as presence of Hepatitis B (HepB) sAg and/or HepB DNA), active Hepatitis C (HEP C) infection (defined as presence of Hep C RNA) and/or known Human Immunodeficiency Virus (HIV) carrier.
• Patients treated with systemic therapies (chemotherapy, interferon-alpha, somatostatin analogues, molecular target therapies) within 1 month prior to screening visit
• Hypersensitivity to the active substance or to any of the excipients, hypersensitivity to dacarbazine (DTIC), known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before study entry, pregnant or lactating females, patients on chronic treatment with valproic acid