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

Study design and rationale: Neuroendocrine neoplasms (NENs ) represent a heterogeneous group of malignancies, which differ in terms of behavio r and prognosis. Most of t hem are advanced at diagnosis t herefore systemic treatment is proposed. While over the last years many advanced have been made especially in terms of molecular targeted therapies (MTA) like everolimus and sunitinib, chemotherapy i n NENs still represents a controversial question. Temozolomide has been reported to be active alone or in combination with other drugs in neuroendocrine neoplasms (NENs) from different origin. So far there is not universal agreement on the right setting an d way of administration of this therapy. Objective: This is a multicentric phase II prospective interventional study to evaluate the clinical features of patients, who are judged unfit for systemic treatments, consecutively treated with a metronomic Temozolomide chemotherapy schedule in Italian centers with expertise in NEN and to explore also the methylation status of O6-methylguanine-DNA-methyltransferase (MGMT) and the polymorphism of thymidylate synthase (TS) by pyrosequencing in those patients of which tissues were available. This study will allow a better understanding of the role of metronomic temozolomide chemotherapy in NENs patients and help clinicians in answering some of the outstanding questions on their management. Method: Prospective analysis of clinical data of patients unfit for chemotherapy consecutively treated with metronomic temozolomide regimen in Italian centers with expertise in clinical and research NEN activity, for one year from the start of the accrual. Planning of study: Data from NENs patients of any age treated at these centers will be retrieved by searching the hospital information system and analysed. Eligible study population: Patients with histological diagnosis of low grade advanced NEN treated unfit for systemic treatments, for one year from the start of the accrual. Endpoints and evaluation parameters: Description of efficacy and toxicity of Temozolomide regimen in patients with advanced NENs with different primary sites unfit for systemic treatment and explored the pote ntial correlation with clinical/biological factors.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

1. Age \> 18 years.
2. 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.
3. Advanced disease (unresectable locally advanced or metastatic).
4. 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
5. Functioning/non functioning.
6. Morphological progressive disease (CT scan or MRI).
7. Recovery from toxicities related to any prior treatments, adequate wash-out period from previous treatments.
8. Ability to swallow pills.
9. 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:

1. Patients pretreated with temozolomide.
2. 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
3. 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
4. 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.
5. Patients treated with systemic therapies (chemotherapy, interferon-alpha, somatostatin analogues, molecular target therapies) within 1 month prior to screening visit
6. 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

• RESULTLambrescu I, Fica S, Martins D, Spada F, Cella C, Bertani E, Rubino M, Gibelli B, Grana C, Bonomo G, Funicelli L, Ravizza D, Pisa E, Zerini D, Ungaro A, Fazio N; IEO ENETS Center of Excellence for GEP NET. Metronomic and metronomic-like therapies in neuroendocrine tumors - Rationale and clinical perspectives. Cancer Treat Rev. 2017 Apr;55:46-56. doi: 10.1016/j.ctrv.2017.02.007. Epub 2017 Feb 24. PMID 28314176
• RESULTKoumarianou A, Kaltsas G, Kulke MH, Oberg K, Strosberg JR, Spada F, Galdy S, Barberis M, Fumagalli C, Berruti A, Fazio N. Temozolomide in Advanced Neuroendocrine Neoplasms: Pharmacological and Clinical Aspects. Neuroendocrinology. 2015;101(4):274-88. doi: 10.1159/000430816. Epub 2015 Apr 29. PMID 25924937
• RESULTWeller M, Tabatabai G, Kastner B, Felsberg J, Steinbach JP, Wick A, Schnell O, Hau P, Herrlinger U, Sabel MC, Wirsching HG, Ketter R, Bahr O, Platten M, Tonn JC, Schlegel U, Marosi C, Goldbrunner R, Stupp R, Homicsko K, Pichler J, Nikkhah G, Meixensberger J, Vajkoczy P, Kollias S, Husing J, Reifenberger G, Wick W; DIRECTOR Study Group. MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial. Clin Cancer Res. 2015 May 1;21(9):2057-64. doi: 10.1158/1078-0432.CCR-14-2737. Epub 2015 Feb 5. PMID 25655102