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

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

NCT ID: NCT05554003

Condition: Neuroendocrine Tumors
Frailty
Chemotherapy Effect

Conditions: Official terms:
Neoplasms
Neuroendocrine Tumors
Frailty
Temozolomide

Conditions: Keywords:
Temozolomide
Neuroendocrine tumors
NETs
NENs
Unfit
Chemotherapy
Metronomic
Advanced
Phase II
Open label

Study type: Interventional

Study phase: Phase 2

Overall status: Recruiting

Study design:

Allocation: N/A

Intervention model: Single Group Assignment

Intervention model description: Open label

Primary purpose: Treatment

Masking: None (Open Label)

Intervention:

Intervention type: Drug
Intervention name: Temozolomide capsule
Description: Metronomic temozolomide 60 mg/die continuously
Arm group label: Metronomic Temozolomide

Summary: 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.

Detailed description: 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)

Criteria for eligibility:
Criteria:
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

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Locations:

Facility:
Name: European Institute of Oncology, IEO, IRCCS

Address:
City: Milan
Zip: 20141
Country: Italy

Status: Recruiting

Contact:
Last name: Darina Tamayo, PharmSc.

Phone: +39(0)294372686
Email: darina.tamayo@ieo.it

Contact backup:
Last name: Cristina Mazzon, Ph.D.

Phone: +39(0)294372686
Email: cristina.mazzon@ieo.it

Investigator:
Last name: Francesca Spada, MD, PhD
Email: Principal Investigator

Investigator:
Last name: Manila Rubino, MD
Email: Sub-Investigator

Start date: January 14, 2022

Completion date: December 31, 2024

Lead sponsor:
Agency: European Institute of Oncology
Agency class: Other

Source: European Institute of Oncology

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT05554003
https://www.ieo.it/it/PER-I-PAZIENTI/Sperimentazioni-cliniche/Sperimentazioni-cliniche/?title=MeTe&pathology=&division=&active=False
https://www.ieo.it/it/PNA/Trova-Medico/?name=spada