Using metronomic temozolomide for patients with advanced neuroendocrine tumors who are unfit for standard treatments

An Italian Multicenter Phase II Trial of Metronomic Temozolomide in Unfit Patients With Advanced Neuroendocrine Neoplasms (NENs): MeTe Study

This study is testing if a continuous low-dose chemotherapy called metronomic temozolomide can help people with advanced neuroendocrine tumors who can't tolerate standard treatments feel better and live longer.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 46 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: European Institute of Oncology (Academic / other)
• Drugs / interventions: chemotherapy, sunitinib
• Locations: 1 site (Milan)
• Trial ID: NCT05554003 on ClinicalTrials.gov

What this trial studies

This phase II interventional study evaluates the effectiveness of metronomic temozolomide chemotherapy in patients with advanced neuroendocrine neoplasms (NENs) who are considered unfit for standard systemic treatments. Conducted across multiple Italian centers, the study aims to assess progression-free survival, overall response rate, and quality of life among participants. Patients will receive oral temozolomide continuously in 28-day cycles, and their clinical features will be analyzed to determine the therapy's impact. The study will also explore the correlation between MGMT status in tumor tissue and clinical outcomes.

Who should consider this trial

Good fit: Ideal candidates include adults over 18 with histologically confirmed low-grade NENs and advanced disease who are unfit for standard systemic treatments.

Not a fit: Patients with high-grade neuroendocrine tumors or those who are fit for standard chemotherapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could provide a new treatment option for patients with advanced NENs who are unable to tolerate conventional chemotherapy.

How similar studies have performed: While there have been studies on temozolomide in NENs, this specific metronomic approach in unfit patients is relatively novel and has not been extensively tested.

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

Where this trial is running

Milan

• European Institute of Oncology, IEO, IRCCS — Milan, Italy (Recruiting)

Study contacts

• Principal investigator: Francesca Spada, MD, PhD — European Institute of Oncology (IEO), IRCCS, Milan (Italy)
• Study coordinator: Francesca Spada, MD, PhD

Conditions Neuroendocrine Tumors; Frailty; Chemotherapy Effect; Temozolomide; Neuroendocrine tumors; NETs; NENs; Unfit