Leflunomide Treatment for MEN1 Patients - the LUMEN1 Trial (LUMEN1)

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder due to mutations in the tumor suppressor gene MEN1 with the corresponding gen product menin. MEN1 is characterized by the occurrence of parathyroid, pancreatic islet and anterior pituitary tumors which can release excessive amounts of hormones (= functional active tumors). Other tumors (e.g. carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas, collagenomas, lipomas) have also been described. There is no geno-phenotype correlation but the disease occurs after a second hit of the corresponding gene within the endocrine organ leading to an uncontrolled growth.

MEN1-patients have a decreased life expectancy, mainly due to pancreatic neuroendocrine tumors (pNETs) which are often multiple and more aggressive than in non-MEN1 patients. To date, no prophylactic treatment exists to prevent tumor development in this hereditary disease.

Leflunomide has been used as a treatment for rheumatoid arthritis for many years. It is a potent inhibitor of the dihydroorotate dehydrogenase (DHODH). According to some preclinical studies, leflunomide showed antineoplastic activities in several malignancies, including prostate, breast, bladder, multiple myeloma, leukemia, and lymphoma. A recent study identified an interaction between MEN1 mutation and DHODH inhibition. In this study, leflunomide selectively killed MEN1 deficient cells in vitro, prevented the occurrence of pancreatic tumor development in xenograft models and led to tumor regression / stabilisation in three MEN1 patients with advanced aggressive pancreatic neuroendocrine tumors.

Accordingly, leflunomide could be used as a new treatment option for patients with known MEN1 germline mutation and associated endocrine disease. The aim of this study is, therefore, to evaluate the antitumor effect of leflunomide treatment on MEN1-associated tumors in patients with known MEN1-syndrome.

Study Overview

• Status: Recruiting
• Conditions: MEN1 Gene Mutation
• Intervention / Treatment: Drug: Leflunomide 20 mg

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Julie Refardt, MD; Phone Number: +41615565618; Email: julie.refardt@usb.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4053
    • Recruiting
    • Unispital Basel
    • Contact: Julie Refardt; Phone Number: +41615565618; Email: julie.refardt@usb.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult (≥18 years) patients with known pathogenic or likely pathogenic MEN1-germline mutation and at least 1 associated tumor lesion OR hormonal syndrome

Exclusion Criteria:

• uncontrolled arterial hypertension, defined as blood pressure >160/100 mmHg
• Impaired kidney function, defined as creatinine clearance <50ml/min
• Impaired liver function, defined as bilirubin or liver transaminases >3 times upper normal range
• Cytopenia, defined as one or several of the following: hemogloin <100 g/l, leucopenia <2x109/l, thrombocytopenia <100x109/l

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Leflunomide 20mg	Drug: Leflunomide 20 mg; once daily for 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary outcome is the effect of a 6 months' treatment with leflunomide 20mg/day on MEN1-associated functional and non-functional tumors	6 months

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2023
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: November 1, 2022
• First Submitted That Met QC Criteria: November 1, 2022
• First Posted (Actual): November 4, 2022

Study Record Updates

• Last Update Posted (Estimated): June 2, 2023
• Last Update Submitted That Met QC Criteria: May 31, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Endocrine System Diseases; Endocrine Gland Neoplasms; Genetic Diseases, Inborn; Neoplastic Syndromes, Hereditary; Neoplasms, Multiple Primary; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type 1; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Leflunomide
• Other Study ID Numbers: LUMEN1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No