Momelotinib in VEXAS Syndrome

NCT07098936 | Recruiting Phase 2 DMC

• 1 other identifier: GFM-VEXAS-MMB
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 11

Brief Summary

Multicenter, phase II trial with safety run-in to evaluate the efficacy and safety of momelotinib in patients with VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory and Somatic) syndrome with or without associated myelodysplastic syndrome (MDS). The study will consist of two consecutive steps, a dose-finding safety run-in and a single-arm prospective phase II. During safety run-in phase, three fixed dose levels will be tested according to a 3+3 design, using cohorts of size 3 in order to establish the maximum tolerated dose. After this safety run-in phase, patients included in phase II will be treated with momelotinib at the maximum tolerated dose preliminary fixed. Patients included in the phase II will receive momelotinib continuously until disease progression or loss of response, at physician's discretion. All patients included in the study will receive glucocorticoids (prednisone/prednisolone equivalent) at baseline (at least \> 10mg/day). Response assessment regarding VEXAS related symptoms will be evaluated after 4, 12, 24 and 48 weeks. Response assessment regarding MDS features will be evaluated at 12 and 24 weeks.

Conditions

VEXAS Syndome; Myelo Dysplastic Syndrome

Keywords

VEXAS syndrome; Momelotinib; Myelodysplastic syndrome

Outcome Measures

Primary Outcomes (2)

• Determination of the maximum tolerated dose of momelotinib

  The maximum tolerated dose (MTD) is defined by a target dose-limiting toxicities (DLT) rate of 30%, assessed during the observation window by a 3+3 design. The 3+3 design will enroll a first cohort of 3 patients at the starting dose of 200 mg/d: * If 0 of the 3 patients at the dose of 200 mg/d experienced a DLT during the first 4-week cycle of momelotinib, the dose will escalate to 300 mg/d for the next cohort. * If 1 of the 3 patients at the dose of 200 mg/d has a DLT, a cohort of three additional patients will be treated at the same dose of 200 mg/d. * If \> 1 patient of the 3 patients at the dose of 200 mg/d have a DLT, the dose will de-escalate to 150 mg/d for the next cohort. The same process will be repeated until reaching the MTD. In total, between 6 and 18 patients will be enrolled during this safety run-in phase.

  First 4-week cycle of momelotinib treatment

• Clinical efficacy

  Determination of overall clinical response rate at 24 weeks after momelotinib initiation on VEXAS related symptoms (including complete (CR) or partial response (PR)) : * CR includes complete disappearance of symptoms related to systemic inflammation according to treating physician and daily dose of steroids ≤ 10 mg/d (equivalent prednisolone). * PR includes complete disappearance of symptoms related to systemic inflammation according to treating physician and reduction of at least 50% of daily dose steroids compared to baseline and/or daily dose of steroids \> 10 mg/d.

  During the 24 first weeks of momelotinib treatment

Secondary Outcomes (11)

• Pharmacokinetic

  At cycle 1 Day 8-9 and cycle 13 Day 8-9

• Incidence of Treatment-Emergent Adverse Events

  From enrollment to the end of treatment at 48 weeks

• Response

  After 4, 12, 24 and 48 weeks of momelotinib treatment

• Hematological response

  After 16 weeks of momelotinib treatment

• Steroids dose reduction

  After 24 weeks of momelotinib treatment

Other Outcomes (1)

• Validation of the VEXAS personal scoring system (VPSS)

  After 4, 12 and 24 weeks of momelotinib treatment

Study Arms (1)

Momelotinib treatment

EXPERIMENTAL

Patients will receive momelotinib.

Drug: Momelotinib treatment

Interventions

Momelotinib treatment DRUG

Patients included will receive momelotinib continuously until disease progression or loss of response, at physician's discretion.

Momelotinib treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ECOG (Eastern Cooperative Oncology Group) performance status 0-2 at the time of screening
• Age ≥ 18 years
• Written informed consent
• Diagnosis of VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory and Somatic) syndrome with UBA1 (Ubiquitin Like Modifier Activating Enzyme 1) mutation and clinically symptomatic disease requiring immunosuppressive treatment and at least 10mg/d of glucocorticoids
• Patients with uncontrolled symptoms related to VEXAS with prior treatment line(s) (including steroids)
• Patients refractory/dependent to steroids
• For patients treated with other immunosuppressive/immunomodulatory therapy than glucocorticoids, a wash out period of 28 days is required prior momelotinib onset
• Erythropoietin/luspatercept used as a growth factor treatment is not allowed 28 days prior enrollment
• Adequate liver function (serum transaminases ≤ 3 x ULN (Upper Limits of Normal), Bilirubin ≤ 1.5 x ULN (isolated bilirubin \> 1.5 x ULN is acceptable if bilirubin fractionated and direct bilirubin \< 35%)
• Adequate renal function (creatinine clearance with MDRD (Modification of Diet in Renal Disease) formula \> 30 ml/min)
• Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must:
• Have a negative serum or urine pregnancy test within 24 hours prior to beginning treatment on this study. Lactating patients are excluded.
• Agree to use, and to be able to comply with, effective contraception without interruption, 4 weeks before starting study drug throughout the entire duration study drug therapy (including doses interruptions) and for 12 weeks after the end of the study drug therapy.
• Agree to learn about the procedures for preservation of egg before starting treatment.
• Male patients must:

You may not qualify if:

• Patients with MDS (Myelodysplastic syndrome) scheduled for allogeneic stem cell transplant or high risk MDS according to IWG (International Working Group) 2023
• Patients who are or have been already treated with Janus Kinase (JAK) inhibitors for VEXAS syndrome or another indication
• Patients who are unable to receive a starting daily dose of momelotinib of at least 100 mg
• Subjects with any other active malignancies are not eligible, except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which subject has been disease-free for at least 3 years
• Uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 12 weeks prior to initiation of momelotinib
• Known infection with acute and chronic active Human Immunodeficiency Virus, Hepatitis B Virus, Hepatitis C Virus
• Any medical or psychiatric condition not allowing the informed consent of the subject
• Presence of clinically meaningful active bacterial, fungal, parasitic or viral infection which requires therapy
• Previous history of Progressive Multifocal Leuko-encephalopathy
• Active gastrointestinal conditions that may affect absorption
• No affiliation to a health insurance system
• Known hypersensitivity to the study investigational medicinal product, the metabolites, or formulation excipients

Sponsors & Collaborators

• Groupe Francophone des Myelodysplasies: lead
• GlaxoSmithKline: collaborator

Study Sites (11)

CHU d'Angers - Service des Maladies du sang

Angers, 49933, France

NOT YET RECRUITING

CHU Estaing - Service d'Hématologie Clinique

Clermont-Ferrand, 63000, France

NOT YET RECRUITING

Hôpital Claude Huriez - Service de Médecine Interne

Lille, 59037, France

NOT YET RECRUITING

CHU Nantes - Hôtel Dieu - Service d'Hématologie Clinique

Nantes, 44093, France

NOT YET RECRUITING

Hôpital Saint Louis - Service hématologie séniors

Paris, 75010, France

NOT YET RECRUITING

Hôpital Saint-Antoine - Service de Médecine Interne

Paris, 75012, France

NOT YET RECRUITING

CHU de Haut-Lévèque - Centre F. Magendie - Service des Maladies du sang

Pessac, 33604, France

NOT YET RECRUITING

CH Lyon sud - Service d'Hématologie Clinique

Pierre-Bénite, 69495, France

RECRUITING

Hôpital Pontchaillou Service d'hématologie clinique et service de médecine interne

Rennes, 35033, France

NOT YET RECRUITING

IUCT Oncopole Département d'hématologie / Unité de médecine interne

Toulouse, 31059, France

NOT YET RECRUITING

CHU de Tours - Hôpital Bretonneau - Service de Médecine Interne

Tours, 37044, France

NOT YET RECRUITING

MeSH Terms

Conditions

VEXAS syndrome; Myelodysplastic Syndromes

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Maël HEIBLIG, MD

  CH Lyon Sud

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maël HEIBLIG, MD

CONTACT

+33 4 72 11 74 01; mael.heiblig@chu-lyon.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: a single-arm phase II with safety run-in study

Study Record Dates

• First Submitted: July 18, 2025
• First Posted: August 1, 2025
• Study Start: November 25, 2025
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): November 1, 2028
• Last Updated: December 10, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

FR (11)