Momelotinib in VEXAS syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Groupe Francophone Des Myelodysplasies

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

25 Nov 2025 → ongoing

Decision date (initial)

2025-10-08

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

GLAXOSMITHKLINE (GSK)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy, Therapy

Safety run-in :To determine the maximum tolerated dose (MTD) of momelotinib (MMB) in VEXAS patients
Phase II : To determine clinical efficacy of MMB at 24 weeks on VEXAS related symptoms in UBA1 mutated and symptomatic patients refractory/dependent to steroids

Secondary objectives 12

1. To further assess the overall safety profile of MMB during safety run-in phase
2. To characterize pharmacokinetics of MMB and active metabolite (M21) in VEXAS patients during the safety run-in phase
3. To assess efficacy of MMB on clinical and biological responses
4. To evaluate hematological improvement (HI-E) in patients with anemia
5. To assess steroids sparing and the number of patients that withdraw steroids
6. To evaluate the probability of survival at 12 months
7. To evaluate the effect of MMB on MDS based on hematological, cytogenetic and molecular parameters
8. To determine the response duration, time to best response, and loss of clinical and RBC transfusion independence in responders
9. To assess the evolution of UBA1 VAF on MMB
10. To further assess the overall safety profile of MMB
11. Biological objective of ancillary study: To assess the rate of molecular response under treatment with MMB
12. Clinical objective of ancillary study: To assess VEXAS personal scoring system (VPSS) on symptoms burden and its correlation to clinical response

Conditions and MedDRA coding

VEXAS (VACUOLES, E1 ENZYME, X-LINKED, AUTOINFLAMMATORY, SOMATIC) syndrome

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. ECOG performance status 0-2 at the time of screening
2. Age ≥ 18 years
3. Written informed consent
4. Diagnosis of VEXAS syndrome with UBA1 mutation and clinically symptomatic disease requiring immunosuppressive treatment and at least 10 mg/d of glucocorticoids
5. With uncontrolled symptoms related to VEXAS with prior treatment line(s) (including steroids)
6. Patients refractory/dependent to steroids
7. Single concomitant steroids therapy (e.g. prednisone or equivalent) at the time of inclusion is allowed
8. For patients treated with other immunosuppressive/immuno-modulatory therapy than glucocorticoids, a wash out period of 28 days is required prior MMB onset
9. Erythropoietin/luspatercept used as a growth factor is not allowed 28 days prior enrollment
10. Adequate liver function (serum transaminases ≤ 3N, Bilirubin ≤ 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%))
11. Adequate renal function (creatinine clearance with MDRD formula > 30 ml/min)
12. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must: 1- Have a negative serum or urine pregnancy test within 24-hours prior to beginning treatment on this study. Lactating patients are excluded. 2- 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. 3- Agree to learn about the procedures for preservation of egg before starting treatment.
13. Male patients must: 1- Agree the need for the use of a condom if engaged in sexual activity with a woman of childbearing potential during the entire period of treatment, even if disruption of treatment and during 12 weeks after end of treatment. 2- Agree to learn about the procedures for preservation of sperm before starting treatment.

Exclusion criteria 12

1. Patients with MDS currently scheduled for allogeneic stem cell transplant or high risk MDS according to IWG 2023.
2. Patients who are or have been already treated with JAK inhibitors for VEXAS syndrome or another indication.
3. Patients who are unable to receive a starting daily dose of MMB of at least 100 mg.
4. 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.
5. 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 MMB.
6. Known infection with acute and chronic active HIV, HBV, HCV infections.
7. Any medical or psychiatric condition not allowing the informed consent of the subject
8. Presence of clinically meaningful active bacterial, fungal, parasitic or viral infection which requires therapy
9. Previous history of Progressive Multifocal Leuko-encephalopathy (PML)
10. Active gastrointestinal conditions that may affect absorption
11. No affiliation to a health insurance system.
12. Known hypersensitivity to the study investigational medicinal product, the metabolites, or formulation excipients.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. For Safety run-in : Documentation of dose-limiting toxicities (DLTs) and identification of a maximal tolerated dose (MTD). DLTs will be defined during a safety observation period corresponding to the first 4-week cycle of MMB. Because of the addition of a 4-week period to observe recovery of adverse events of interest, the observation window for DLT will be up to 8 weeks.
2. For phase II : Overall clinical response rate at 24 weeks after MMB initiation on VEXAS related symptoms (including complete (CR) or partial response (PR))

Secondary endpoints 12

1. For safety run-in: Adverse events (AE), serious AE (SAE) and toxicity as measured by NCI CTCAE v5.0
2. For safety run-in phase : Plasma MMB/M21 pharmacokinetic parameters (i.e. AUC, Cmax) as data permits
3. Overall clinical response rates (including CR or PR) and biological response rates (complete or partial) at 4, 12, 24 and 48 weeks after MMB initiation
4. Erythroid hematological improvement (HI-E) evaluated at 16 weeks according to IWG 2018
5. Steroids dose reduction compared to baseline and/or steroids withdrawal rates at 24 weeks
6. Overall survival at 12 months
7. Changes in the underlying MDS from baseline, at 12 and 24 weeks, including MDS progression based on hematological, cytogenetic and molecular analysis
8. Responses: 1-Duration of Response (DoR) on VEXAS symptoms defined as the time from the date of initial documentation of a clinical response (CR or PR) to the date of first documented evidence of relapse or death ; 2-Time to first and best clinical response ; 3-Duration of RBC independency in patients with RBC dependency at time of inclusion, according to IWG 2018 criteria
9. Evolution of UBA1 VAF on MMB
10. Adverse events (AE), serious AE (SAE) and toxicity as measured by NCI CTCAE v5.0
11. For ancillary study (biological end point): Evolution of UBA1 VAF from baseline to W4, W12 and W24
12. For ancillary study (Clinical end point): Evolution of VPSS from baseline to W4, W12 and W24

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Groupe Francophone Des Myelodysplasies

Sponsor organisation

Groupe Francophone Des Myelodysplasies

Address

Opital St Louis Hemato Seniors T4, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris

Postcode

75010

Country

France

Scientific contact point

Organisation

Groupe Francophone Des Myelodysplasies

Contact name

Maël HEIBLIG

Public contact point

Organisation

Groupe Francophone Des Myelodysplasies

Contact name

Maël HEIBLIG

Locations

1 EU/EEA country · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications