Momelotinib in VEXAS Syndrome

Not Applicable

Not yet recruiting

• Conditions: VEXAS Syndome; Myelo Dysplastic Syndrome
• Interventions: Drug: Momelotinib treatment

• Registration Number: NCT07098936
• Lead Sponsor: Groupe Francophone des Myelodysplasies

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.

Detailed Description

During safety run-in phase, the three fixed dose levels tested are :

* Dose level (DL) -1: 150 mg once daily (QD)

* DL1: 200 mg QD

* DL2: 300 mg QD. Between 6 and 18 patients will be enrolled during the safety run-in phase. Up to 39 patients could be included in the phase II study and will be treated with momelotinib at the maximum tolerated dose preliminary fixed during the safety run-in phase.

Baseline steroids daily dose required for VEXAS inflammatory manifestations will be defined during screening period (28 days period) for each patient. It is defined as the minimal daily dose of steroids used in the last 14 days prior momelotinib onset (according to physician disposition) that allow disease control. In case of related VEXAS inflammatory manifestation during screening period with a first fixed dose, an increased dose of steroids should be evaluated during at least an extra 14 days prior momelotinib onset. This baseline dose defined during screening period will be used for response criteria during follow-up.

Momelotinib treatment will be discontinued after 24 weeks at optimal dosing regimen (up to 300 mg/day), in case of absence of response.

Treatment might also be discontinued during follow-up in case of loss of response/hematological progression or non-tolerable adverse event.

Study Timeline

• Status Verified: 2025-07
• Study First Submitted: 2025-07-18
• Study First Submitted QC: 2025-07-25
• Last Update Submitted: 2025-07-25
• Study First Posted: 2025-08-01
• Last Update Posted: 2025-08-01
• Study Start: 2025-10-01
• Primary Completion: 2028-05
• Study Completion: 2028-10-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 57

Inclusion Criteria

• 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

• Single concomitant steroids therapy (e.g., prednisone or equivalent) at the time of inclusion is allowed

• 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:

  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.

• 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

• 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Momelotinib treatment	Momelotinib treatment	Patients will receive momelotinib.

Primary Outcome Measures

Name	Time	Method
Determination of the maximum tolerated dose of momelotinib	First 4-week cycle of momelotinib treatment	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.
Clinical efficacy	During the 24 first weeks of momelotinib treatment	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.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic	At cycle 1 Day 8-9 and cycle 13 Day 8-9	Concentrations of momelotinib and its major metabolite M21 will be determined in plasma samples using the currently approved bioanalytical methodology by Frontage Laboratories Inc.; Pharmacokinetic sampling will be only performed for patients in safety run-in phase.; Samples should be obtained at cycle 1 Day 8 and cycle 13 Day 8, at times following : Pre-dose then at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8h and at 24 h post Day 8 dose.
Hematological response	After 16 weeks of momelotinib treatment	Erythroid hematological improvement will be assessed by the investigators according to IWG 2018 criteria through collection of transfusion records and hematology parameters.
Overall survival	From enrollment to the end of treatment at 12 months	Overall survival assessment
Myelodysplastic syndrome (MDS) evolution	From baseline at 12 and 24 weeks of momelotinib treatment	Changes in the underlying MDS from baseline, at 12 and 24 weeks, including MDS progression based on hematological, cytogenetic and molecular analysis
RBC independency	From enrollment to the end of treatment at 48 weeks	Duration of Red Blood Count (RBC) independency in patients with RBC dependency at time of inclusion, according to IWG 2018 criteria
Incidence of Treatment-Emergent Adverse Events	From enrollment to the end of treatment at 48 weeks	Collection of Adverse events (AE), serious AE (SAE) and toxicities as measured by NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) v5.0
Response	After 4, 12, 24 and 48 weeks of momelotinib treatment	Determination of overall clinical response rates (including Complete Response or Partial Response) and biological response rates (complete or partial)
Duration of response	From enrollment to the end of treatment at 48 weeks	Duration of response on VEXAS symptoms defined as the time from the date of initial documentation of a clinical response (Complete Response or Partial Response) to the date of first documented evidence of relapse or death
Steroids dose reduction	After 24 weeks of momelotinib treatment	Steroids dose reduction compared to baseline and/or steroids withdrawal rates
UBA1 VAF	From enrollment to the end of treatment at 24 weeks	Evolution of UBA1 (Ubiquitin Like Modifier Activating Enzyme 1) VAF (Variant Allelic Frequency) from baseline to W4, W12 and W24 after momelotinib treatment
Best clinical response	From enrollment to the end of treatment at 48 weeks	Determination of time to the first and best clinical response

Trial Locations

Locations (11)

CHU d'Angers - Service des Maladies du sang; 🇫🇷 Angers, France

CHU Estaing - Service d'Hématologie Clinique; 🇫🇷 Clermont-Ferrand, France

Hôpital Claude Huriez - Service de Médecine Interne; 🇫🇷 Lille, France

CHU Nantes - Hôtel Dieu - Service d'Hématologie Clinique; 🇫🇷 Nantes, France

Hôpital Saint Louis - Service hématologie séniors; 🇫🇷 Paris, France

Hôpital Saint-Antoine - Service de Médecine Interne; 🇫🇷 Paris, France

CHU de Haut-Lévèque - Centre F. Magendie - Service des Maladies du sang; 🇫🇷 Pessac, France

CH Lyon sud - Service d'Hématologie Clinique; 🇫🇷 Pierre-Bénite, France

Hôpital Pontchaillou Service d'hématologie clinique et service de médecine interne; 🇫🇷 Rennes, France

IUCT Oncopole Département d'hématologie / Unité de médecine interne; 🇫🇷 Toulouse, France

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