A Phase 2 interventional study of Momelotinib treatment in VEXAS Syndome and Myelo Dysplastic Syndrome, sponsored by Groupe Francophone des Myelodysplasies. Recruiting at 11 sites in France. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-08-10.
Sponsored by Groupe Francophone des Myelodysplasies · Phase 2, Interventional, and Treatment
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.
During safety run-in phase, the three fixed dose levels tested are :
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.
Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must:
Male patients must:
Exclusion Criteria:
Patients will receive momelotinib.
Drug: Momelotinib treatment
Patients included will receive momelotinib continuously until disease progression or loss of response, at physician's discretion.
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.
Time frame: 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.
Time frame: During the 24 first weeks of momelotinib treatment
Pharmacokinetic
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.
Time frame: At cycle 1 Day 8-9 and cycle 13 Day 8-9
Incidence of Treatment-Emergent Adverse Events
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
Time frame: From enrollment to the end of treatment at 48 weeks
Response
Determination of overall clinical response rates (including Complete Response or Partial Response) and biological response rates (complete or partial)
Time frame: After 4, 12, 24 and 48 weeks of momelotinib treatment
Hematological response
Erythroid hematological improvement will be assessed by the investigators according to IWG 2018 criteria through collection of transfusion records and hematology parameters.
Time frame: After 16 weeks of momelotinib treatment
Steroids dose reduction
Steroids dose reduction compared to baseline and/or steroids withdrawal rates
Time frame: After 24 weeks of momelotinib treatment
Overall survival
Overall survival assessment
Time frame: From enrollment to the end of treatment at 12 months
Myelodysplastic syndrome (MDS) evolution
Changes in the underlying MDS from baseline, at 12 and 24 weeks, including MDS progression based on hematological, cytogenetic and molecular analysis
Time frame: From baseline at 12 and 24 weeks of momelotinib treatment
Duration of response
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
Time frame: From enrollment to the end of treatment at 48 weeks
Best clinical response
Determination of time to the first and best clinical response
Time frame: From enrollment to the end of treatment at 48 weeks
RBC independency
Duration of Red Blood Count (RBC) independency in patients with RBC dependency at time of inclusion, according to IWG 2018 criteria
Time frame: From enrollment to the end of treatment at 48 weeks
UBA1 VAF
Evolution of UBA1 (Ubiquitin Like Modifier Activating Enzyme 1) VAF (Variant Allelic Frequency) from baseline to W4, W12 and W24 after momelotinib treatment
Time frame: From enrollment to the end of treatment at 24 weeks
Validation of the VEXAS personal scoring system (VPSS)
Measurement of VPSS to validate the score currently under development which would allow objectively quantifying the impact of VEXAS-related symptoms on patients' quality of life.
Time frame: After 4, 12 and 24 weeks of momelotinib treatment
Plan to share: No
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VEXAS syndrome
Groupe Francophone des Myelodysplasies