Momelotinib in VEXAS Syndrome
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorGroupe Francophone des Myelodysplasies
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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
Disqualifiers
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
Trial design
Design model
Single group
Treatments tested in this trial
Momelotinib treatment
DrugPatients included will receive momelotinib continuously until disease progression or loss of response, at physician's discretion.
Treatment groups
57 Participants
are divided into 1 treatment groupGroup A: Momelotinib treatmentExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
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 treatment2
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 treatmentSecondary outcomes
1
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 8-92
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 weeks3
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 treatment4
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 treatmentOther outcomes
1
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 treatmentSponsors and contacts
Click on the lead sponsor to view all of their trials.
Groupe Francophone des Myelodysplasies
Lead sponsor
GlaxoSmithKline
Collaborator
Source ClinicalTrials.gov