A Study Evaluating the Efficacy and Safety of Momelotinib in Participants With Vacuoles, E1-enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome

Official title

A Randomized Phase 2/3, Double-blind, Placebo Controlled Adaptive Study Evaluating the Efficacy and Safety of Momelotinib in Participants With VEXAS Syndrome

Overview

This study will assess the efficacy and safety of momelotinib in participants with a diagnosis of VEXAS.

Interventions

• Drug Momelotinib
  Momelotinib will be administered
• Drug Glucocorticoids
  Glucocorticoids (prednisone or prednisolone) will be administered
• Drug Placebo
  Placebo will be administered

Primary outcome measures

• ORR (Objective response rate) at Week 26 [Time frame: At Week 26]

Secondary outcome measures (12)

• Phase 2: Percentage of participants with partial response (PR) or complete response (CR) at Week 26 [Time frame: At Week 26]
• Phase 2: Number of participants with adverse events and clinically significant changes in laboratory parameters, and vital signs to support identification of the RP3D [Time frame: Up to 26 Weeks]
• Phase 2: Plasma concentrations of momelotinib and metabolite of momelotinib 21 (M21) to support identification of the RP3D [Time frame: Up to 26 Weeks]
• Number of flare-free days [Time frame: Up to 26 Weeks]
• Duration of response (DoR) [Time frame: Up to 104 Weeks]
• Number of flare-free days with glucocorticoid (GC) dose <=10 mg/day [Time frame: Up to 104 Weeks]
• Percentage of participants achieving complete and partial biochemical response [Time frame: Up to 26 Weeks]
• Objective response rate (ORR) at Week 52 [Time frame: At Week 52]
• Number of Participants with Hematologic Improvement- Erythroid (HI-E) response per International Working Group (IWG) 2018 criteria [Time frame: Up to 26 Weeks]
• Change from Baseline in Short Form 36 (SF-36) domain and summary scores [Time frame: Baseline and up to Week 48]
• Change from Baseline in European Organization for Research and Treatment of Cancer Item Library (EORTC IL) 479 score [Time frame: Baseline and up to Week 156]
• Change From Baseline in Patient Reported Outcome Measurement Information System (PROMIS) Physical Function Short Form 10b [Time frame: Baseline and up to Week 156]

Eligibility criteria

Inclusion criteria

• Age greater than equal to (>=)18 years OR of legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the Informed Consent Form.
• Confirmed diagnosis of clinical VEXAS defined by:

• Documented evidence of a canonical, pathogenic Ubiquitin-like modifier activating enzyme 1 (UBA1) mutation
• Inflammatory manifestations: current or documented past involvement within 6 months of at least one organ system
• Receiving glucocorticoid (GC) treatment (prednisone/prednisolone) for >=4 consecutive weeks for >=10 days prior to randomization.
• A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies:

• Is a Participant of non-childbearing potential (PONCBP) OR
• Is a Participant of childbearing potential (POCBP) and using a contraceptive method that is highly effective
• Is capable of giving signed informed consent including compliance with the requirements and restrictions
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2 at the time of screening.
• Has adequate organ function

Exclusion criteria

• More than 1 prior admission to an intensive care unit due to a VEXAS flare within the 6 months prior to randomization.
• History of severe corticosteroid toxicity: uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), psychiatric, osteoporosis/osteomalacia, glaucoma, corneal ulcers/injuries, nausea or vomiting or gastrointestinal disease.
• High risk/very high risk Myelodysplastic syndrome (MDS), according to the Revised International Prognostic Scoring System (IPSS-R) with overall risk score >3.5.
• Peripheral blood blast counts >=10%.
• Multiple myeloma (all stages) and other active plasma cell dyscrasias requiring treatment.
• Malignancy (except disease under study including Lower-risk myelodysplastic syndrome \[LR-MDS\]) that has progressed or required active treatment within the past (24 months) except for basal cell or squamous cell carcinomas of the skin or in-situ carcinomas).
• Uncontrolled intercurrent illness within 12 weeks prior to initiation of momelotinib.
• Ongoing adverse reaction(s) from prior therapy that have not recovered to Grade <=1 per NCI CTCAE v6.0 or to the Baseline status preceding prior therapy
• Psychiatric illness, social situation, or any other condition that would limit informed consent and/or compliance with trial requirements or may interfere with the interpretation of study results, as judged by Investigator or Sponsor.
• Has any clinically significant gastrointestinal conditions or abnormalities that may alter absorption or swallowing
• Known contraindication or hypersensitivity to momelotinib and its metabolites, or any of their excipients.
• Presence of peripheral neuropathy >=Grade 2 per NCI CTCAE v6.0.
• Known history of disseminated mycobacterial infection.
• Known positive status for human immunodeficiency virus (HIV).
• Positive QuantiFERON (or other interferon gamma release assay) during Screening.
• Unable to receive any Pneumocystis jiroveci pneumonia (PJP) medical prophylaxis
• Known clinically significant anemia due to iron, vitamin B12 or folate deficiencies, or autoimmune or hereditary hemolytic anemia, gastrointestinal bleeding, or thalassemia.
• More than 1 prior line of VEXAS directed therapy before or after VEXAS diagnosis or other medical condition.
• Use of the following treatments within the noted time periods referenced from date of randomization:

• VEXAS-directed therapies (washout period) up to 5 half-lives or up 14 days if half-life is <3 days
• Other non-GC anti-inflammatory therapies: for non-biologics): 14 days or five half-lives, whichever is longer; for biologics): 28 days or two half-lives whichever is longer.
• Hematologic support therapy (e.g., ESAs, danazol, luspatercept, G-CSF): 4 weeks
• Cell-depleting therapies such as anti-CD20 (rituximab): 12 months
• Investigational agent from a class not otherwise specified: 5 half-lives or 60 days, whichever is longer
• GC use for conditions other than VEXAS, which would interfere with adherence to the fixed GC taper regimen and/or to assessment of efficacy.
• Chronic use of systemic corticosteroids for >4 years or inability to withdraw corticosteroid treatment
• Planned allogeneic HSCT for MDS or VEXAS, within 1 year.
• Any major surgery within 28 days prior to randomization.
• Prior allogeneic/autologous stem cell transplant or solid organ transplant (other than corneal).
• Presence of peripheral neuropathy >=Grade 2 per NCI CTCAE v6.0.
• Hepatitis B or C active infection, unless protocol defined criteria are met.
• Any of the following conditions within 6 months prior to randomization:

• Unstable angina pectoris
• Symptomatic congestive heart failure
• Uncontrolled cardiac arrhythmia
• QTc >450 msec or QTc >480 msec for participants with bundle branch block.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07569081 · 223401 · 2025-524416-11-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗