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

Phase 3Not Yet RecruitingNCT07569081

GlaxoSmithKline136 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

136

Conditions

VEXAS Syndrome

Interventions

MomelotinibDRUG

Momelotinib will be administered

GlucocorticoidsDRUG

Glucocorticoids (prednisone or prednisolone) will be administered

PlaceboDRUG

Placebo will be administered

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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: 1. Documented evidence of a canonical, pathogenic Ubiquitin-like modifier activating enzyme 1 (UBA1) mutation 2. 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: 1. Is a Participant of non-childbearing potential (PONCBP) OR 2. 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: 1. VEXAS-directed therapies (washout period) up to 5 half-lives or up 14 days if half-life is \<3 days 2. 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. 3. Hematologic support therapy (e.g., ESAs, danazol, luspatercept, G-CSF): 4 weeks 4. Cell-depleting therapies such as anti-CD20 (rituximab): 12 months 5. 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: 1. Unstable angina pectoris 2. Symptomatic congestive heart failure 3. Uncontrolled cardiac arrhythmia 4. QTc \>450 msec or QTc \>480 msec for participants with bundle branch block.

Outcomes

Primary Outcomes

ORR (Objective response rate) at Week 26

ORR is defined as the proportion of participants who have achieved complete response (CR) or partial response (PR) during the 26-week Primary Treatment Period.

Time frame: At Week 26

Secondary Outcomes

Phase 2: Percentage of participants with partial response (PR) or complete response (CR) at Week 26

Percentage of participants with PR or CR at Week 26 to support identification of the Recommended Phase 3 dose (RP3D)

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

Flare-free days are calendar days without clinical evidence of VEXAS flare and without treatment escalation. Total number of flare-free days is defined as the cumulative number of consecutive and non-consecutive flare-free days.

Time frame: Up to 26 Weeks

Duration of response (DoR)

DoR defined as the date of clinical response (CR or PR) to the date of relapse.

Time frame: Up to 104 Weeks

Number of flare-free days with glucocorticoid (GC) dose <=10 mg/day

Central Contacts

US GSK Clinical Trials Call Center

CONTACT

877-379-3718 GSKClinicalSupportHD@gsk.com

EU GSK Clinical Trials Call Center

CONTACT

+44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

Data from ClinicalTrials.gov

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