VEXAS Syndrome
Conditions
Keywords
VEXAS Syndrome, Momelotinib, Adaptive, Ubiquitin-like modifier activating enzyme 1 mutation, ATLAS
Brief summary
This study will assess the efficacy and safety of momelotinib in participants with a diagnosis of VEXAS.
Interventions
DRUGMomelotinib
Momelotinib will be administered
DRUGGlucocorticoids
Glucocorticoids (prednisone or prednisolone) will be administered
DRUGPlacebo
Placebo will be administered
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ORR (Objective response rate) at Week 26 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Percentage of participants with partial response (PR) or complete response (CR) at Week 26 | At Week 26 | Percentage of participants with PR or CR at Week 26 to support identification of the Recommended Phase 3 dose (RP3D) |
| Phase 2: Number of participants with adverse events and clinically significant changes in laboratory parameters, and vital signs to support identification of the RP3D | Up to 26 Weeks | — |
| Phase 2: Plasma concentrations of momelotinib and metabolite of momelotinib 21 (M21) to support identification of the RP3D | Up to 26 Weeks | — |
| Number of flare-free days | Up to 26 Weeks | 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. |
| Duration of response (DoR) | Up to 104 Weeks | DoR defined as the date of clinical response (CR or PR) to the date of relapse. |
| Number of flare-free days with glucocorticoid (GC) dose <=10 mg/day | Up to 104 Weeks | 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. |
| Percentage of participants achieving complete and partial biochemical response | Up to 26 Weeks | Complete biological response is defined as complete or partial normalization of C-reactive protein. |
| Objective response rate (ORR) at Week 52 | At Week 52 | ORR is defined as the proportion of participants who have achieved complete response or partial response |
| Number of Participants with Hematologic Improvement- Erythroid (HI-E) response per International Working Group (IWG) 2018 criteria | Up to 26 Weeks | HI-E response is measured based on the combined incidence of: Low transfusion burden participants defined as absence of any transfusion for greater than or equal to (\>=)8 consecutive weeks. High transfusion burden participants: minor response defined as reduction by \>=50% of red blood cell (RBC) units for \>=8 consecutive weeks. Major response defined as absence of RBC transfusions for \>=8 consecutive weeks or longer up to 26 weeks. |
| Change from Baseline in Short Form 36 (SF-36) domain and summary scores | Baseline and up to Week 48 | Short-Form 36 is a health-related survey that assesses quality of life covering 8 domains: vitality; physical functioning; bodily pain; general health perceptions; physical role functioning; emotional role functioning; social role functioning; and mental health. The domain scores are weighted to a scale ranging between 0 to 100, where higher score represents better health. The Physical Component Summary (PCS) and Mental Component Summary (MCS) scores are derived from the eight domain scores. These scores are standardized to a general U.S. population average of 50, with a standard deviation of 10. For both PCS and MCS, scores range from 0 to 100, higher scores indicate a better health outcome. |
| Change from Baseline in European Organization for Research and Treatment of Cancer Item Library (EORTC IL) 479 score | Baseline and up to Week 156 | The EORTC Item Library is a database containing \>1000 individual items from more than 70 EORTC quality of life measures. A subset of 7 items from the library were selected based on symptoms experienced by participants with VEXAS syndrome. Scores range from 1 to 100 with higher scores representing a higher ("worse") level of symptoms. |
| Change From Baseline in Patient Reported Outcome Measurement Information System (PROMIS) Physical Function Short Form 10b | Baseline and up to Week 156 | PROMIS Physical Function Short Form 10b consists of 10 questions; each with a 5-point response. PROMIS short form assesses self-reported capability of a participant rather than actual performance of physical activities. Higher scores indicate better functioning. Total possible range of scores is 10 to 50, with higher scores corresponding to a greater physical function ability. |
| Change from Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-FATIGUE) | Baseline and up to Week 156 | The FACIT-Fatigue is a short, 13-item questionnaire that assesses self-reported fatigue and its associated impact on daily activities over the past 7 days. A higher score indicates a better outcome (no fatigue). The total score ranges from 0 to 52, with 0 being the worst possible score and 52 being the best possible score (indicating no fatigue). |
| Changes from Baseline in Patient Global Impression of Severity (PGIS) scores | Baseline and up to Week 156 | The PGIS is a single global question which asks participants to rate the severity of their VEXAS syndrome symptoms on a 5-point rating scale with response categories of "No symptoms", "Mild", "Moderate", "Severe", and "Very Severe." The PGIS scores ranges from 0 (absent) to 4 (very severe). |
| Changes in Patient Global Impression of Change (PGIC) scores | Baseline and up to Week 156 | The PGIC is a single global question which asks participants to rate the change in severity of their VEXAS syndrome symptoms since starting study medication using a 5-point rating scale with response categories of "much better", "a little better", "no change", "a little worse", "much worse". The PGIC score ranges from +2 (much better) to -2 (much worse). |
| Changes from Baseline in European quality of life 5 dimensions 5 level version (EQ-5D-5L) | Baseline and up to Week 48 | EQ-5D-5L is self-assessment questionnaire, consisting of 5 items covering 5 dimensions (mobility, self care, usual activities, pain/discomfort, and anxiety/depression). Each dimension is measured by 5-point Likert scale ranging from 1=no problems to 5=extreme problems. |
| Changes from Baseline in European quality of life-Visual Analogue Scale (EQ-VAS) | Baseline and up to Week 48 | The EQ-VAS records the respondents self-rated health on a vertical VAS, ranging from 0 to 100, where 0 represents the worst imaginable health and 100 represents the best imaginable health. |
| Number of participants with adverse events (AEs) and Serious adverse events (SAEs) | Up to Week 108 | — |
| Number of participants with adverse events (AEs) and Serious adverse events (SAEs) by severity | Up to Week 108 | — |
| Number of participants with AEs leading to discontinuation or dose modifications | Up to Week 108 | — |
| Plasma concentration of momelotinib and M21 | Up to 26 Weeks | — |
| Overall Survival | At Months 12, 24 and 36 | Overall survival is defined as the time from randomization to the date of death due to any cause. |
Contacts
CONTACTUS GSK Clinical Trials Call Center
CONTACTEU GSK Clinical Trials Call Center
STUDY_DIRECTORGSK Clinical Trials
GlaxoSmithKline
Outcome results
None listed