Not Yet RecruitingPhase 2ACTRN12625000619448

Efficacy of assigning treatment for participants with VEXAS syndrome with lenzilumab plus azacitidine

Targeted Immunotherapy for VEXAS syndrome: A Phase II Trial Exploring the Efficacy of Lenzilumab in Combination with Azacitidine

Sponsor

South Australian Health & Medical Research Institute Ltd

Enrollment

10 participants

Start Date

Aug 1, 2025

Study Type

Interventional

Conditions

V - vacuoles are often seen in cells identified in bone marrow biopsies from patients with VEXAS syndrome. E - E1 ubiquitin activating enzyme, encoded by the UBA1 gene which is mutated in patients X - the UBA1 gene is located on the X chromosome. A - patients have autoinflammation. S - the mutations are somatic, meaning they are acquired at some point in life and not inherited. (VEXAS)

Summary

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a recently discovered rare disease (incidence less than 1 in 20,000 persons) characterized by severe inflammatory symptoms and no known effective treatment. Although the disease superficially appears similar to typical autoimmune rheumatological diseases, emerging research suggests that it is driven by proinflammatory monocytes that are produced in the bone marrow by the cytokine granulocytemacrophage colony stimulating factor (GM-CSF). Patients are often misdiagnosed and there are no effective therapies and at least half of VEXAS patients also suffer with myelodysplastic syndrome, according to our local VEXAS Registry. Our preliminary studies suggest that the combination of azacitidine and Lenzilumab can be effective in reducing progenitor cells. Secondly, ongoing clinical trial of CMML (ACTRN12621000223831) this combination is found to be safe and effective. We will conduct a pilot study to assess the feasibility of Lenzilumab with azacitidine as a potential life-saving treatment for VEXAS

Eligibility

Sex: Both males and femalesMin Age: 18 Yearss

Inclusion Criteria27

Confirmed diagnosis VEXAS with documented evidence of mutation in UBA1
Aged 18 or older.
Documented evidence of current or past involvement of at least one of the following organ systems in VEXAS syndrome:
(a) cutaneous ( skin rash eg. neutrophilic dermatosis, cutaneous vasculitis, periorbital inflammation);
(b) vasculature (e.g., vasculitis);
(c) musculoskeletal (e.g., arthralgia, arthritis, articular chondritis);
(d) ocular (e.g., uveitis);
(e) genitourinary (e.g., epididymitis);
(f) pulmonary (e.g., pulmonary infiltrates, alveolitis), or
(g) fever.
(h) other Patients with sensorineural hearing loss, pleural effusion, thrombosis, splenomegaly, hepatomegaly, myocarditis, weight loss.
Other inflammatory signs may be considered for enrolment at the discretion of the trial management committee.
Chronic glucocorticoid therapies (More than or equal to 3 consecutive months leading up to enrolment) for treatment of VEXAS syndrome
OR
Documented prednisolone threshold dose >10 mg daily (highest prednisolone monotherapy dose at which CRP >25 mg/L (except patients on tocilizumab, anti-IL6 therapy) or at which new or worsening objectives clinical manifestations of VEXAS syndrome emerge)
Baseline prednisolone dose 15-60 mg/day and that has been stable for >10 days prior to enrolment
Willing and able to switch to prednisone from other glucocorticoids for the duration of the study.
ECOG greater than or equal to 2
Must have the following local laboratory results:
i. Liver function (total bilirubin greater than or equal to 4 x upper limit of normal [ULN], aspartate aminotransferase [AST] greater than or equal to 3 x ULN).:
ii. Kidney function: creatinine clearance >30 mL/min using Cockcroft-Gault formula. Note: the Adjusted Body Weight formula should be used for participants with a BMI of > 30. Actual Body weight should be used when BMI is < 30.
Ability to understand the requirements of the study and informed consent.
Reproductive status
(a)Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 8 days prior to the start of study drug.
(b)Women must not be breastfeeding.
(c) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug, until 90 days post-treatment completion.
(d) Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug until 90 days post-treatment completion (duration of sperm turnover).

Exclusion Criteria18

Major surgery within 2 weeks or having not recovered from surgery.
Treatment with G-CSF within 7 days of screening.
Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
Other concurrent uncontrolled medical conditions. These include, but are not limited to:, uncontrolled infections, acute or chronic liver and renal disease (not considered disease related), uncontrolled cardiovascular conditions, including ongoing cardiac arrhythmias (e.g., ventricular arrhythmias, Torsades de Pointes, or third-degree heart block without pacemaker insertion) or uncontrolled congestive cardiac failure.
Myocardial infarction or clinically significant pericardial effusion within the past month.
Stroke or transient ischemic attack within 3 months prior to treatment.
Active malignancy with and expected survival <3 months prior to enrolment.
Acute or chronic liver disease (including chronic hepatitis B and C infections). Hepatitis B Virus core antibody positivity is not an automatic exclusion and should be discussed with Trial Management Committee.
Patients with known active Hepatitis A infection. Testing for Hepatitis A is not required as part of screening for this study.
Participants with known human immunodeficiency viruses (HIV). Screening for HIV is not required for this study.
Participants who are unable to comply with requirements for contraception as per study requirements.
Current participation in another therapeutic clinical trial (participation in clinical trials that do not involve active interventions is not an exclusion for the study).
Prior treatment with an investigational agent within 28 days before Cycle 1 Day 1 (or within 5 half-lives of the investigational agent, whichever is longer). Participants must have recovered from any toxic effects of that therapy to greater than or equal to grade 1 or baseline grade.
Known presence of antibodies against Lenzilumab
Previous or pre-existing diagnosis of pulmonary alveolar proteinosis.
Hypoxaemia at screening (oxygen saturation on room air <94%).
Known active tuberculosis (TB), history of incompletely treated TB or suspected or known extrapulmonary TB. Screening for TB is not required for this study.
Prior allogeneic haematopoietic stem cell transplant (allo-HSCT) or solid organ transplant (other than corneal)

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Interventions

VEXAS is an adult-onset autoinflammatory disease, caused by a genetic mutation (UBA1). The name is an acronym for features of the disease: Vacuoles in bone marrow cells, E1 ubiquitin conjugating enzyme This prospective study will assess whether treatment responses for participants with VEXAS can be improved by targeting certain mutation sub-groups based on individual molecular profiling. Lenzilumab 552 mg will be administered intravenously on days 1 & 15 of Cycle 1 and Day 1 only for the remaining 5 cycles. Azacitidine will be administered subcutaneously at 75 mg/m2. Doses will be administered daily on 7 days out of the first 9 days of each cycle. Azacitidine will be administered for a total of 6 cycles.

Locations(1)

The Royal Adelaide Hospital - Adelaide

SA, Australia

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ACTRN12625000619448