Pacritinib in Vacuoles, E1 Ubiqutin-activating Enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome

NCT ID: NCT06538181

Last Updated: 2025-07-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-02-13
• Study Completion Date: 2029-02-28

Brief Summary

VEXAS (vacuoles, E1 ubiqutin-activating enzyme, X-linked, autoinflammatory, somatic syndrome) is a recently described disorder with severe hematologic and rheumatologic manifestations caused by somatic variants in the ubiquitin- activating enzyme gene, UBA1, that is acquired in hematopoietic progenitor cells. Patients are often debilitated by autoinflammatory symptoms and there is currently no standard of care available. There is a clinically unmet need for better therapies in VEXAS Syndrome. There have been no prospective clinical trials of JAK-I in VEXAS syndrome. The investigators hypothesize that pacritinib, as a JAK2/IRAK1 inhibitor with a manageable safety profile in myelofibrosis patients with thrombocytopenia, will improve the autoinflammatory and hematologic manifestations of VEXAS syndrome with a tolerable toxicity profile.

The investigators propose a single arm, pilot Phase 1 study evaluating the safety and tolerability of pacritinib in patients with VEXAS syndrome with an initial safety run-in phase of 6 patients treated with pacritinib 200mg twice daily (BID) on days 1-28 of a continuous 28 day cycle. If no more than 1 patient experiences a dose-limiting toxicity (DLT), the investigators will enroll an expansion cohort to gain additional toxicity and efficacy data, for a total enrollment of 15 patients. If more than 1 patient experiences a DLT during the safety run-in phase, the investigators will decrease the dose to 100 mg BID, and if no more than 1 of 6 patients experiences a DLT, the investigators will complete the expansion cohort as above for up to a total enrollment of 15 patients. If more than 1 patient experiences a DLT at 100 mg BID, the investigators will discontinue the study. Patients will be treated for up to 12 cycles.

Conditions

E1 Ubiqutin-activating Enzyme, X-linked, Autoinflammatory, Somatic Syndrome; VEXAS; Vexas Syndrome

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dose De-Escalation (Safety Run-in): Pacritinib

Assigned dose of pacritinib by mouth twice per day. Each cycle is 28 days and participants can receive up to 12 cycles of treatment.

Group Type: EXPERIMENTAL

No interventions assigned to this group

Dose Expansion: Pacritinib

Recommended phase II dose of pacritinib by mouth twice per day. Each cycle is 28 days and participants can receive up to 12 cycles of treatment.

Group Type: EXPERIMENTAL

No interventions assigned to this group

Interventions

Pacritinib

Starting dose is 200 mg twice per day by mouth. Dose level -1 is 100 mg twice per day by mouth.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Patients must have UBA1 mutation with a variant allele frequency (VAF) of ≥ 2% detected on a next generation sequencing panel and have at least one of the following current or past clinical manifestation of VEXAS syndrome, as determined by the attending physician:

• skin rash
• vasculitis
• chondritis
• ocular/orbital inflammation (e.g., uveitis/iritis, episcleritis)
• genitourinary inflammation (e.g., epididymitis/orchitis)
• arthritis/arthralgias
• pulmonary inflammation (e.g., alveolitis/pleural effusion,)
• fever
• thrombosis
• splenomegaly
• hepatomegaly
• myocarditis or pericarditis
• cytopenias (defined as hemoglobin <11 g/dL, platelets < 100 X 10^9 /L, OR absolute neutrophil count <1.0 X 10^9 /L).
• Patients with VEXAS syndrome who have never been treated with a JAK-I will be eligible to enroll on study. A stable corticosteroid dose must be maintained for at least 14 days prior to start of pacritinib.
• Patients who have previously been treated with a JAK-I other than pacritinib, or who are currently being treated with a JAK-I other than pacritinib, may be eligible after a 28 day washout if either (i) their symptoms are not adequately controlled, as determined by the treating physician, or (ii) they have been unable to taper corticosteroids to an equivalent of <10 mg prednisone/day, and in the opinion of the treating physician, may benefit from a change in JAK-I. A stable corticosteroid dose must be maintained for at least 14 days prior to start of pacritinib.
• At least 18 years of age.
• ECOG performance status ≤ 3.
• Organ function as defined below:

• Absolute neutrophil count ≥ 0.5 K/cumm
• Platelets ≥ 25 K/cumm
• PT/PTT <2.5 X upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 x IULN
• AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
• Creatinine clearance ≥ 30 mL/min by Cockcroft-Gault
• QTcF < 480 msec.
• The effects of pacritinib on the developing human fetus are unknown. For this reason and because pacritinib was shown to be teratogenic in animal studies, women of childbearing potential and men must agree to use highly effective contraception prior to study entry, for the duration of study participation, and for 30 days after completion of study treatment. Hormonal contraception is no longer considered highly effective alone as pacritinib is a CYP3A4 inducer and accelerated progesterone metabolism. The contraceptive methods considered highly effective for WOCBP who receive pacritinib are intrauterine devices, bilateral tubal occlusion, vasectomized partner, or total sexual abstinence. Hormonal contraceptives (e.g., Depo-Provera) alone are not considered highly effective methods of contraception on their own when in treatment with pacritinib; such hormonal contraceptives must be combined with an additional barrier method (condom, diaphragm with spermicidal gel, or condoms with spermicides to be considered highly effective. Highly effective contraceptive methods in males include vasectomy, sexual abstinence, and condoms when combined with their partner using a highly effective method (including oral contraceptives).
• Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Ability to understand and willingness to sign an IRB approved written informed consent document or that of legally authorized representative, if applicable.
• Patients with myelodysplastic neoplasms (MDS) or plasma cell dyscrasias are eligible if they are not undergoing active treatment. Supportive care is permitted.

Exclusion Criteria

• Prior use of pacritinib.
• Use of another JAK inhibitor within 28 days of C1D1 of pacritinib.
• Currently receiving any other investigational agents. Patients may be eligible after 28 day washout.
• Thrombotic events (arterial or venous) within 60 days prior to enrollment.
• Any recent clinically significant bleeding within at least 7 days prior to enrollment.
• Any active or acute infection.
• History of malignancy within the prior 2 years, with the exception of MDS and plasma cell dyscrasias, or non-melanoma skin cancers that have been treated.
• History of clinically significant cardiovascular disease or clinically significant abnormalities in rhythm or conduction during screening EKG, including severe cardiac events, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or heart failure.
• Currently receiving immunosuppressants (other than corticosteroids), disease-modifying antirheumatic drugs (DMARDs), or biologic cytokine inhibitors. Patients may be eligible after 28 day washout.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to pacritinib.
• Concurrent use of strong CYP3A4 inhibitors or inducers. Patients may be eligible after washout period of 28 days (or 5 half-lives, whichever is shorter).
• Diagnosis or history of moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C).
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 7 days of C1D1 or negative urine pregnancy test within 3 days of C1D1.
• Known active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).
• Patients with latent tuberculosis. Patients must have a negative T-Spot during screening to be eligible.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Swedish Orphan Biovitrum

INDUSTRY

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Meagan A Jacoby, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Washington University School of Medicine

St Louis, Missouri, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Meagan A Jacoby, M.D., Ph.D.

Role: CONTACT

mjacoby@wustl.edu

314-454-8306

Facility Contacts

Meagan A Jacoby, M.D., Ph.D.

Role: primary

mjacoby@wustl.edu

314-454-8306

Related Links

http://www.siteman.wustl.edu

Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Other Identifiers

202412141

Identifier Type: -

Identifier Source: org_study_id