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

NCT06538181 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 202412141
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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

Keywords

VEXAS; Autoinflammatory; UBA1; Pacritinib

Outcome Measures

Primary Outcomes (2)

• Number of participants with dose-limiting toxicities (DLTs)

  Dose-limiting toxicities (DLTs) are adverse events defined by the protocol that occur during the DLT observation period (Cycle 1) of the study, unless clearly attributable to underlying disease or another cause unrelated to the study.

  Through completion of cycle 1 (estimated to be 28 days)

• Recommended phase II dose (RP2D)

  The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity (DLT) during the first cycle. The recommended phase II dose (RP2D) will be less than or equal to the MTD. If the MTD is not reached, and in the opinion of the investigators, the toxicity profile is acceptable, Dose Level 1 will be the RP2D.

  Through completion of cycle 1 (each cycle is 28 days) for all treated participants

Secondary Outcomes (14)

• Change in white blood cell count

  Baseline, 1 month, 3 months, 6 months, and 12 months

• Change in absolute neutrophil count

  Baseline, 1 month, 3 months, 6 months, and 12 months

• Change in absolute lymphocyte count

  Baseline, 1 month, 3 months, 6 months, and 12 months

• Change in hemoglobin

  Baseline, 1 month, 3 months, 6 months, and 12 months

• Change in platelets

  Baseline, 1 month, 3 months, 6 months, and 12 months

Study Arms (2)

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

EXPERIMENTAL

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

Dose Expansion: Pacritinib

EXPERIMENTAL

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.

Interventions

Pacritinib DRUG

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Swedish Orphan Biovitrum: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

Related Links

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

MeSH Terms

Conditions

VEXAS syndrome

Interventions

11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene

Study Officials

• Meagan A Jacoby, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

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

CONTACT

314-454-8306; mjacoby@wustl.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 31, 2024
• First Posted: August 5, 2024
• Study Start: February 13, 2025
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): February 28, 2029
• Last Updated: July 16, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data 9 available months to 36 months after publication
• Access Criteria: Investigators who proposed use of the data has been approved by independent review committee identified for this purpose

Locations

US (1)