A Phase 1 Study of Pacritinib in Vacuoles, E1 Ubiqutin-activating Enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome

Status: Recruiting
Location: See location...
Intervention Type: Drug
Study Type: Interventional
Study Phase: Phase 1
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.

Eligibility
Participation Requirements
Sex: All
Minimum Age: 18
Healthy Volunteers: f
View:

• 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 3 months 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. 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.

Locations
United States
Missouri
Washington University School of Medicine
RECRUITING
Saint Louis
Contact Information
Primary
Meagan A Jacoby, M.D., Ph.D.
mjacoby@wustl.edu
314-454-8306
Time Frame
Start Date: 2025-02-13
Estimated Completion Date: 2029-02-28
Participants
Target number of participants: 15
Treatments
Experimental: 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.
Experimental: 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.
Sponsors
Leads: Washington University School of Medicine
Collaborators: Swedish Orphan Biovitrum

This content was sourced from clinicaltrials.gov