Pacritinib in Vacuoles, E1 Ubiqutin-activating Enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome
NCT Number: NCT06538181
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE1
Conditions: E1 Ubiqutin-activating Enzyme, X-linked, Autoinflammatory, Somatic Syndrome|VEXAS|Vexas Syndrome
Interventions: DRUG: Pacritinib
Sponsor: Washington University School of Medicine
Collaborators: Swedish Orphan Biovitrum
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 15
Study Design: Allocation: NON_RANDOMIZED|Intervention Model: SEQUENTIAL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-10-31
Completion Date: 2028-10-31
Locations: Washington University School of Medicine, Saint Louis, Missouri, 63110, United States

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.

Primary Outcome Measures: 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, determined to be possibly, probably, or definitely related to the study drug., 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 Outcome Measures: 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|Number of participants with hematologic improvement as measured with neutrophils, Using IWG 2018 criteria, Through completion of treatment (estimated to be 12 months)|Number of participants with hematologic improvement as measured with hemoglobin, Using IWG 2018 criteria, Through completion of treatment (estimated to be 12 months)|Number of participants with hematologic improvement as measured with platelets, Using IWG 2018 criteria, Through completion of treatment (estimated to be 12 months)|UBA1 variant allele frequency, Baseline, 1 month, 3 months, 6 months, and 12 months|Change in C reactive protein (CRP), Baseline, 1 month, 3 months, 6 months, and 12 months|Change in ferritin, Baseline, 1 month, 3 months, 6 months, and 12 months|Change in ESR, Baseline, 1 month, 3 months, 6 months, and 12 months|Change in inflammatory and rheumatologic symptoms as measured by the VEXAS Disease Activity Index, Baseline, 1 month, 3 months, 6 months, and 12 months|Time to next treatment, Through completion of follow-up (estimated to be 24 months)