A Study to Assess the Effectiveness and Safety of Pacritinib in Patients With VEXAS Syndrome (PAXIS)

This study is to assess the effectiveness and safety of pacritinib in patients with VEXAS (i.e., Vacuoles in myeloid progenitors, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory manifestations, and somatic) syndrome. 78 patients will be enrolled, randomized to either pacritinib dose A, pacritinib dose B + placebo, or placebo. Randomization will be stratified by prescribed GC dose on the day of randomization.

This study is a randomized, multicenter, double-blind, placebo-controlled phase 2 study (Part 1) followed by an open-label treatment period (Part 2) designed to evaluate the efficacy and safety of pacritinib for the prevention of VEXAS flares after glucocorticoid (GC) taper. The study will enroll patients ≥18 years with inflammatory VEXAS syndrome receiving ongoing GC therapy for ≥4 consecutive weeks, requiring between 15 and 45 mg daily (of prednisone / prednisolone or equivalent) at the time of enrollment (randomization). Patients will be randomized 1:1:1 to receive pacritinib dose A (n=26), pacritinib dose B plus placebo (n=26), or placebo (n=26) for up to 24 weeks during a double-blind treatment period, followed by treatment with pacritinib during an open-label treatment period for up to 48 weeks, and a 30-day post-End of Treatment (EOT) follow-up period. Randomization will be stratified by prescribed GC dose on the day of randomization. All outcomes will be reported by treatment arm, and pair-wise comparison between each pacritinib arm and placebo will be performed in the double-blind treatment period.

Patients who complete the double-blind treatment period at End of Week 24 or meet Early Failure criteria at End of Week 12 will transition to an open-label pacritinib treatment period through End of Week 48. In addition, if a study arm closes due to interim futility or safety, all patients currently randomized to that arm will transition to open-label treatment.

Study termination is planned approximately 1 year from the first dose of the last patient.

Eligibility Criteria:
Key Inclusion Criteria:

* Documented evidence of a pathogenic mutation at methionine-41 (M41) or neighboring splice site mutation (c.118-1, c.118-2) position in UBA1 mutation based on myeloid next-generation sequencing (NGS) droplet digital polymerase chain reaction (ddPCR), or Sanger sequencing in peripheral blood or bone marrow samples.
* Current or documented evidence of past involvement within 6 months prior to enrollment of at least one of the following organ systems by VEXAS syndrome: cutaneous (e.g., neutrophilic dermatosis, cutaneous vasculitis), vasculature (e.g., vasculitis), musculoskeletal (e.g., chondritis, arthritis), ocular (e.g., uveitis, scleritis), periorbital (e.g. periorbital edema), genitourinary (e.g., epididymitis), or pulmonary (e.g., alveolitis).
* Receiving ongoing GC therapy (stable prednisone or prednisolone dose of 15-45 mg/day) leading up to enrollment. Note that patients who are stable on GC doses of 10-14 mg/day in addition to another non-GC anti-inflammatory therapy at Screening who have a previously documented VEXAS flare on a GC dose \>=10mg/day may be eligible provided that their GC dose is escalated to 15-45 mg/day after washout.
* Karnofsky Performance Status ≥50%
* Adequate organ function, meeting all the following criteria within 30 days prior to enrollment:

  1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN)
  2. Total bilirubin ≤4 × ULN (≤8 × ULN in the setting of Gilbert's syndrome)
  3. Creatinine clearance (CrCl) ≥30 mL/min based on the Cockcroft-Gault formula
  4. Absolute neutrophil count ≥500/μL
  5. Prothrombin time (PT) or international normalized ratio (INR) ≤1.5 × ULN (unless prolonged due to therapeutic anticoagulation)
  6. Partial thromboplastic time (PTT) or activated PTT ≤1.5 × ULN (unless prolonged due to therapeutic anticoagulation)
  7. Platelet count ≥25 × 10\^9/L
  8. Peripheral blasts \<5%
* Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test within 30 days prior to enrollment and a negative urine pregnancy test on Day 1 prior to randomization and dosing.
* WOCBP and male patients must agree to use a highly effective method of contraception starting at the first dose of study therapy through 90 days after the last dose of study therapy.

Key Exclusion Criteria

* Prior allogenic hematopoietic stem cell transplant (allo-HSCT) or solid organ transplant (other than corneal).
* Current use of systemic GCs for conditions other than VEXAS syndrome, which, in the opinion of the Investigator, would interfere with adherence to a GC taper regimen and/or assessment of efficacy.
* More than one prior admission to an intensive care unit due to a VEXAS Syndrome flare within the prior 6 months.
* Received ≥9 units of intensive red blood cell (RBC) transfusions in the 90 days prior to enrollment.
* Known concurrent myelodysplastic syndrome (MDS) requiring antineoplastic treatment, or allo-HSCT, or known high-risk or very high-risk MDS based on the Revised International Prognostic Scoring System (IPSS-R). Patients with MDS who do not meet these criteria may enroll.
* Malignancy within 1 year prior to enrollment with the exception of MDS (per exclusion criterion), curatively treated non-melanoma skin cancer, or curatively treated carcinoma in situ. Patients with pre-malignant hematologic conditions (e.g., monoclonal gammopathy of unknown significance \[MGUS\], clonal cytopenia of unknown significance) may enroll.
* Exposure to hypomethylating agents (HMA) within 6 months prior to enrollment, or exposure to more than 4 cycles of HMAs at any time.
* Exposure to non-GC anti-inflammatory therapy or hematologic support therapy within protocol defined timeframes prior to enrollment
* Exposure to anti-platelet therapy with the exception of low-dose aspirin (≤100 mg daily) within 28 days prior to enrollment.
* Known concomitant multiple myeloma, or serum M-protein ≥3 g/dL, involved-to uninvolved free light chain (FLC) ratio ≥100, or involved FLC level ≥100 mg/dL. Patients with MGUS may enroll.
* Systemic treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducer within 5 half-lives prior to enrollment.
* Significant recent bleeding history defined as National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2 within 3 months prior to enrollment, unless precipitated by an inciting event.
* History of clinically significant cardiovascular disease, or clinically significant abnormalities in rhythm or conduction during Screening ECG, including:

  1. QT corrected by the Fridericia method (QTcF) \> 480 msec within 30 days prior to enrollment; if QTcF is thought to be prolonged due to a modifiable factor (e.g., medication / electrolyte abnormality), QTcF may be re-evaluated
  2. Severe cardiac event (CTCAE grade ≥3) within 3 months prior to enrollment
  3. Heart failure resulting in limitations during ordinary activity.
* Arterial or venous thrombotic or embolic events, including deep vein thrombosis, pulmonary embolism, and cerebrovascular accident (including transient ischemic attacks), within 60 days prior to enrollment.
* Moderate or severe hepatic impairment that meets criteria for Child-Pugh Class B or C, or active viral hepatitis.
* Uncontrolled human immunodeficiency virus (HIV) off antiretrovirals, or on antiretrovirals with detectable viral load.
* Positive Quantiferon (or other interferon gamma release assay) during Screening.
* Known history of disseminated mycobacterial infection.
* Concurrent enrollment in another interventional study, or treatment with an experimental therapy within 28 days or five half-lives prior to enrollment, whichever is longer.
* Pregnant, intending to become pregnant during the study, or currently breastfeeding/lactating.
* Patients with any acute, active infection requiring systemic antimicrobial treatment at the time of enrollment. Exceptions are made for prophylactic antibiotics or chronic antibiotic therapy for non-acute conditions.
* Known hypersensitivity to pacritinib or any of the following inactive ingredients: microcrystalline cellulose, polyethylene glycol, and magnesium stearate.