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

Phase 2

Recruiting

• Conditions: VEXAS; VEXAS Syndrome
• Interventions: Drug: Placebo; Drug: Pacritinib

• Registration Number: NCT06782373
• Lead Sponsor: Swedish Orphan Biovitrum

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2025-01-07
• Study First Submitted QC: 2025-01-14
• Study First Posted: 2025-01-17
• Status Verified: 2025-05
• Study Start: 2025-05
• Last Update Submitted: 2025-05-12
• Last Update Posted: 2025-05-13
• Primary Completion: 2027-08
• Study Completion: 2027-08

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 78

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.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	To receive oral administration of placebo for up to 24 weeks.
Pacritinib	Pacritinib	To receive oral administration of pacritinib dose A for up to 24 weeks.
Pacritinib + placebo	Pacritinib	To receive oral administration of pacritinib dose B plus placebo for up to 24 weeks
Pacritinib + placebo	Placebo	To receive oral administration of pacritinib dose B plus placebo for up to 24 weeks

Primary Outcome Measures

Name	Time	Method
Overall Clinical Response (OCR), defined as achieving Clinical Response or better at any time during the double-blind treatment period.	up to End of Week 24	Difference in the proportion of patients achieving OCR for the pairwise comparison of pacritinib dose A vs. placebo and pacritinib dose B plus placebo vs. placebo

Secondary Outcome Measures

Name	Time	Method
Proportion of patients on each arm achieving each Best Response category (Clinical Biochemical Response, Clinical Response, Partial Clinical Response, Stable Disease, or Non-response).	up to End of Week 24
Number of flare-free days with GC dose <10 mg	up to End of Week 24
Hematologic Improvement - Erythroid	up to End of Week 24	Erythroid (HI-E) at any time among patients with baseline hemoglobin \<10 g/dL per modified International Working Group (IWG) criteria
Hematologic Improvement - Platelets	up to End of Week 24	Platelets (HI-P) at any time among patients with baseline platelet count \<100 × 10\^9/L per modified IWG criteria
Change in health-related quality of life (QOL) as measured by Patient-Reported Outcomes Measurement Information Systems (PROMIS) fatigue short form	up to End of Week 24	The PROMIS short form domains of fatigue 4a will be summarized, raw score from 4 to 20 (T-score from 33.7 to 75.8). A higher score is associated with more fatigue.
Change in health-related QOL as measured by PROMIS physical function short form	up to End of Week 24	The PROMIS short form domains of physical function 4a will be summarized, raw score from 4 to 20 (T-score from 22.5 to 57.0). A higher score is associated with better physical function.
Change in health-related QOL as measured by PROMIS sleep disturbance short form	up to End of Week 24	The PROMIS short form domains of sleep disturbance 4a will be summarized, raw score from 4 to 20 (T-score from 32.0 to 73.3). A higher score is associated with more sleep disturbance.
Change in health-related QOL as measured by the 36-item short form (SF) Survey	up to End of Week 24	The SF-36 Survey measures eight domains of health status; physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy/fatigue, emotional well-being, social functioning, pain, and general health. The values for each domain range from 0 to 100, with the higher score indicating a better health status.
Change in health-related QOL as measured by Patient's Global Impression of Change (PGIC) response	up to End of Week 24	The number and percentage of patients achieving PGIC response (reporting symptoms as "much" or "very much" improved).
Mean plasma concentration of pacritinib	up to Week 24 (pre-dose only)	Mean plasma concentrations (pre-dose and post-dose) will be determined for each pharmacokinetic sampling timepoint.
Change in pharmacodynamic (PD) inflammatory biomarker: C-reactive protein (CRP)	up to 30-day Post-End of Trial
Change in PD inflammatory biomarker: erythrocyte sedimentation rate (ESR)	up to 30-day Post-End of Trial
Change in PD inflammatory biomarker: ferritin	up to 30-day Post-End of Trial

Trial Locations

Locations (40)

Tenon Hospital - APHP; 🇫🇷 Paris, France

Hospices Civils de Lyon - Lyon Sud; 🇫🇷 Pierre-Bénite, France

Mayo Clinic - Scottsdale; 🇺🇸 Scottsdale, Arizona, United States

University of Maryland Medical Center Midtown Campus; 🇺🇸 Baltimore, Maryland, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Mayo Clinic - Rochester; 🇺🇸 Rochester, Minnesota, United States

NYU Langone Health; 🇺🇸 New York, New York, United States

Cleveland Clinic - Cleveland; 🇺🇸 Cleveland, Ohio, United States

The James Cancer Hospital and Solove Research Institute; 🇺🇸 Columbus, Ohio, United States

UT MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

University of Utah Healthcare; 🇺🇸 Salt Lake City, Utah, United States

Fred Hutchinson Cancer Center; 🇺🇸 Seattle, Washington, United States

Vancouver Coastal Health Research Institute; 🇨🇦 Vancouver, British Columbia, Canada

Royal Free Hospital; 🇬🇧 London, United Kingdom

Queen Elizabeth II Health Sciences Center; 🇨🇦 Halifax, Nova Scotia, Canada

Princess Margaret Cancer Centre; 🇨🇦 Toronto, Ontario, Canada

Hospital du Sacre-Coeur in Montreal; 🇨🇦 Montréal, Quebec, Canada

Lille University Hospital Center; 🇫🇷 Lille, France

Saint-Antoine Hospital - APHP; 🇫🇷 Paris, France

University Hospital Center of Poitiers; 🇫🇷 Poitiers, France

IUCT-Oncopole; 🇫🇷 Toulouse, France

University Hospital Tuebingen, Medical Clinic II, Hematology, Oncology, Clinical Immunology and Rheumatology; 🇩🇪 Tuebingen, Baden-Wuerttemberg, Germany

Hospital Rechts der Isar of the Technical University of Munich, Clinic and Polyclinic for Internal Medicine III: Hematology and Internal Oncology; 🇩🇪 Munich, Bavaria, Germany

University Hospital Duesseldorf; 🇩🇪 Duesseldorf, North Rhine-Westphalia, Germany

University Hospital Carl Gustav Carus Dresden, Medical Clinic and Polyclinic I; 🇩🇪 Dresden, Saxony, Germany

University Hospital Schleswig-Holstein; 🇩🇪 Luebeck, Schleswig-Holstein, Germany

University Hospital Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

Hospital San Raffaele, IRCCS, Unit of Immunology, Rheumatology, Allergy and Rare Diseases; 🇮🇹 Milan, Italy

University Hospital of Padova, Rheumatology Unit, Department of Medicine - DIMED; 🇮🇹 Padova, Italy

AUSL of Reggio Emilia - Hospital Arcispedale S. Maria Nuova, Complex Structure of Rheumatology; 🇮🇹 Reggio Emilia, Italy

Foundation PTV - Polyclinic Tor Vergata Biomedicine and prevention; 🇮🇹 Roma, Italy

Fukushima Medical University Hospital; 🇯🇵 Fukushima, Japan

Nagasaki University Hospital; 🇯🇵 Nagasaki, Japan

Yokohama City University Hospital; 🇯🇵 Yokohama, Japan

Hospital Clinic of Barcelona; 🇪🇸 Barcelona, Spain

Catalan Institute of Oncology, Hospital Duran i Reynals, Department of Clinical Hematology; 🇪🇸 Hospitalet de Llobregat, Spain

University Clinical Hospital of Salamanca; 🇪🇸 Salamanca, Spain

St James's University Hospital; 🇬🇧 Leeds, United Kingdom

King's College Hospital, Department of Hematology; 🇬🇧 London, United Kingdom

Churchill Hospital; 🇬🇧 Oxford, United Kingdom