Clinical trial NCT06782373: A Study to Assess the Effectiveness and Safety of Pacritinib in Patients With VEXAS Syndrome (PAXIS)
Official title: PAXIS: A Randomized, Double-blind, Placebo-controlled Dose-finding Phase 2 Study (Part 1) Followed by an Open-label Period (Part 2) to Assess the Efficacy and Safety of Pacritinib in Patients With VEXAS Syndrome
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: VEXAS
VEXAS Syndrome
Keywords: Vacuoles
E1 Ubiquitin-activating enzyme
X-linked
Autoinflammatory
Somatic syndrome
UBA1
Hematologic neoplasms
Myelodysplastic Syndromes
Pacritinib
Myeloid progenitors
Lead sponsor: Swedish Orphan Biovitrum
Sponsor class: INDUSTRY
Collaborators: name: PSI CRO
First posted: 2025-01-17
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomized 1:1:1 to receive pacritinib dose A, pacritinib dose B plus placebo, or placebo 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. Randomization will be stratified by prescribed GC dose on the day of randomization.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Overall Clinical Response (OCR), defined as achieving Clinical Response or better at any time during the double-blind treatment period.
timeFrame: up to End of Week 24
Secondary outcomes:
measure: Proportion of patients on each arm achieving each Best Response category (Clinical Biochemical Response, Clinical Response, Partial Clinical Response, Stable Disease, or Non-response).
timeFrame: up to End of Week 24
measure: Number of flare-free days with GC dose <10 mg
timeFrame: up to End of Week 24
measure: Hematologic Improvement - Erythroid
timeFrame: up to End of Week 24
measure: Hematologic Improvement - Platelets
timeFrame: up to End of Week 24
measure: Change in health-related quality of life (QOL) as measured by Patient-Reported Outcomes Measurement Information Systems (PROMIS) fatigue short form
timeFrame: up to End of Week 24
measure: Change in health-related QOL as measured by PROMIS physical function short form
timeFrame: up to End of Week 24
measure: Change in health-related QOL as measured by PROMIS sleep disturbance short form
timeFrame: up to End of Week 24
measure: Change in health-related QOL as measured by the 36-item short form (SF) Survey
timeFrame: up to End of Week 24
measure: Change in health-related QOL as measured by Patient's Global Impression of Change (PGIC) response
timeFrame: up to End of Week 24
measure: Mean plasma concentration of pacritinib
timeFrame: up to Week 24 (pre-dose only)
measure: Change in pharmacodynamic (PD) inflammatory biomarker: C-reactive protein (CRP)
timeFrame: up to 30-day Post-End of Trial
measure: Change in PD inflammatory biomarker: erythrocyte sedimentation rate (ESR)
timeFrame: up to 30-day Post-End of Trial
measure: Change in PD inflammatory biomarker: ferritin
timeFrame: up to 30-day Post-End of Trial
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic - Scottsdale
state: Arizona
city: Baltimore
country: United States
facility: University of Maryland Medical Center Midtown Campus
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic - Cleveland
state: Ohio
city: Columbus
country: United States
facility: The James Cancer Hospital and Solove Research Institute
state: Ohio
city: Houston
country: United States
facility: UT MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Healthcare
state: Utah
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Vancouver
country: Canada
facility: Vancouver Coastal Health Research Institute
state: British Columbia
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Center
state: Nova Scotia
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montréal
country: Canada
facility: Hospital du Sacre-Coeur in Montreal
state: Quebec
city: Lille
country: France
facility: Lille University Hospital Center
city: Paris
country: France
facility: Saint-Antoine Hospital - APHP
city: Paris
country: France
facility: Tenon Hospital - APHP
city: Pierre-Bénite
country: France
facility: Hospices Civils de Lyon - Lyon Sud
city: Poitiers
country: France
facility: University Hospital Center of Poitiers
city: Toulouse
country: France
facility: IUCT-Oncopole
city: Tuebingen
country: Germany
facility: University Hospital Tuebingen, Medical Clinic II, Hematology, Oncology, Clinical Immunology and Rheumatology
state: Baden-Wuerttemberg
city: Munich
country: Germany
facility: Hospital Rechts der Isar of the Technical University of Munich, Clinic and Polyclinic for Internal Medicine III: Hematology and Internal Oncology
state: Bavaria
city: Duesseldorf
country: Germany
facility: University Hospital Duesseldorf
state: North Rhine-Westphalia
city: Dresden
country: Germany
facility: University Hospital Carl Gustav Carus Dresden, Medical Clinic and Polyclinic I
state: Saxony
city: Luebeck
country: Germany
facility: University Hospital Schleswig-Holstein
state: Schleswig-Holstein
city: Hamburg
country: Germany
facility: University Hospital Hamburg-Eppendorf
city: Milan
country: Italy
facility: Hospital San Raffaele, IRCCS, Unit of Immunology, Rheumatology, Allergy and Rare Diseases
city: Padova
country: Italy
facility: University Hospital of Padova, Rheumatology Unit, Department of Medicine - DIMED
city: Reggio Emilia
country: Italy
facility: AUSL of Reggio Emilia - Hospital Arcispedale S. Maria Nuova, Complex Structure of Rheumatology
city: Roma
country: Italy
facility: Foundation PTV - Polyclinic Tor Vergata Biomedicine and prevention
city: Fukushima
country: Japan
facility: Fukushima Medical University Hospital
city: Nagasaki
country: Japan
facility: Nagasaki University Hospital
city: Yokohama
country: Japan
facility: Yokohama City University Hospital
city: Barcelona
country: Spain
facility: Hospital Clinic of Barcelona
city: Hospitalet de Llobregat
country: Spain
facility: Catalan Institute of Oncology, Hospital Duran i Reynals, Department of Clinical Hematology
city: Salamanca
country: Spain
facility: University Clinical Hospital of Salamanca
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: King's College Hospital, Department of Hematology
city: Oxford
country: United Kingdom
facility: Churchill Hospital
Study officials:
affiliation: Sobi, Inc.
name: Study Physician
role: STUDY_DIRECTOR
References: