VEXAS syndrome
Conditions
Interventions
Double-blind treatment period: pacritinib 200 mg b.i.d. or pacritinib 100 mg b.i.d. plus placebo 1 capsule b.i.d. or placebo 2 capsules b.i.d. administered orally for up to 24 weeks.
Open label treatm
all participants tarting open label pacritinib will start on 100 mg b.i.d. All participants who have had their dose reduced while in the double-blind treatment period will start pacritinib at 100 mg b
Sponsors
Yamazaki Hiroshi
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age >-18 years at the time of signing the informed consent form (ICF). 2. Documented evidence of a pathogenic or likely pathogenic mutation at methionine-41 (M41) or neighboring splice site mutation (c.118-1, c.118-2) position in UBA1 based on myeloid NGS, droplet digital polymerase chain reaction (ddPCR), or Sanger sequencing in peripheral blood or bone marrow samples. 3. Current or documented evidence of past inflammatory 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). Note: Other inflammatory signs may be considered for enrollment at the discretion of the Investigator provided that these signs have been previously demonstrated to be GC-responsive (i.e., resolve after administration of or escalation in GC therapy). 4. Receiving ongoing GC therapy (with prednisone or prednisolone) for >-4 consecutive weeks leading up to enrollment for the treatment of VEXAS syndrome. 5. Prednisone or prednisolone baseline dose of 15-45 mg/day that has been stable for >-10 days prior to enrollment. 6. Karnofsky Performance Status >-50%
Exclusion criteria
Exclusion criteria: 1. Prior allogenic hematopoietic stem cell transplant (allo-HSCT) or solid organ transplant (other than corneal). 2. 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. 3. More than one prior admission to an intensive care unit due to a VEXAS syndrome flare within the prior 6 months. 4. Received >-9 units of red blood cell (RBC) transfusion in the 90 days prior to enrollment 5. Known concurrent myelodysplastic syndrome (MDS) requiring antineoplastic treatment (e.g.,hypomethylating agents [HMAs]) or allo-HSCT, or known high-risk or very high-risk MDS based on the Revised International Prognostic Scoring System (IPSS-R). Participants with MDS who do not meet these criteria may enroll. 6. 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. Participants with pre-malignant hematologic conditions (e.g., monoclonal gammopathy of unknown significance [MGUS], clonal cytopenia of unknown significance) may enroll. 7. Exposure to HMAs (e.g., azacitidine, decitabine) within 6 months prior to enrollment, or exposure to HMAs for more than 6 cycles at any time. Note: a cycle refers to a dosing period of approximately 28 days. 8. Exposure to the following agents within the following timeframe prior to enrollment a. Anti-CD20 agents (e.g., rituximab): 180 days b. Anti-interleukin (IL)-23 agents (e.g., ustekinumab): 90 days c. Anti-tumor necrosis factor (TNF)alpha except for etanercept (e.g., infliximab): 60 days d. Canakinumab: 60 days e. Intravenous anti-IL-6 agents (e.g., tocilizumab): 42 days f. Subcutaneous anti-IL-6 agents: 28 days g. Anti-IL-17 agents (e.g., secukinumab): 28 days h. Anti-integrins (e.g., vedolizumab): 60 days i. Intravenous immunoglobulin: 28 days j. Omalizumab: 28 days k. Danazol, immunomodulatory imide drugs (IMiDs), luspatercept, or thrombopoietin receptor agonists: 28 days l. Cytotoxic chemotherapy: 28 days m. Etanercept: 21 days n. Oral Janus kinase (JAK) inhibitors: 14 days o. Anti-IL-1 agents except for canakinumab: 14 days p. Any other non-GC anti-inflammatory therapy (e.g., mycophenolate, azathioprine, cyclosporine, sulfasalazine, methotrexate): 14 days or 5 half-lives, whichever is longer Note: Participants on erythropoiesis stimulating agents (ESAs) at the time of informed consent may continue to receive ESAs during Screening and on trial, but new ESA use is not permitted during this 28-day period or on trial. 9. Exposure to anti-platelet therapy with the exception of low-dose aspirin (--3 g/dL, involved-to-uninvolved free light chain (FLC) ratio >-100, or involved FLC level >-100 mg/L. Participants with MGUS may enroll. 11. Systemic treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducer within 5 half-lives prior to enrollment. 12. 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 (e.g., surgery or trauma). 13. For Japan only: Participants with a history of or concurrent interstitial lung disease.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Overall Clinical Response (OCR), defined as achieving Clinical Response or better at any time during the double-blind treatment period. | — |
Secondary
| Measure | Time frame |
|---|---|
| - Number of flare-free days with GC dose <10 mg - Hematologic Improvement - Erythroid (HI-E) at any time among participants with baseline hemoglobin <10 g/dL per modified International Working Group (IWG) criteria - Hematologic Improvement - Platelets (HI-P) at any time among participants with baseline platelet count <100 x 109/L per modified IWG criteria - Change in health-related QOL as measured by the Patient-Reported Outcomes Measurement Information Systems (PROMIS) short forms (fatigue, physical function, sleep disturbance), 36-Item Short Form Health Survey (SF-36), and the Patient Global Impression of Change (PGIC) - PK of pacritinib - PD inflammatory biomarkers (CRP, erythrocyte sedimentation rate [ESR], ferritin) | — |
Countries
Canada, Germany, Italy, Japan, UK, USA
Contacts
Public ContactHiroshi Yamazaki
CMIC Co., Ltd
Outcome results
None listed