a study to assess the effectiveness and safety of pacritinib in patients with vexas syndrome (paxis)

Conditions: VEXAS; VEXAS Syndrome

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.

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.

Keywords: vacuoles e1 ubiquitin-activating enzyme x-linked autoinflammatory somatic syndrome uba1 hematologic neoplasms myelodysplastic syndromes pacritinib myeloid progenitors