PAXIS: A Phase 2a and 2b Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Pacritinib in Patients With VEXAS Syndrome
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 156
- 试验地点
- 117
- 主要终点
- Overall Clinical Response (OCR), defined as achieving Clinical Response or better at any time during the double-blind treatment period.
研究概览
简要总结
This trial 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. In phase 2a, approximately 78 participants will be randomized to either pacritinib dose A, pacritinib dose B + placebo, or placebo. In Phase 2b, approximately 78 participants will be randomized. Phase 2b participants will initially be randomized to either pacritinib dose A, pacritinib dose B + placebo, or placebo. After dose selection, Phase 2b further participants will be randomized to either the selected pacritinib dose or placebo.
Randomization will be stratified by prescribed GC dose on the day of randomization.
详细描述
This trial is a randomized, multicenter, double-blind, placebo-controlled phase 2a and 2b trial designed to evaluate the efficacy and safety of pacritinib for the prevention of VEXAS flares after glucocorticoid (GC) taper. The trial will enroll participants ≥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).
In phase 2a, participants 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.
In Phase 2b, approximately 78 participants will be randomized (enrollment starts after completion of Phase 2a enrollment). Randomization will initially be conducted in a 1:1:1 ratio to receive pacritinib dose A, pacritinib dose B plus placebo, or placebo, consistent with Phase 2a. Following Phase 2a results, a single pacritinib dose will be selected for continued evaluation. After dose selection, Phase 2b further participants will be randomized in a 2:1 ratio of the selected pacritinib dose to placebo until the total target of 78 participants are randomized.
Randomization will be stratified by prescribed GC dose on the day of randomization. All outcomes will be reported by treatment arm, and comparisons between each pacritinib arm and placebo (Phase 2a) or between the selected pacritinib dose and placebo (Phase 2b) will be performed in the double-blind treatment periods.
Participants who complete the double-blind treatment period at EOW 24 or meet Early Failure criteria at EOW 12 will transition to an open-label pacritinib treatment period through EOW 48. In addition, if a trial arm closes (due to interim futility or safety in Phase 2a or due to dose selection in Phase 2b), all participants currently randomized to the terminated arm will transition to open-label treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
In the double-blind portion of the trial, the Sponsor, trial participants, and Investigators will be blinded to treatment assignments. Active and placebo products will be of identical appearance. The Independent Data Monitoring Committee will have access to unblinded data.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 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).
- •Receiving ongoing GC therapy (stable prednisone or prednisolone dose of 15-45 mg/day) leading up to enrollment.
- •Karnofsky Performance Status ≥50%
- •Adequate organ function, meeting all the following criteria within 30 days prior to enrollment:
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN)
- •Total bilirubin ≤4 × ULN (≤8 × ULN in the setting of Gilbert's syndrome)
- •Creatinine clearance (CrCl) ≥30 mL/min based on the Cockcroft-Gault formula
- •Absolute neutrophil count ≥500/μL
- •Prothrombin time (PT) or international normalized ratio (INR) ≤1.5 × ULN (unless prolonged due to therapeutic anticoagulation)
- •Partial thromboplastic time (PTT) or activated PTT ≤1.5 × ULN (unless prolonged due to therapeutic anticoagulation)
- •Platelet count ≥25 × 10^9/L (value must be obtained in the absence of platelet transfusion in the prior 7 days)
- •Peripheral blasts <5%
- •QT corrected by the Fridericia method (QTcF) ≤450 msec in males or ≤470 msec in females. Participants with QRS prolongation >100 msec may enroll if their QTcF is ≤480 msec. Participants with ventricular paced rhythms may enroll if their QTcF is ≤500 msec. If QTcF is thought to be prolonged due to a modifiable factor (e.g., medication / electrolyte abnormality), QTcF may be reevaluated.
- •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 participants must agree to use a highly effective method of contraception starting at the first dose of trial therapy through 30 days after the last dose of trial therapy.
排除标准
- •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). Participants 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. Participants 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 6 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. Participants 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:
- •Severe cardiac event (CTCAE grade ≥3) within 3 months prior to enrollment
- •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 or prior enrollment in another prospective interventional trial of VEXAS-directed therapy, or concurrent enrollment in another interventional trial of non-VEXAS-directed therapy, or treatment with a non-VEXAS-directed experimental therapy within 28 days or five half-lives prior to enrollment, whichever is longer.
- •Pregnant, intending to become pregnant during the trial, or currently breastfeeding/lactating.
- •Participants 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.
研究组 & 干预措施
Pacritinib + placebo
To receive oral administration of pacritinib dose B plus placebo for up to 24 weeks
干预措施: Placebo (Drug)
Placebo
To receive oral administration of placebo for up to 24 weeks.
干预措施: Placebo (Drug)
Pacritinib + placebo
To receive oral administration of pacritinib dose B plus placebo for up to 24 weeks
干预措施: Pacritinib (Drug)
Pacritinib
To receive oral administration of pacritinib dose A for up to 24 weeks.
干预措施: Pacritinib (Drug)
结局指标
主要结局
Overall Clinical Response (OCR), defined as achieving Clinical Response or better at any time during the double-blind treatment period.
时间窗: up to End of Week 24
Difference in the proportion of participants achieving OCR for the pairwise comparison of pacritinib dose A vs. placebo and pacritinib dose B plus placebo vs. placebo
Overall Response Rate (ORR), defined as achieving Partial Clinical Response or better at any time during the double-blind treatment period.
时间窗: up to End of Week 24
Difference in the proportion of participants achieving ORR for the pairwise comparison of pacritinib dose A vs. placebo and pacritinib dose B plus placebo vs. placebo (Phase 2a) and selected pacritinib dose compared to placebo (Phase 2b)
Overall Clinical Response (OCR), defined as achieving Clinical Response or better at any time during the double-blind treatment period.
时间窗: up to End of Week 24
Difference in the proportion of participants achieving OCR for the pairwise comparison of pacritinib dose A vs. placebo and pacritinib dose B plus placebo vs. placebo
次要结局
- Hematologic Improvement - Platelets(up to End of Week 24)
- Proportion of participants 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)
- 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)
- Change in health-related QOL as measured by PROMIS physical function short form(up to End of Week 24)
- Change in health-related QOL as measured by PROMIS sleep disturbance short form(up to End of Week 24)
- Change in health-related QOL as measured by the 36-item short form (SF) Survey(up to End of Week 24)
- Change in health-related QOL as measured by Patient's Global Impression of Change (PGIC) response(up to End of Week 24)
- Mean plasma concentration of pacritinib(up to Week 24 (pre-dose only))
- 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)
- 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)
- Number of flare-free days with GC dose ≤10 mg(up to End of Week 24)
- Proportion of participants 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)
- Hematologic Improvement - Platelets(up to End of Week 24)
- 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)
- Change in health-related QOL as measured by PROMIS physical function short form(up to End of Week 24)
- Change in health-related QOL as measured by PROMIS sleep disturbance short form(up to End of Week 24)
- Change in health-related QOL as measured by the 36-item short form (SF) Survey(up to End of Week 24)
- Change in health-related QOL as measured by Patient's Global Impression of Change (PGIC) response(up to End of Week 24)
- Mean plasma concentration of pacritinib(up to Week 24 (pre-dose only))
- 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)