NCT07569081尚未招募2 期
A Randomized Phase 2/3, Double-blind, Placebo Controlled Adaptive Study Evaluating the Efficacy and Safety of Momelotinib in Participants With VEXAS Syndrome
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 136
- 主要终点
- ORR (Objective response rate) at Week 26
研究概览
简要总结
This study will assess the efficacy and safety of momelotinib in participants with a diagnosis of VEXAS.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Age greater than equal to (>=)18 years OR of legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the Informed Consent Form.
- •Confirmed diagnosis of clinical VEXAS defined by:
- •Documented evidence of a canonical, pathogenic Ubiquitin-like modifier activating enzyme 1 (UBA1) mutation
- •Inflammatory manifestations: current or documented past involvement within 6 months of at least one organ system
- •Receiving glucocorticoid (GC) treatment (prednisone/prednisolone) for >=4 consecutive weeks for >=10 days prior to randomization.
- •A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies:
- •Is a Participant of non-childbearing potential (PONCBP) OR
- •Is a Participant of childbearing potential (POCBP) and using a contraceptive method that is highly effective
- •Is capable of giving signed informed consent including compliance with the requirements and restrictions
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2 at the time of screening.
- •Has adequate organ function
排除标准
- •More than 1 prior admission to an intensive care unit due to a VEXAS flare within the 6 months prior to randomization.
- •History of severe corticosteroid toxicity: uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), psychiatric, osteoporosis/osteomalacia, glaucoma, corneal ulcers/injuries, nausea or vomiting or gastrointestinal disease.
- •High risk/very high risk Myelodysplastic syndrome (MDS), according to the Revised International Prognostic Scoring System (IPSS-R) with overall risk score >3.
- •Peripheral blood blast counts >=10%.
- •Multiple myeloma (all stages) and other active plasma cell dyscrasias requiring treatment.
- •Malignancy (except disease under study including Lower-risk myelodysplastic syndrome [LR-MDS]) that has progressed or required active treatment within the past (24 months) except for basal cell or squamous cell carcinomas of the skin or in-situ carcinomas).
- •Uncontrolled intercurrent illness within 12 weeks prior to initiation of momelotinib.
- •Ongoing adverse reaction(s) from prior therapy that have not recovered to Grade <=1 per NCI CTCAE v6.0 or to the Baseline status preceding prior therapy
- •Psychiatric illness, social situation, or any other condition that would limit informed consent and/or compliance with trial requirements or may interfere with the interpretation of study results, as judged by Investigator or Sponsor.
- •Has any clinically significant gastrointestinal conditions or abnormalities that may alter absorption or swallowing
- •Known contraindication or hypersensitivity to momelotinib and its metabolites, or any of their excipients.
- •Presence of peripheral neuropathy >=Grade 2 per NCI CTCAE v6.
- •Known history of disseminated mycobacterial infection.
- •Known positive status for human immunodeficiency virus (HIV).
- •Positive QuantiFERON (or other interferon gamma release assay) during Screening.
- •Unable to receive any Pneumocystis jiroveci pneumonia (PJP) medical prophylaxis
- •Known clinically significant anemia due to iron, vitamin B12 or folate deficiencies, or autoimmune or hereditary hemolytic anemia, gastrointestinal bleeding, or thalassemia.
- •More than 1 prior line of VEXAS directed therapy before or after VEXAS diagnosis or other medical condition.
- •Use of the following treatments within the noted time periods referenced from date of randomization:
- •VEXAS-directed therapies (washout period) up to 5 half-lives or up 14 days if half-life is <3 days
- •Other non-GC anti-inflammatory therapies: for non-biologics): 14 days or five half-lives, whichever is longer; for biologics): 28 days or two half-lives whichever is longer.
- •Hematologic support therapy (e.g., ESAs, danazol, luspatercept, G-CSF): 4 weeks
- •Cell-depleting therapies such as anti-CD20 (rituximab): 12 months
- •Investigational agent from a class not otherwise specified: 5 half-lives or 60 days, whichever is longer
- •GC use for conditions other than VEXAS, which would interfere with adherence to the fixed GC taper regimen and/or to assessment of efficacy.
- •Chronic use of systemic corticosteroids for >4 years or inability to withdraw corticosteroid treatment
- •Planned allogeneic HSCT for MDS or VEXAS, within 1 year.
- •Any major surgery within 28 days prior to randomization.
- •Prior allogeneic/autologous stem cell transplant or solid organ transplant (other than corneal).
- •Presence of peripheral neuropathy >=Grade 2 per NCI CTCAE v6.
- •Hepatitis B or C active infection, unless protocol defined criteria are met.
- •Any of the following conditions within 6 months prior to randomization:
- •Unstable angina pectoris
- •Symptomatic congestive heart failure
- •Uncontrolled cardiac arrhythmia
- •QTc >450 msec or QTc >480 msec for participants with bundle branch block.
研究组 & 干预措施
Momelotinib Dose level 1 + Glucocorticoids
Experimental
Participants will receive momelotinib at dose level 1 along with glucocorticoids as a background therapy (prednisone or prednisolone). Due to adaptive design of the study, additional participants may be randomized to this arm in phase 3.
干预措施: Glucocorticoids (Drug)
Momelotinib Dose level 2 + Glucocorticoids
Experimental
Participants will receive momelotinib at dose level 2 along with glucocorticoids as a background therapy (prednisone or prednisolone). Due to adaptive design of the study, additional participants may be randomized to this arm in phase 3
干预措施: Glucocorticoids (Drug)
Placebo + Glucocorticoids
Placebo Comparator
Participants will receive momelotinib matched placebo along with glucocorticoids as a background therapy(prednisone or prednisolone). Due to adaptive design of the study, additional participants may be randomized to this arm in phase 3
干预措施: Glucocorticoids (Drug)
Placebo + Glucocorticoids
Placebo Comparator
Participants will receive momelotinib matched placebo along with glucocorticoids as a background therapy(prednisone or prednisolone). Due to adaptive design of the study, additional participants may be randomized to this arm in phase 3
干预措施: Placebo (Drug)
Momelotinib Dose level 1 + Glucocorticoids
Experimental
Participants will receive momelotinib at dose level 1 along with glucocorticoids as a background therapy (prednisone or prednisolone). Due to adaptive design of the study, additional participants may be randomized to this arm in phase 3.
干预措施: Momelotinib (Drug)
Momelotinib Dose level 2 + Glucocorticoids
Experimental
Participants will receive momelotinib at dose level 2 along with glucocorticoids as a background therapy (prednisone or prednisolone). Due to adaptive design of the study, additional participants may be randomized to this arm in phase 3
干预措施: Momelotinib (Drug)
结局指标
主要结局
ORR (Objective response rate) at Week 26
时间窗: At Week 26
ORR is defined as the proportion of participants who have achieved complete response (CR) or partial response (PR) during the 26-week Primary Treatment Period.
次要结局
- Phase 2: Percentage of participants with partial response (PR) or complete response (CR) at Week 26(At Week 26)
- Phase 2: Number of participants with adverse events and clinically significant changes in laboratory parameters, and vital signs to support identification of the RP3D(Up to 26 Weeks)
- Phase 2: Plasma concentrations of momelotinib and metabolite of momelotinib 21 (M21) to support identification of the RP3D(Up to 26 Weeks)
- Number of flare-free days(Up to 26 Weeks)
- Duration of response (DoR)(Up to 104 Weeks)
- Number of flare-free days with glucocorticoid (GC) dose <=10 mg/day(Up to 104 Weeks)
- Percentage of participants achieving complete and partial biochemical response(Up to 26 Weeks)
- Objective response rate (ORR) at Week 52(At Week 52)
- Number of Participants with Hematologic Improvement- Erythroid (HI-E) response per International Working Group (IWG) 2018 criteria(Up to 26 Weeks)
- Change from Baseline in Short Form 36 (SF-36) domain and summary scores(Baseline and up to Week 48)
- Plasma concentration of momelotinib and M21(Up to 26 Weeks)
- Change from Baseline in European Organization for Research and Treatment of Cancer Item Library (EORTC IL) 479 score(Baseline and up to Week 156)
- Change From Baseline in Patient Reported Outcome Measurement Information System (PROMIS) Physical Function Short Form 10b(Baseline and up to Week 156)
- Change from Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-FATIGUE)(Baseline and up to Week 156)
- Changes from Baseline in Patient Global Impression of Severity (PGIS) scores(Baseline and up to Week 156)
- Changes in Patient Global Impression of Change (PGIC) scores(Baseline and up to Week 156)
- Changes from Baseline in European quality of life 5 dimensions 5 level version (EQ-5D-5L)(Baseline and up to Week 48)
- Changes from Baseline in European quality of life-Visual Analogue Scale (EQ-VAS)(Baseline and up to Week 48)
- Number of participants with adverse events (AEs) and Serious adverse events (SAEs)(Up to Week 108)
- Number of participants with adverse events (AEs) and Serious adverse events (SAEs) by severity(Up to Week 108)
- Number of participants with AEs leading to discontinuation or dose modifications(Up to Week 108)
- Overall Survival(At Months 12, 24 and 36)
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