NCT07738510尚未招募2 期
A Phase 2b, Multicenter, Open-label, Randomized, Dose Optimization Study of Ofirnoflast (HT-6184) for the Treatment of Anemia in Adults With Very Low- to Intermediate-Risk Myelodysplastic Syndromes Requiring Red Blood Cell Transfusions
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
- 50
- 主要终点
- Assess safety of ofirnoflast
研究概览
简要总结
The primary objective of this study is to evaluate the efficacy and safety of ofirnoflast administered orally once daily in adults with very low- to intermediate-risk myelodysplastic syndromes (MDS) who are transfusion-dependent and have failed one to three prior therapies, in order to identify the optimal dose for continuation into a Phase 3 study.
The secondary objectives of this study are to evaluate the extended hematologic response to ofirnoflast, to assess the safety and tolerability of ofirnoflast during the dose-selection phase, and to evaluate hematologic improvement with ofirnoflast treatment.
详细描述
- Ofirnoflast (HT-6184) is a first-in-class, orally administered small-molecule allosteric inhibitor of the NIMA-related protein kinase 7 (NEK7)-NLRP3 inflammasome, developed to address the inflammatory mechanisms implicated in ineffective hematopoiesis in myelodysplastic syndromes (MDS). Chronic activation of the NLRP3 inflammasome in MDS triggers pyroptosis, driving the ineffective hematopoiesis and cytopenias that define the disease. By selectively targeting NEK7, an essential mediator of NLRP3 assembly, ofirnoflast disrupts this inflammatory cascade without broadly suppressing innate immunity, with the goal of restoring hematopoiesis.
- Participants with very low- to intermediate-risk MDS who have failed one or more prior lines of therapy face limited treatment options and often develop chronic, symptomatic cytopenias requiring ongoing red blood cell (RBC) transfusions, which are associated with iron overload, reduced quality of life, and increased healthcare utilization. This study is designed to evaluate ofirnoflast in this defined, multiply-relapsed population and to identify the optimal dose to advance into a Phase 3 study.
- Enrollment will proceed in two sequential phases. Phase A (Safety Lead-in) will open with five participants administered ofirnoflast, observed for a minimum of 4 weeks. Following this observation period, the Safety Review Committee (SRC) will conduct a formal safety review; if no more than 1 of the 5 participants experiences a dose-limiting toxicity (DLT), enrollment will proceed to Phase B. Phase B (Randomized Enrollment) will dose arms concurrently with an additional formal safety review conducted by the SRC after the first 10 participants randomized.
- For all participants, the study consists of four periods. A Screening Period of up to 28 days prior to first dose will be used to confirm eligibility. A 24-Week Initial Treatment Period begins on Day 1 with administration of the first dose and continues for 24 weeks; all participants receive study intervention for a minimum of 24 weeks to allow complete assessment of hematologic response, with the primary endpoint evaluated during Weeks 1-24 using a landmark assessment at Week 24 to ensure comparability across the population. An Extension Period begins after Week 24 for participants who demonstrate clinical benefit as determined by the investigator; these participants may continue ofirnoflast at their established dose until disease progression.
- The SRC will conduct a dose-selection analysis after enrollment is complete and the last enrolled participant has completed 8 weeks of dosing, with final analysis following completion of the 24-week Initial Treatment Period. Dose selection will be based on a pre-specified composite assessment incorporating RBC transfusion-independence and hematologic improvement response rates by arm, incidence and severity of treatment-emergent adverse events, dose modifications and discontinuations due to toxicity, and pharmacokinetic exposure parameters.
- The SRC will monitor participant safety, including safety signal detection, throughout the study, with the frequency of routine safety reviews subject to adjustment based on observed enrollment rate. All participants will receive best supportive care throughout the study.
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
- None
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
- •At least 18 years of age at the time of signing informed consent.
- •Capable of giving signed informed consent
- •Documented diagnosis of very low-, low-, or intermediate-risk MDS
- •Documented diagnosis of anemia
- •Relapsed or refractory disease after 1 to 3 prior lines of therapy for lower-risk MDS
- •Willing to provide a bone marrow aspirate at Screening.
- •Life expectancy of more than 6 months at screening.
- •Participants of childbearing potential must have a negative pregnancy test at screening (serum) and Day 1 (urine).
- •Participants and partners must use contraception consistent with local regulations and protocol-defined criteria during the intervention period and for at least 30 days after the last dose; periodic abstinence and withdrawal are not acceptable methods.
排除标准
- •Anemia due to other causes (e.g., iron deficiency).
- •Known clinically significant anemia due to iron, vitamin B12, or folate deficiency; autoimmune or hereditary hemolytic anemia; or gastrointestinal bleeding.
- •History of hemoglobinopathies, intrinsic RBC membrane/enzyme defects, or hemolytic anemia.
- •Prior history of AML, secondary MDS, or other malignancy (except non-melanoma skin cancer or in situ cervical/breast carcinoma) unless disease-free for >1 year.
- •Diagnosis of MPN, CMML, or overlap MDS/MPN per WHO classification.
- •Any condition or concomitant treatment that may impair absorption of orally administered study intervention.
- •Uncontrolled infection or severe organ dysfunction.
- •Concomitant intercurrent illness or condition that, per investigator judgment, would compromise safe participation (e.g., uncontrolled hypertension, uncontrolled seizure, unstable angina, new-onset/exacerbated cardiac arrhythmia).
- •Prior treatment with disease-modifying agents (e.g., hypomethylating agents) or immunosuppressive therapy, except prior lenalidomide (permitted).
- •Treatment with cytotoxic chemotherapy or experimental agents within 4 weeks prior to first dose.
- •History of stem cell, bone marrow, or solid organ transplant.
- •Known hypersensitivity to ofirnoflast or its excipients.
- •Severe renal or hepatic impairment
- •Inability to swallow tablets.
- •Participation in another interventional clinical study within 90 days prior to first dose.
- •QTcF >480 ms.
- •Prior treatment with ofirnoflast.
研究组 & 干预措施
Arm 1: Ofirnoflast
Experimental
Participants receive ofirnoflast once daily, including the 5 participants enrolled in the Phase A safety lead-in cohort. Treatment continues through the 24-Week Initial Treatment Period and, for participants demonstrating clinical benefit, the Extension Period (up to an additional 24 weeks).
干预措施: Ofirnoflast (Drug)
Arm 2: Ofirnoflast
Experimental
Participants randomized to this arm in Phase B receive ofirnoflast once daily. Treatment continues through the 24-Week Initial Treatment Period and, for participants demonstrating clinical benefit, the Extension Period (up to an additional 24 weeks).
干预措施: Ofirnoflast (Drug)
结局指标
主要结局
Assess safety of ofirnoflast
时间窗: Weeks 1-24
The safety and tolerability of ofirnoflast will be evaluated based on the incidence of treatment-emergent adverse events (TEAEs)
Assess the hematologic response to ofirnoflast
时间窗: Weeks 1-24
The hematologic response to ofirnoflast will be evaluated by the duration of time the participants do not require red blood cell transfusions
次要结局
- Assess the extended hematologic response to ofirnoflast(Weeks 1-24)
- Assess the hematologic improvement on orfirnoflast(Weeks 1-24)
研究者
相似试验
招募中
2 期
FOLFIRI and Bevacizumab With or Without Pelareorep for Second-Line Treatment of Metastatic RAS-Mutated, Microsatellite-Stable Colorectal CancerNCT07446322Oncolytics Biotech60
招募中
2 期
Usnoflast Neuromuscular Investigation for Treatment Efficacy in ALS (UNITE-ALS)2025-522580-15-00Zydus Therapeutics Inc.206
尚未招募
2 期
Safety and Efficacy of PSMA-Targeted Fluorescent Contrast Agent DGPR1008 for Intraoperative Imaging in Robot-Assisted Radical ProstatectomyProstate CancerNCT07415135Zhu Yinjie18
尚未招募
不适用
A study to evaluate the efficacy of test regime in lactating females with hair fall.CTRI/2025/07/090485ANVEYA LIVING PRIVATE LIMITED50
招募中
2 期
A Study Evaluating the Efficacy and Safety of ABP1011T Tablets in Patients With Advanced Solid TumorsNCT07321574Shanghai AB PharmaTech Ltd.110