An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of TL-895 Combined With Ruxolitinib in Janus-associated Kinase Inhibitor (JAKi) Treatment-Naïve Myelofibrosis (MF) Subjects and Subjects With MF Who Have a Suboptimal Response to Ruxolitinib
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 70
- 试验地点
- 19
- 主要终点
- Phase 2 - Spleen Volume Reduction (SVR) at Week 24
研究概览
简要总结
This study evaluates TL-895, a potent, orally-available and highly selective irreversible tyrosine kinase inhibitor for the treatment of Myelofibrosis. Participants must have MF (PMF, Post PV MF, or Post ET MF) who are JAKi treatment-naïve or those who have a suboptimal response to ruxolitinib.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Subjects with suboptimal response to ruxolitinib:
- •Treatment with at a stable dose of ruxolitinib prior to study entry
- •Subjects ≥ 18 years of age and able to provide informed consent.
- •Confirmed diagnosis of PMF, post-PV MF, or post-ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria
- •High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS)
- •Palpable spleen measuring ≥ 5 cm below the left lower coastal margin (LLCM) or spleen volume of ≥ 450 cm3 by MRI or CT scan assessment
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
- •Adequate hematological, hepatic, & renal function.
排除标准
- •Treatment-naive subjects:
- •Prior treatment with any JAKi
- •Subjects with suboptimal response to ruxolitinib:
- •Documented disease progression while on ruxolitinib treatment
- •All subjects:
- •Prior splenectomy or splenic irradiation within 24 weeks prior to first dose of study treatment
- •Prior treatment with a BTK or BMX inhibitor
研究组 & 干预措施
Phase 1b - Dose Level 1
150 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib.
干预措施: TL-895 (Drug)
Phase 1b - Dose Level 1
150 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib.
干预措施: Ruxolitinib (Drug)
Phase 1b - Dose Level 2
300 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib.
干预措施: TL-895 (Drug)
Phase 1b - Dose Level 2
300 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib.
干预措施: Ruxolitinib (Drug)
Phase 1b - Dose Level 3
450 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib.
干预措施: TL-895 (Drug)
Phase 1b - Dose Level 3
450 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib.
干预措施: Ruxolitinib (Drug)
Phase 2 - Cohort 1 JAKi treatment-naïve MF
The RP2D of TL-895 as determined in Phase 1b will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle.
The dose of ruxolitinib will be based on the subject's baseline platelet count.
干预措施: TL-895 (Drug)
Phase 2 - Cohort 1 JAKi treatment-naïve MF
The RP2D of TL-895 as determined in Phase 1b will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle.
The dose of ruxolitinib will be based on the subject's baseline platelet count.
干预措施: Ruxolitinib (Drug)
Phase 2 - Cohort 2 suboptimal response to Ruxolitinib
The RP2D of TL-895 as determined in Phase 1b will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle.
The dose schedule will be the stable ruxolitinib dose schedule as the subject is currently taking prior to entry into the study.
干预措施: TL-895 (Drug)
Phase 2 - Cohort 2 suboptimal response to Ruxolitinib
The RP2D of TL-895 as determined in Phase 1b will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle.
The dose schedule will be the stable ruxolitinib dose schedule as the subject is currently taking prior to entry into the study.
干预措施: Ruxolitinib (Drug)
结局指标
主要结局
Phase 2 - Spleen Volume Reduction (SVR) at Week 24
时间窗: 24 Weeks
The proportion of subjects achieving SVR of ≥35% at Week 24 by magnetic resonance imaging (MRI) or computed tomography (CT) scan.
Phase 1b - Recommended Phase 2 dose of TL-895 in combination with ruxolitinib
时间窗: 28 days
Dose-limiting toxicities (DLTs) will be used to establish the maximum-tolerated dose (MTD) of TL-895 in combination with ruxolitinib. The safety review committee (SRC) will determine the RP2D based on safety and efficacy data of the combination of TL-895 and ruxolitinib.
次要结局
- Phase 2 - TSS reduction at Week 24(24 Weeks)
- Progression Free Survival(48 Month)
- Phase 1b - TSS reduction at Week 24(24 Weeks)
- DOR Spleen(48 Months)
- Overall Survival(48 Months)
- Phase 1b - Spleen Volume Reduction (SVR) at Week 24(24 Weeks)