A Phase 1/2, Open-label, Dose-Escalation Multi-center Study to Assess the Safety, Tolerability, PK and PD of Orally Administered NS-018 in Patients With Primary Myelofibrosis (MF), Post-polycythemia Vera MF, or Post-essential Thrombocythemia MF
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 77
- 试验地点
- 9
- 主要终点
- Part 2: Change From Baseline in Spleen Size
研究概览
简要总结
The purpose of this study is to determine the safety and tolerability of orally administered NS-018 in patients with Primary Myelofibrosis (PMF), Post-polycythemia Vera Myelofibrosis (post-PV MF), or Post-essential Thrombocythemia Myelofibrosis (post-ET MF)
详细描述
This is a Phase 1/2 study that is currently enrolling Janus kinase 2 (JAK2) failures into the Phase 2 portion of the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 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
- •Primary myelofibrosis, post-PV MF, or post-ET MF that requires therapy
- •MF patients must have received prior JAK2 inhibitor therapy, and been found to be intolerant, or refractory/relapsed from prior JAK2 inhibitor therapy, based on investigator assessment
- •≥18 years old
- •ECOG Performance Status of ≤ 3
- •Estimated life expectancy of ≥12 weeks
- •Male or non-pregnant, non-lactating female patients
- •Serum creatinine of ≤1.5 × the upper limit of normal (ULN)OR estimated creatinine clearance (CrCl) ≥ 40 ml/min/1.73 m2
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × the upper limit of normal (ULN) and total bilirubin ≤1.5 × ULN. If the total bilirubin is elevated between 1.5 x and 3 x ULN, patients with a direct bilirubin ≤ 1.5 X ULN are eligible during the Phase II portion.
- •Absolute neutrophil count (ANC) >1000/μL and Platelet count > 25,000/μL
- •QTcB ≤ 480 msec
- •No MF-directed treatment for at least 2 weeks prior to initiation of NS-018, including any use of corticosteroids for Myelofibrosis symptom or blood count management. Low dose corticosteroids ≤ 10 mg/day prednisone or equivalent is allowed for non-myelofibrosis purposes.
排除标准
- •Active, uncontrolled systemic infection
- •Patients with any unresolved toxicity greater than Grade 1 from previous anticancer therapy
- •Potentially curative therapy is available
- •Currently taking medication that is substantially metabolized by cytochrome P450 (CYP) 1A2 or CYP3A4 or taking medication known to be strong inhibitors or inducers of CYP3A4
- •Patients with a serious cardiac condition within the past 6 months
- •Pregnant or lactating
- •Radiation therapy for splenomegaly within 6 months prior to study entry
- •Splenectomy (Phase 2 portion of the study only)
- •Known HIV positive status
- •Known active hepatitis, a history of viral hepatitis B or hepatitis C
研究组 & 干预措施
Intervention: Drug: NS-018
In Phase 1 part, subjects were treated with oral NS-018 at a dose of 75 - 400 mg once daily or 100 - 400 mg twice daily. In Phase 2 part, subjects were treated with oral NS-018 at a dose of 300 mg once daily.
干预措施: NS-018 (Drug)
结局指标
主要结局
Part 2: Change From Baseline in Spleen Size
时间窗: From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
Change from baseline in spleen size was assessed by magnetic resonance imaging (MRI) (computed tomography \[CT\] scan for patients not able to tolerate MRI).
Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event
时间窗: From screening to until study discontinuation (approximate 8 years 10 months)
AEs (non-serious, serious) as variables of safety and tolerability of NS-018 were assesed. The number of patients were presented as Overall summary of AEs including treatment-emergent AEs (TEAEs); Treatment-emergent SAEs; Drug-related TEAEs; Treatment-emergent AEs leading to permanent discontinuation of study drug; Hospitalization or prolongation of existing hospitalization; Death.
Part 2: Number of Patient With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Net (ELN)
时间窗: Cycle 7 Day 1 (duration of cycle was 4 weeks)
Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-symptomatic burden were annotated as clinical improvement, anemia response, spleen response, orsymptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The objective response was defined as the number of patients with confirmed complete remission (CR) + partial response (PR) + clinical improvement (CI) during the treatment period.
Part 2: Change From Baseline in Bone Marrow Assessment
时间窗: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)
Bone marrow was assessed by aspiration and biopsy for grade changes in osteomyelofibrosis. Fibrosis was graded according to European Consensus Myelofibrosis Grading Criteria, ranging from grade 0, which corresponds to normal bone marrow, to grade 3, in which coarse bundles of collagen fibrosis are identifiable with significant osteosclerosis.
次要结局
- Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF)(From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks))
- Part 1: Change From Baseline in Spleen Size(From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks))
- Part 1: Change From Baseline in Bone Marrow Assessment(From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks))
- Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)(Cycle 7 Day 1 (duration of cycle was 4 weeks))
- Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3)(From Baseline to Pre-dose at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks))
- Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels(Part 1 and Part 2: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks))
- Part 2: Change From Baseline in Quality of Life Assessments Using Myeloproliferative Neoplasm Symptom Assessment Form (MPN SAF (MPN 10)(From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks))
- Part1 and Part 2: Observed Maximum Concentration (Cmax)(Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks))
- Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax)(Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 2 Day 1 (duration of cycle was 4 weeks))
- Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24)(Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1 (duration of cycle was 4 weeks))
- Part 1 and Part 2: Terminal Elimination Half-life (t½)(Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 2 Day 1 (duration of cycle was 4 weeks))
- Part1 and Part 2: Accumulation Ratio (AR)(Part 1 and Part 2: Cycle 2 Day 1 (duration of cycle was 4 weeks))