A Randomized, Open-label, Phase I/II Open Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Myelofibrosis Patients
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 45
- 试验地点
- 1
- 主要终点
- Incidence and Severity of Dose Limiting Toxicities Within the First 2 Cycles in Part 1
研究概览
简要总结
The purpose of this study was to investigate the safety, pharmacokinetics and preliminary efficacy of combination treatment of ruxolitinib with 5 novel compounds: siremadlin, crizanlizumab, sabatolimab, rineterkib and NIS793 in myelofibrosis (MF) subjects.
详细描述
This open-label, multi-center, Phase Ib/II platform study design consisted of 3 parts. Part 1 was a Phase Ib dose escalation and safety run-in for the 5 novel agents in combination with ruxolitinib to assess safety, tolerability and to confirm a recommended Phase II dose. Dose escalation cohorts were treated with ruxoltinib + siremadlin or ruxolitinib + rineterkib. Safety run-in cohorts were treated with either ruxolitinb + sabatolimab, ruxolitinb + crizanlizumab or ruxolitinib + NIS7913.
Parts 2 and 3 were Phase II selection and expansion, respectively, to assess preliminary efficacy of the combination treatments from Part 1 that were evaluated as safe and tolerable. The number of combination treatment arms opening in Part 2 depended on the results of Part 1. In Part 2, an interim analysis was planned to determine if combination treatment(s) could be expanded in Part 3.
In June 2022, Novartis decided to permanently halt the study enrollment in all ongoing parts (Part 1 and Part 2), and Part 3 (expansion) was not initiated. With Protocol Amendment 8, an extension treatment phase of 12 cycles was added in Part 1 to allow access to the combination treatment for ongoing subjects deriving clinical benefit. In consideration of the enrollment halt, Parts 2 and 3 objectives were not pursued, and Part 1 objectives were updated accordingly.
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
盲法说明
Open label
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects have diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria, or diagnosis of post-essential thrombocythemia (ET) (PET-MF) or post-polycythemia vera (PV) myelofibrosis (PPV-MF) according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) 2007 criteria
- •Palpable spleen of at least 5 cm from the left costal margin (LCM) to the point of greatest splenic protrusion or enlarged spleen volume of at least 450 cm3 per MRI or CT scan at baseline (a MRI/CT scan up to 8 weeks prior to first dose of study treatment can be accepted).
- •Have been treated with ruxolitinib for at least 12 weeks prior to first dose of study treatment
- •Are stable (no dose adjustments) on the prescribed ruxolitinib dose (between 5 and 25 mg twice a day (BID)) for ≥ 4 weeks prior to first dose of study treatment
- •Extension treatment phase inclusion criteria:
- •Signed consent for the extension treatment phase
- •ongoing in the core treatment phase
- •demonstrates clinical benefit of treatment in core treatment phase per investigator's assessment.
- •Core treatment phase
排除标准
- •Not able to understand and to comply with study instructions and requirements.
- •Received any investigational agent for the treatment of MF (except ruxolitinib) within 30 days of first dose of study treatment or within 5 half-lives of the study treatment, whichever is greater
- •Peripheral blood blasts count of > 10%.
- •has documented severe hypersensitivity reactions/immunogenicity (IG) to a prior biologic product or Received a monoclonal antibody (Ab) or immunoglobulin-based agent within 1 year of screening in NIS793, crizanlizumab or sabatolimab arms, or in rineterkib or siremadlin arms within <=4 weeks of screening or <=5 half-lives whichever is shorter
- •Splenic irradiation within 6 months prior to the first dose of study drug
- •Received blood platelet transfusion within 28 days prior to first dose of study treatment.
- •Extension treatment phase Exclusion Criteria:
- •meets any of study treatment discontinuation criteria
- •current evidence of treatment failure per investigator, following treatment in core treatment phase
- •enrolled in another interventional study
- •evidence of non-compliance to study procedures or withdrew consent in core treatment phase
- •currently has unresolved toxicities for which study treatment has been interrupted in the core treatment phase
- •local access to alternative myelofibrosis treatment including those currently under investigation in clinical trials as assessed suitable in the opinion of the investigator.
研究组 & 干预措施
Part 1: Ruxolitinib + Siremadlin 20 mg
Dose escalation of siremadlin added to existing stable dose of ruxolitinib
干预措施: Ruxolitinib (Drug)
Part 1: Ruxolitinib + Siremadlin 20 mg
Dose escalation of siremadlin added to existing stable dose of ruxolitinib
干预措施: Siremadlin (Drug)
Part 1: Ruxolitinib + Siremadlin 30 mg
Dose escalation of siremadlin added to existing stable dose of ruxolitinib
干预措施: Ruxolitinib (Drug)
Part 1: Ruxolitinib + Siremadlin 30 mg
Dose escalation of siremadlin added to existing stable dose of ruxolitinib
干预措施: Siremadlin (Drug)
Part 1: Ruxolitinib + Siremadlin 40 mg
Dose escalation of siremadlin added to existing stable dose of ruxolitinib
干预措施: Ruxolitinib (Drug)
Part 1: Ruxolitinib + Siremadlin 40 mg
Dose escalation of siremadlin added to existing stable dose of ruxolitinib
干预措施: Siremadlin (Drug)
Part 1: Ruxolitinib + Rineterkib 200 mg
Dose escalation of rineterkib added to existing stable dose of ruxolitinib
干预措施: Ruxolitinib (Drug)
Part 1: Ruxolitinib + Rineterkib 200 mg
Dose escalation of rineterkib added to existing stable dose of ruxolitinib
干预措施: Rineterkib (Drug)
Part 1: Ruxolitinib + Crizanlizumab
Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib
干预措施: Ruxolitinib (Drug)
Part 1: Ruxolitinib + Crizanlizumab
Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib
干预措施: Crizanlizumab (Drug)
Part 1: Ruxolitinib + Sabatolimab
Safety run-in of sabatolimab added to existing stable dose of ruxolitinib
干预措施: Ruxolitinib (Drug)
Part 1: Ruxolitinib + Sabatolimab
Safety run-in of sabatolimab added to existing stable dose of ruxolitinib
干预措施: Sabatolimab (Drug)
Part 1: Ruxolitinib + NIS793
Safety run-in of NIS793 added to existing stable dose of ruxolitinib
干预措施: Ruxolitinib (Drug)
Part 1: Ruxolitinib + NIS793
Safety run-in of NIS793 added to existing stable dose of ruxolitinib
干预措施: NIS793 (Drug)
Part 2: Ruxolitinib
Existing stable dose of ruxolitinib as control for Part 2
干预措施: Ruxolitinib (Drug)
结局指标
主要结局
Incidence and Severity of Dose Limiting Toxicities Within the First 2 Cycles in Part 1
时间窗: Baseline to the end of Cycle 2 (6 or 8 weeks)
Incidence and severity of dose limiting toxicities within the first 2 cycles (6 or 8 weeks) in Part 1 of the study. DLTs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria Version 5.0. Grade 0 was assigned for all non-missing values not graded as 1 or higher. Higher grade indicated more severity. Grade 5 was not used.
Response Rate at the End of Cycle 6 or Cycle 8 in Part 1
时间窗: Baseline to the end of Cycle 6 or 8 (24 weeks)
Composite of anemia improvement (hemoglobin level) and no spleen volume progression and no symptom worsening in Part 2 and Part 3 of the study. For a subject to be considered a responder, all three components of the composite had to be fulfilled.
次要结局
- Percentage of Subjects Achieving an Improvement in Hemoglobin Level of ≥ 1.5 g/dL From Baseline in Part 1(Week 24, Week 48)
- Percentage of Subjects Achieving an Improvement in Hemoglobin Level of at Least >= 2.0 g/dL From Baseline in Part 1(Week 24, Week 48)
- Change in Spleen Length From Baseline in Part 1(Baseline, Week 24, Week 48)
- Percentage of Subjects With >=35% Reduction in Spleen Volume From Baseline in Part 1(Week 24, Week 48)
- Percentage of Subjects With >=25% Reduction in Spleen Volume From Baseline in Part 1(Week 24, Week 48)
- Percentage of Subjects in Part 1 With >=50% Reduction From Baseline in Myelofibrosis Symptom Assessment Form, Version 4.0 (MFSAF v4.0)(Week 12, Week 24, Week 48)
- Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) for Siremadlin, Rineterkib, Crizanlizumab, Sabatolimab, and NIS793 in Part 1(Days 1 and 5 of Cycles 1 and 2 for siremadlin and Cycles 1 and 3 for crizanlizumab, sabatolimab, and NIS793; Days 1 and 15 of Cycle 1 for rineterkib)
- Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) for Ruxolitinib in Part 1(Days 1 and 5 of Cycles 1 and 2; Day 15 of Cycle 1)
- Maximum (Peak) Observed Plasma Drug Concentration (Cmax) for Siremadlin, Rineterkib, Crizanlizumab, Sabatolimab, and NIS793 in Part 1(Days 1 and 5 of Cycles 1 and 2 for siremadlin and Cycles 1 and 3 for crizanlizumab, sabatolimab, and NIS793; Days 1 and 15 of Cycle 1 for rineterkib)
- Maximum (Peak) Observed Plasma Drug Concentration (Cmax) for Ruxolitinib in Part 1(Days 1 and 5 of Cycles 1 and 2; Day 15 of Cycle 1)
- Time to Reach Maximum (Peak) Plasma, Blood, Serum or Other Body Fluid Drug Concentration After Single Dose Administration (Tmax) for Siremadlin, Rineterkib, Crizanlizumab, Sabatolimab, and NIS793 in Part 1(Days 1 and 5 of Cycles 1 and 2 for siremadlin and Cycles 1 and 3 for crizanlizumab, sabatolimab, and NIS793; Days 1 and 15 of Cycle 1 for rineterkib)
- Time to Reach Maximum (Peak) Plasma, Blood, Serum or Other Body Fluid Drug Concentration After Single Dose Administration (Tmax) for Ruxolitinib in Part 1(Days 1 and 5 of Cycles 1 and 2; Day 15 of Cycle 1)
- Concentration Versus Time Profile for Siremadlin in Part 1(Day 1 of Cycles 1 and 2; Day 6 of Cycle 1; Days 2 and 5 of Cycles 1, 2, 3, 4, 5, and 6. Each cycle was 28 days.)
- Concentration Versus Time Profile for Rineterkib in Part 1(Days 1, 2, 15, and 16 of Cycle 1; Day 1 of Cycles 2, 3, 4, 5, and 6. Each cycle was 28 days.)
- Concentration Versus Time Profile for Crizanlizumab in Part 1(Days 1, 2, 8, and 15 of Cycles 1, 2, and 3; Day 1 of Cycles 4, 5, 6, and 9. Each cycle was 28 days.)
- Concentration Versus Time Profile for Sabatolimab in Part 1(Days 1, 2, 8, and 15 of Cycles 1, 2, and 3; Day 1 of Cycles 4 and 5. Each cycle was 28 days.)
- Concentration Versus Time Profile for NIS793 in Part 1(Days 1, 2, 4, 8, 11, and 15 of Cycles 1, 2, and 3; Day 1 of Cycles 4 and 5. Each cycle was 28 days.)
- Concentration Versus Time Profile for Ruxolitinib in Part 1(Days 1, 2, 5, 6, and 15 of Cycles 1 and 2; Day 16 of Cycle 1; Days 1, 2, and 15 of Cycle 3; Days 1 and 5 of Cycles 4, 5, and 6. Each cycle was 28 days.)