A Randomized, Single-Blind, Multicenter Phase 2 Study to Evaluate the Activity of 2 Dose Levels of Imetelstat in Subjects With Intermediate-2 or High-Risk Myelofibrosis (MF) Relapsed/Refractory to Janus Kinase (JAK) Inhibitor
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 107
- 主要终点
- Percentage of Participants With Spleen Response
研究概览
简要总结
The purpose of this study is to evaluate the efficacy and safety of 2 dose regimens of imetelstat in participants with intermediate-2 or high-risk myelofibrosis (MF) whose disease is relapsed after or is refractory to Janus Kinase (JAK) inhibitor treatment. Key secondary endpoint includes overall survival.
详细描述
This is a randomized (study medication assigned to participants by chance), multicenter (more than one hospital, medical school team or medical clinic work on a medical research study) study of 2 dosing regimens (treatment arms) of single-agent imetelstat in participants with intermediate-2 or high risk myelofibrosis (MF) whose disease is relapsed after or refractory to Janus Kinase (JAK) inhibitor treatment. The main study consists of 3 parts: Screening Phase (21 days before randomization); Treatment Phase (from randomization until study drug discontinuation); and Follow up Phase (until death, lost to follow-up, withdrawal of consent or study end, whichever occurs first). Participants received imetelstat 9.4 milligram (mg)/kilogram (kg) intravenously (IV) for every 3 weeks until disease progression, unacceptable toxicity, or study end OR imetelstat 4.7 mg/kg IV for every 3 weeks until disease progression, unacceptable toxicity, or study end. Initially, all participants were blinded to the treatment. After the first interim analysis, treatment for all participants was unblinded and participants assigned to the imetelstat 4.7 mg/kg arm could continue with their same imetelstat dose or have it increased to 9.4 mg/kg at the investigator's discretion. The percentage of spleen response and symptom response were evaluated as co-primary endpoints. Following completion of the primary analysis, participants benefiting from study treatment could continue to receive imetelstat in Extension phase for up to 2 years or until loss of benefit or unacceptable toxicity. Participants who had already stopped study treatment could enter the Extension phase to continue follow up for safety via serious adverse event collection and for survival status.
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
- Single (Participant)
盲法说明
Initially single-blind; treatments unmasked after 1st Interim Analysis and continued as open-label treatment.
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
- •Diagnosis of primary myelofibrosis (PMF) according to the revised WHO criteria; or post-essential thrombocythemia-myelofibrosis (PET-MF) or post-polycythemia vera-myelofibrosis (PPV-MF) according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria.
- •Dynamic International Prognostic Scoring System (DIPSS) intermediate-2 or highrisk MF.
- •Measurable splenomegaly prior to study entry as demonstrated by palpable spleen measuring ≥ 5 cm below the left costal margin OR spleen volume of ≥ 450 cm^3 measured by magnetic resonance imaging (MRI).
- •Active symptoms of MF as demonstrated by a symptom score of at least 5 points (on a 0 to 10 scale) on at least one of the symptoms or a score of 3 or greater on at least 2 of the symptoms.
- •Documented progressive disease during or after Janus kinase (JAK) inhibitor therapy.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.
排除标准
- •Peripheral blood blast count of ≥ 10% or bone marrow blast count of ≥ 10%.
- •Prior treatment with imetelstat.
- •Any chemotherapy or MF-directed therapy, investigational drug, hydroxyurea, immunomodulatory or immunosuppressive therapy, corticosteroids or JAK inhibitor therapy ≤14 days prior to randomization.
- •Major surgery within 4 weeks prior to randomization.
- •Active systemic hepatitis infection requiring treatment (carriers of hepatitis virus are permitted to enter the study), of any type or known acute or chronic liver disease including cirrhosis.
- •Prior history of hematopoietic stem cell transplant.
研究组 & 干预措施
Imetelstat 4.7 mg/kg
干预措施: Imetelstat 4.7 mg/kg (Drug)
Imetelstat 9.4 mg/kg
干预措施: Imetelstat 9.4 mg/kg (Drug)
结局指标
主要结局
Percentage of Participants With Spleen Response
时间窗: Week 24
Spleen response rate is defined as the percentage of participants who achieved ≥ 35% reduction in spleen volume at Week 24 from baseline performed by the IRC using magnetic resonance imaging (MRI).
Percentage of Participants With Symptom Response
时间窗: Week 24
Symptom response rate is defined as percentage of participants who achieved ≥ 50% reduction in total symptom score (TSS) at Week 24 from baseline as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) version 2.0 diary. The MFSAF assessed following symptoms due to Myelofibrosis (MF): night sweats, itchiness, abdominal discomfort, pain under ribs on left side, feeling of fullness, bone or muscle pain and degree of inactivity. Each item is scored on a scale of 0 (absent) to 10 (worst imaginable) with higher scores indicating more severe symptoms and greater inactivity. The total score ranges from 0-70, where 0 indicates absent/as good as it can be and 70 indicates worst imaginable/as bad as it can be.
次要结局
- Percentage of Participants With Overall Response as Per Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria(Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years))
- Percentage of Participants With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria(Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years))
- Percentage of Participants With Clinical Response Per Modified 2013 IWG-MRT(Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years))
- Percentage of Participants With Spleen Response Per Modified 2013 IWG-MRT Criteria(Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years))
- Percentage of Participants With Symptoms Response Per Modified 2013 IWG-MRT Criteria(Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years))
- Percentage of Participants With Anemia Response Per Modified 2013 IWG-MRT Criteria(Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years))
- Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria(From date of initial documentation of a response to the date of first documented evidence of PD or death, whichever occurs first (approximately up to 2.3 years))
- Overall Survival(Day 1 of Cycle 1 (each cycle was of 21 days), up to the date of the participant's death (approximately up to 4.1 years))
- Percentage of Participants With Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-30 (QLQ-C30): Global Health Status(Up to end of the treatment (approximately up to 2.3 years))
- EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS)(At the end of treatment, up to approximately 2.3 years)
- Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI)(Up to end of treatment (approximately up to 2.3 years))
- Patient's Global Impression of Change (PGIC)(At the end of treatment, up to approximately 2.3 years)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs)(Up to end of extension phase (approximately up to 4.2 years))
- Maximum Observed Plasma Concentration (Cmax) of Imetelstat(0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days))
- Time to Reach Maximum Observed Plasma Concentration (Tmax) of Imetelstat(0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days))
- Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24) of Imetelstat(0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days))
- Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUC0-inf) of Imetelstat(0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days))
- Elimination Half-Life (t1/2) of Imetelstat(0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days))
- Total Systemic Clearance (CL) of Imetelstat(0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days))
- Volume of Distribution (Vd) of Imetelstat(0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days))