An Open Label, Phase 1/1b Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of Imetelstat in Combination With Ruxolitinib in Patients With Myelofibrosis
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 30
- 试验地点
- 12
- 主要终点
- Part 1: Incidence, Type, and Severity of Adverse Events, Including Dose-limiting Toxicity (DLT) During the DLT Observation Period and/or Study Treatment
研究概览
简要总结
The purpose of the study is to identify the recommended Part 2 dose (R2PD) of imetelstat sodium in combination with ruxolitinib in participants with myelofibrosis (MF) in Part 1, and to evaluate the safety and preliminary clinical activity of the R2PD of imetelstat sodium in combination with ruxolitinib in participants with MF in Part 2.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •Diagnosis of primary myelofibrosis (PMF) according to the revised World Health Organization (WHO) criteria or post-essential thrombocythemia-MF or post-polycythemia vera according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria.
- •Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, intermediate-2 or high-risk MF.
- •Candidate for ruxolitinib treatment:
- •Part 1 participants: On ruxolitinib treatment for at least 12 weeks with at least 4 consecutive weeks immediately prior to enrollment at a stable dose.
- •Part 2 participants: Candidate for ruxolitinib treatment as assessed by the investigator and has not previously been treated with a JAK inhibitor (Cohort A) OR currently receiving ruxolitinib per standard of care for at least 12 weeks with at least 4 consecutive weeks at a stable dose prior to enrollment (Cohort B). Note that the study will no longer recruit participants into Cohort A.
- •Active symptoms of MF on the MFSAF v4.0 demonstrated by:
- •Part 1 participants only: At least 2 symptoms with a score ≥ 1
- •Part 2 participants only: At least 2 symptoms with a score of ≥ 3, or a total score of at least
- •Ineligible for or unwilling to undergo hematopoietic stem cell transplant at time of study entry.
- •Hematology laboratory test values within protocol defined limits.
- •Biochemical laboratory test values within protocol defined limits.
- •Eastern Cooperative Oncology Group Performance Status score of 0, 1, or
- •Participants should follow protocol defined contraceptives procedures.
- •A woman of childbearing potential must have a negative serum or urine pregnancy test at screening.
排除标准
- •Peripheral blood blast count of ≥10% or bone marrow blast count of ≥10%.
- •Prior treatment with JAK inhibitor (except for participants being dosed optimized on ruxolitinib treatment prior to screening and enrollment in part 1 or Part 2 Cohort B).
- •Known allergies, hypersensitivity, or intolerance to imetelstat or ruxolitinib or excipients.
- •Prior treatment with imetelstat.
- •Major surgery within 28 days prior to enrollment.
- •Any investigational drug regardless of class or mechanism of action, hydroxyurea, chemotherapy, (except for ruxolitinib for participants being dose optimized prior to enrollment), immunomodulatory or immunosuppressive therapy, corticosteroids >30 mg/day prednisone or equivalent ≤14 days prior to enrollment.
- •Prior history of hematopoietic stem cell transplant.
- •Diagnosis or treatment for malignancy other than MF, except:
- •Malignancy treated with curative intent and with no known active disease present for ≥3 years before enrollment.
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- •Adequately treated cervical carcinoma in situ without evidence of disease.
- •Clinically significant cardiovascular disease.
- •Known history of human immunodeficiency virus (HIV) or any uncontrolled active systemic infection requiring IV antibiotics.
- •Active systemic hepatitis infection requiring treatment or any known acute or chronic liver disease unless related to MF. Carriers of hepatitis virus are permitted to enter the study.
研究组 & 干预措施
Part 1: Imetelstat sodium + Ruxolitinib
Participants who have received ruxolitinib orally (PO) as part of standard of care (SOC) for at least 12 weeks prior to Screening will be enrolled. After enrollment, participants will initiate imetelstat sodium therapy. Dose levels of imetelstat sodium may include 4.7, 6, 7.5, 9.4 mg/kg, until a RP2D is established.
干预措施: Imetelstat sodium (Drug)
Part 1: Imetelstat sodium + Ruxolitinib
Participants who have received ruxolitinib orally (PO) as part of standard of care (SOC) for at least 12 weeks prior to Screening will be enrolled. After enrollment, participants will initiate imetelstat sodium therapy. Dose levels of imetelstat sodium may include 4.7, 6, 7.5, 9.4 mg/kg, until a RP2D is established.
干预措施: Ruxolitinib (Drug)
Part 2: Imetelstat sodium + Ruxolitinib
Cohort A: Janus Kinase (JAK) inhibitor naive participants will receive initial treatment with ruxolitinib on study for at least 12 weeks, including 4 consecutive weeks at a stable dose, prior to the addition of imetelstat sodium. Participants can begin imetelstat sodium treatment after sponsor review and approval and meet the following requirements: platelet value is ≥75 x 10^9/L for two consecutive measurements, at least 1 week apart, and the participant does not meet criteria for dose delay.
Note that the study will no longer recruit participants into Cohort A.
Cohort B: Participants will receive treatment with ruxolitinib for 12 weeks with at least 4 consecutive weeks at a stable dose prior to enrollment and will start combination treatment with imetelstat on study.
干预措施: Imetelstat sodium (Drug)
Part 2: Imetelstat sodium + Ruxolitinib
Cohort A: Janus Kinase (JAK) inhibitor naive participants will receive initial treatment with ruxolitinib on study for at least 12 weeks, including 4 consecutive weeks at a stable dose, prior to the addition of imetelstat sodium. Participants can begin imetelstat sodium treatment after sponsor review and approval and meet the following requirements: platelet value is ≥75 x 10^9/L for two consecutive measurements, at least 1 week apart, and the participant does not meet criteria for dose delay.
Note that the study will no longer recruit participants into Cohort A.
Cohort B: Participants will receive treatment with ruxolitinib for 12 weeks with at least 4 consecutive weeks at a stable dose prior to enrollment and will start combination treatment with imetelstat on study.
干预措施: Ruxolitinib (Drug)
结局指标
主要结局
Part 1: Incidence, Type, and Severity of Adverse Events, Including Dose-limiting Toxicity (DLT) During the DLT Observation Period and/or Study Treatment
时间窗: 28 days after first dose
Part 2: Number of Participants With Treatment-emergent Adverse Event (AE)
时间窗: First dose of study treatment until 30 days after the last dose of study treatment (up to approximately 5 years)
Safety will be assessed based on incidence and severity (according to Common Terminology Criteria for Adverse Events) of treatment emergent adverse events from the first dose of study treatment until 30 days after completion of treatment.
Part 2: Symptom Response Rate at Week 24
时间窗: Week 24
Symptom response rate is defined as percentage of participants with \>=50% reduction in the Total Symptom Score (TSS) measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 e-diary at 24 week compared to baseline.
Part 2: Number of Participants With Treatment-emergent Adverse Event (AE)
时间窗: First dose of study treatment until 30 days after the last dose of study treatment (up to approximately 5 years)
Safety will be assessed based on incidence and severity (according to Common Terminology Criteria for Adverse Events) of treatment emergent adverse events from the first dose of study treatment until 30 days after completion of treatment.
Part 2: Symptom Response Rate at Week 24
时间窗: Week 24
Symptom response rate is defined as percentage of participants with \>=50% reduction in the Total Symptom Score (TSS) measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 e-diary at 24 week compared to baseline.
Part 1: Incidence, Type, and Severity of Adverse Events, Including Dose-limiting Toxicity (DLT) During the DLT Observation Period and/or Study Treatment
时间窗: 28 days after first dose
次要结局
- Part 1: Pharmacokinetic Profile of Ruxolitinib Time to Reach Maximum Plasma Concentration [Tmax])(From first dose of imetelstat treatment up to approximately 5 years)
- Part 1 and Part 2: Pharmacokinetic Profile of Imetelstat Sodium Maximum Observed Plasma Concentration [Cmax](From first dose of imetelstat treatment up to approximately 5 years)
- Part 1 and Part 2: Pharmacokinetic Profile of Imetelstat Time to Reach Maximum Plasma Concentration [Tmax])(From first dose of imetelstat treatment up to approximately 5 years)
- Part 1 and Part 2: Percentage of Participants with Anti-imetelstat Antibodies(From first dose of imetelstat treatment up to approximately 5 years)
- Part 1: Symptom Response at Week 24(Baseline, Week 24)
- Part 1 and Part 2: Absolute Change From Baseline in TSS at Week 24(Baseline, Week 24)
- Part 1 and Part 2: Average Absolute Change in TSS Over 24 weeks(Baseline, Week 24)
- Part 1 and Part 2: Spleen Response at Week 24(Week 24)
- Part 1 and Part 2: Progression Free Survival (PFS)(From start of study treatment date to the disease progression or death (up to approximately 5 years))
- Part 1 and Part 2: Percentage of Participants With Complete Remission (CR), Partial Remission (PR), Clinical Improvement (CI) Per the Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria.(From first dose to end of the treatment (up to approximately 5 years))
- Part 1 and Part 2: Duration of Response (DOR) Per IWG-MRT Criteria(From time of initial response to PD or death whichever occurs first (up to approximately 5 years))
- Part 1 and Part 2: Reduction of Bone Marrow Fibrosis(From first dose to end of the treatment (up to approximately 5 years))
- Part 1: Pharmacokinetic Profile of Ruxolitinib Time to Reach Maximum Plasma Concentration [Tmax])(From first dose of imetelstat treatment up to approximately 5 years)
- Part 1 and Part 2: Percentage of Participants with Anti-imetelstat Antibodies(From first dose of imetelstat treatment up to approximately 5 years)
- Part 1 and Part 2: Pharmacokinetic Profile of Imetelstat Sodium Maximum Observed Plasma Concentration [Cmax](From first dose of imetelstat treatment up to approximately 5 years)
- Part 1: Pharmacokinetic Profile of Ruxolitinib (Maximum Observed Plasma Concentration [Cmax](From first dose of Ruxolitinib treatment up to approximately 5 years)
- Part 1 and Part 2: Pharmacokinetic Profile of Imetelstat Time to Reach Maximum Plasma Concentration [Tmax])(From first dose of imetelstat treatment up to approximately 5 years)
- Part 1 and Part 2: Absolute Change From Baseline in TSS at Week 24(Baseline, Week 24)
- Part 1 and Part 2: Average Absolute Change in TSS Over 24 weeks(Baseline, Week 24)
- Part 1 and Part 2: Spleen Response at Week 24(Week 24)
- Part 1 and Part 2: Progression Free Survival (PFS)(From start of study treatment date to the disease progression or death (up to approximately 5 years))
- Part 1: Symptom Response at Week 24(Baseline, Week 24)
- Part 1 and Part 2: Percentage of Participants With Complete Remission (CR), Partial Remission (PR), Clinical Improvement (CI) Per the Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria.(From first dose to end of the treatment (up to approximately 5 years))
- Part 1 and Part 2: Time to Response(From first dose of study treatment to the earliest date that a response was first documented (Up to approximately 5 years))
- Part 1 and Part 2: Duration of Response (DOR) Per IWG-MRT Criteria(From time of initial response to PD or death whichever occurs first (up to approximately 5 years))
- Part 1 and Part 2: Reduction of Bone Marrow Fibrosis(From first dose to end of the treatment (up to approximately 5 years))
- Part 1 and Part 2: Time to Progression to Acute Myeloid Leukemia (AML)(From first dose to end of the treatment (up to approximately 5 years))