A Phase 3, Randomized, Double-blind, Active-control Study of Pelabresib (DAK539) and Ruxolitinib vs. Placebo and Ruxolitinib in Adult Patients With Myelofibrosis Who Are JAK Inhibitor Naive
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 460
- 试验地点
- 77
- 主要终点
- Number of Participants with Splenic Response (SVR35) by Central Radiology Reads at Week 24 in participants with baseline total symptom score (TSS) ≥ 25
研究概览
简要总结
The purpose of this trial is to evaluate whether treatment with pelabresib in combination with ruxolitinib leads to improved clinical outcomes compared to ruxolitinib alone in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF) who have not previously received Janus kinase (JAK) inhibitor therapy.
详细描述
The study for each participant is composed of several distinct periods: a screening period, a study treatment period, and a post-treatment follow-up phase.
- Screening Period:
The screening period lasts for up to 28 days prior to Cycle 1 Day 1, which marks the beginning of treatment. During this time, the participant's eligibility for the study is confirmed, informed consent is obtained, and all required baseline assessments are completed. 2. Treatment Period:
The treatment period begins on Cycle 1 Day 1, which is the point of randomization and the start of study treatment. This period continues until the participant permanently discontinues study treatment, which may occur due to disease progression, unacceptable toxicity, participant withdrawal, or other reasons specified in the protocol. Throughout this period, participants receive study drugs in 21-day cycles, with pelabresib or placebo administered for 14 days and ruxolitinib given continuously. Regular site visits and assessments are conducted according to the Schedule of Activities. 3. Safety Follow-up Period:
The safety follow-up period extends for 30 days (with a window of plus or minus 3 days) after the participant receives their last dose of pelabresib or placebo. During this period, participants are monitored for any late-onset adverse events or safety concerns that may arise after discontinuing the study treatment. 4. Efficacy Follow-up Period:
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Participants have diagnosis of primary myelofibrosis (PMF) or post-polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocythemia myelofibrosis (post-ET MF) according to the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias 2022
- •DIPSS risk category of intermediate-1, intermediate-2 or high-risk
- •Spleen volume ≥ 450 cm3 by CT or MRI scan (local read sufficient if no central read available)
- •Have an average TSS of ≥15 within 7 days prior to randomization, using MFSAF v. 4.0 (at least 4 out of 7 TSS assessments required for average calculation)
- •Participants with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
- •Blasts <5% in peripheral blood. Assessment of blasts in peripheral blood is mandatory at screening
- •Platelet count ≥ 100 x 10^9/L in the absence of growth factors or transfusions for the previous 4 weeks
排除标准
- •Prior splenectomy at any time or splenic irradiation in the previous 6 months
- •Prior hematopoietic cell transplant or participant anticipated to receive a hematopoietic cell transplant within 24 weeks from the date of randomization
- •Blasts ≥ 5% in bone marrow if results available at screening or history of accelerated phase (AP) or leukemic transformation
- •History of a malignancy (other than MF, PPV-MF or PET-MF) in the past 3 years in need of systemic treatment
- •Received any approved or investigational agent other than hydroxyurea or anagrelide for the treatment of MF within 14 days of first dose of study treatment or within 5 half-lives of the approved or investigational agent, whichever is longer
- •Prior treatment with any JAK inhibitor or Bromodomain and extraterminal domain (BET) inhibitor
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Arm 2: Placebo + Ruxolitinib
Participants in this arm receive a matching placebo orally once daily for 14 days of each 21-day cycle, together with ruxolitinib, which is also taken orally twice daily throughout each cycle.
Participants may continue receiving study treatment until they experience unacceptable toxicity, disease progression, or until either the investigator or the participant decides to discontinue treatment.
干预措施: Placebo (Drug)
Arm 1: Pelabresib + Ruxolitinib
Participants in this arm receive pelabresib (DAK539) orally once daily for 14 days of each 21-day cycle, in combination with ruxolitinib, which is taken orally twice daily throughout each cycle. Participants may continue receiving study treatment until they experience unacceptable toxicity, disease progression, or until either the investigator or the participant decides to discontinue treatment.
干预措施: Ruxolitinib (Drug)
Arm 2: Placebo + Ruxolitinib
Participants in this arm receive a matching placebo orally once daily for 14 days of each 21-day cycle, together with ruxolitinib, which is also taken orally twice daily throughout each cycle.
Participants may continue receiving study treatment until they experience unacceptable toxicity, disease progression, or until either the investigator or the participant decides to discontinue treatment.
干预措施: Ruxolitinib (Drug)
Arm 1: Pelabresib + Ruxolitinib
Participants in this arm receive pelabresib (DAK539) orally once daily for 14 days of each 21-day cycle, in combination with ruxolitinib, which is taken orally twice daily throughout each cycle. Participants may continue receiving study treatment until they experience unacceptable toxicity, disease progression, or until either the investigator or the participant decides to discontinue treatment.
干预措施: Pelabresib (Drug)
结局指标
主要结局
Number of Participants with Splenic Response (SVR35) by Central Radiology Reads at Week 24 in participants with baseline total symptom score (TSS) ≥ 25
时间窗: Week 24
Spleen Response (SVR35) is defined as achieving a reduction of at least 35 percent in spleen volume from baseline to Week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and assessed by a centralized radiology review in participants with baseline TSS ≥ 25.
Absolute change from baseline in total symptom score (TSS) at Week 24 in participants with baseline TSS ≥ 25
时间窗: Baseline, Week 24
Symptom improvement at Week 24 is defined as the absolute change from baseline in the total symptom score (TSS) at Week 24, as measured by the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) in participants with baseline TSS ≥ 25.
Number of Participants with Splenic Response (SVR35) by Central Radiology Reads at Week 24 in participants with baseline TSS ≥ 15
时间窗: Week 24
Spleen Response (SVR35) is defined as achieving a reduction of at least 35 percent in spleen volume from baseline to Week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and assessed by a centralized radiology review in participants with baseline TSS ≥ 15.
Absolute change from baseline in total symptom score (TSS) at Week 24 in participants with baseline TSS ≥ 15
时间窗: Baseline, Week 24
Symptom improvement at Week 24 is defined as the absolute change from baseline in the total symptom score (TSS) at Week 24, as measured by the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) in participants with baseline TSS ≥ 15.
次要结局
- Number of Participants with Splenic Response (SVR35) by Central Radiology Reads over time(Week 12, Week 36, Week 48 and every 12 weeks thereafter till End of Study (an average of 3 years))
- Absolute change from baseline and percentage change from baseline in spleen volume over time(Baseline, Week 12, Week 24, Week 36, Week 48, and every 12 weeks thereafter till End of Study (an average of 3 years))
- Time to first SVR35 response(From date of randomization to the date of first SVR35 response, assessed up to approximately 3 years)
- Duration of first SVR35 response(From first SVR35 response to loss of response, assessed up to approximately 3 years)
- Number of Participants with TSS50 response at Week 24(Week 24)
- Number of Participants with TSS50 response over time(Baseline, Week 12, Week 24, Week 36, Week 48, and every 12 weeks thereafter till End of Study (an average of 3 years))
- Absolute and percentage change from baseline in TSS over time(Baseline, Week 12, Week 24, Week 36, Week 48, and every 12 weeks thereafter till End of Study (an average of 3 years))
- Time to first TSS50 response(From date of randomization till date of first TSS50 response, assessed up to approximately 3 years)
- Duration of TSS50 response(From first TSS50 response to loss of response, assessed up to approximately 3 years)
- Dual Response (SVR35 + TSS50)(Baseline, Week 12, Week 24, Week 36, Week 48, and every 12 weeks thereafter till End of Study (an average of 3 years))
- Hemoglobin response(12 consecutive weeks (rolling window) up to 7 days following last dose of pelabresib/placebo)
- Change from baseline in hemoglobin over time(Up to 7 days following last dose of pelabresib/placebo)
- Anemia response over time(Up to 7 days following last dose of pelabresib/placebo)
- Overall survival (OS)(From date of randomization till date of death due to any cause, assessed up to approximately 3 years)
- Progression-free survival (PFS)(From date of randomization till date of documented disease progression, or death due to any cause whichever comes first, assessed up to approximately 3 years)
- Leukemia-free survival (LFS)(From date of randomization till date of leukemic transformation, or death due to any cause whichever comes first, assessed up to approximately 3 years)
- Exposure-Adjusted Incidence Rate (EAIR) of Participants with Leukemic Transformation(Throughout study completion (an average of 3 years))
- Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to 30 days following last dose of pelabresib/placebo)
- Pelabresib plasma concentrations(Cycle 1: Day 1 (0/Pre-dose and 0.5 post dose), Day 7 (0/Pre-dose), Day 14 (0/Pre-dose, 2, and 5 hours post-dose). 1 cycle = 21 days.)
- Maximum observed plasma Concentration (Cmax) of pelabresib in participants enrolled in China and Japan(Cycle 1 Day Day 14 (0/Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose). 1 cycle = 21 days.)
- Time to Maximum observed plasma Concentration (Tmax) of pelabresib in participants enrolled in China and Japan(Cycle 1 Day Day 14 (0/Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose). 1 cycle = 21 days.)
- Area Under the Concentration-Time Curve over a dosing interval (AUCtau) of pelabresib in participants enrolled in China and Japan(Cycle 1 Day Day 14 (0/Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose). 1 cycle = 21 days.)
- Change from baseline over time in fatigue as measured by PROMIS SF v1.0 Fatigue 7a(Baseline, once per week from Cycles 1 to 9 (each cycle is 21 days), day 1 of every odd cycle thereafter, within 7 days of last dose of pelabresib/placebo and at 12 weeks following last dose of pelabresib/placebo)
- Change from baseline over time in overall QOL and functional scales as measured by the EORTC QLQ-C30(Baseline, day 1 of every cycle from Cycle 1 to 9 (each cycle is 21 days), day 1 of every odd cycle thereafter, within 7 days of last dose of pelabresib/placebo and at 12 weeks following last dose of pelabresib/placebo)