A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Of Navitoclax In Combination With Ruxolitinib Versus Ruxolitinib In Subjects With Myelofibrosis (TRANSFORM-1)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 252
- 试验地点
- 194
- 主要终点
- Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume at Week 24 (SVR35W24)
研究概览
简要总结
Myelofibrosis is a type of bone marrow cancer that usually develops slowly and disrupts body's normal production of blood cells. It causes bone marrow scarring, leading to severe anemia that can cause weakness and fatigue. It can also cause a low number of blood-clotting cells called platelets, which increases risk of bleeding. Myelofibrosis often causes an enlarged spleen. The purpose of this study is to see if a combination of navitoclax and ruxolitinib is more effective and safe in assessment of change in spleen volume when compared to ruxolitinib in participants with myelofibrosis.
Navitoclax is an investigational drug for the treatment of myelofibrosis. Participants in this study are divided into two groups, called treatment arms. Each group receives a different treatment. Adult participants with a diagnosis of myelofibrosis will be enrolled. Around 230 participants will be enrolled in approximately 190 sites worldwide.
Participants will receive oral navitoclax tablet with oral ruxolitinib tablet or oral ruxolitinib tablet with oral placebo (no active drug) tablet and treatment may continue untill the participant cannot tolerate the study drug, or benefit is not achieved, or other reasons which qualify for discontinuation of the study drug.
There may be a higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the course of the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, magnetic resonance imaging (MRI) or computed tomography (CT) scan, bone marrow tests, checking for side effects, and completing questionnaires.
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
- •Documented diagnosis of Primary MyeloFibrosis (MF) as defined by World Health Organization (WHO) classification or Secondary MF (post polycythemia vera [PPV] - MF or Post Essential Thrombocythemia [PET] - MF) .
- •Must be able to complete the MF Symptom Assessment Form (MFSAF) v4.0 on at least 4 out of 7 days immediately preceding the date of randomization.
- •-- Must have at least 2 symptoms with a score >=3 or a total score of >=12, as measured by the MFSAF v4.
- •Classified as intermediate-2, or high-Risk MF as defined by the Dynamic International Prognostic Scoring System Plus (DIPSS+).
- •Has splenomegaly defined as spleen palpation measurement >= 5 centimeters (cm) below costal margin or spleen volume greater than or equal to 450 cubic cm as assessed centrally by magnetic resonance imaging (MRI) or computed tomography (CT) scan.
- •Ineligible for stem cell transplantation at time of study entry due to age, comorbidities, or unfit for unrelated or unmatched donor transplant and other criteria per National Comprehensive Cancer Network guidelines.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
排除标准
- •Prior treatment with a Janus Kinase-2 (JAK-2) inhibitor.
- •Prior treatment with a B-cell lymphoma 2 homology 3 (BH3)-mimetic compound or bromodomain and extra-terminal motif (BET) inhibitor or stem cell transplant.
- •Receiving medication that interferes with coagulation or platelet function within 3 days prior to the first dose of study drug or during the study treatment period except for low dose aspirin (up to 100 milligram daily) and low molecular weight heparin (LMWH).
研究组 & 干预措施
Navitoclax + Ruxolitinib
Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (>150 × 10^9/L starting dose of 200 mg; ≤150 × 10^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 25, Day 1 visit, navitoclax dose may be increased to 300 mg QD at Investigator's discretion for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Ruxolitinib tablets were administered orally twice daily (BID) per Baseline platelet count (>200 × 10^9/L starting dose of 20 mg; 100-200 × 10^9/L starting dose of 15 mg). Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).
干预措施: Navitoclax (Drug)
Navitoclax + Ruxolitinib
Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (>150 × 10^9/L starting dose of 200 mg; ≤150 × 10^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 25, Day 1 visit, navitoclax dose may be increased to 300 mg QD at Investigator's discretion for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Ruxolitinib tablets were administered orally twice daily (BID) per Baseline platelet count (>200 × 10^9/L starting dose of 20 mg; 100-200 × 10^9/L starting dose of 15 mg). Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).
干预措施: Ruxolitinib (Drug)
Placebo for Navitoclax + Ruxolitinib
Placebo for navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (>150 × 10^9/L starting dose of 200 mg; ≤150 × 10^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10^9/L). Placebo for navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 25, Day 1 visit, placebo for navitoclax dose may be increased to 300 mg QD at Investigator's discretion for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Ruxolitinib tablets were administered orally twice daily (BID) per Baseline platelet count (>200 × 10^9/L starting dose of 20 mg; 100-200 × 10^9/L starting dose of 15 mg). Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).
干预措施: Ruxolitinib (Drug)
Placebo for Navitoclax + Ruxolitinib
Placebo for navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (>150 × 10^9/L starting dose of 200 mg; ≤150 × 10^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10^9/L). Placebo for navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 25, Day 1 visit, placebo for navitoclax dose may be increased to 300 mg QD at Investigator's discretion for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Ruxolitinib tablets were administered orally twice daily (BID) per Baseline platelet count (>200 × 10^9/L starting dose of 20 mg; 100-200 × 10^9/L starting dose of 15 mg). Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).
干预措施: Placebo for Navitoclax (Drug)
结局指标
主要结局
Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume at Week 24 (SVR35W24)
时间窗: Baseline, Week 24
Reduction in spleen volume is measured by magnetic resonance imaging (MRI) or computed tomography (CT), per International Working Group (IWG) criteria.
次要结局
- Change From Baseline in Total Symptom Score (TSS) at Week 24 as Measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0(Baseline, Week 24)
- Overall Survival (OS)(Up to 50 months)
- Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume (SVR35) at Any Time(Up to Week 97)
- Duration of 35% Spleen Volume Reduction (SVR35)(Baseline (Week 0) Up to Month 48)
- Change From Baseline In Fatigue at Week 24 as Measured by the PROMIS Fatigue Short Form (SF) 7a(Baseline, Week 24)
- Change From Baseline at Week 24 in Physical Functioning as Measured by the Physical Functioning Domain of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30(Baseline, Week 24)
- Percentage of Participants Achieving Anemia Response(Up to Week 97)
- Leukemia-Free Survival(Up to 50 months)
- Percentage of Participants Who Achieved Reduction in Grade of Bone Marrow Fibrosis From Baseline at Any Time(Up to Week 97)