A Randomized, Double-Blind Phase 3 Study of Ibrutinib in Combination With Corticosteroids Versus Placebo in Combination With Corticosteroids in Subjects With New Onset Chronic Graft Versus Host Disease (cGVHD)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 193
- 试验地点
- 102
- 主要终点
- Primary Analysis: Response Rate at 48 Weeks
研究概览
简要总结
To evaluate the safety and efficacy of ibrutinib in combination with prednisone in subjects with newly diagnosed moderate to severe cGVHD.
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
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •New onset moderate or severe cGVHD as defined by the 2014 National Institutes of Health (NIH) Consensus Development Project Criteria
- •Need for systemic treatment with corticosteroids for cGVHD
- •No previous systemic treatment for cGVHD (including extracorporeal photopheresis [ECP])
- •Participants may be receiving other immunosuppressants for the prophylaxis or treatment of acute GVHD but if the subject is receiving prednisone for prophylaxis or treatment of acute GVHD it must be at or below 0.5 mg/kg/d
- •Age ≥12 years old
- •Karnofsky or Lansky (subjects <16 years) performance status ≥60
排除标准
- •Received any previous systemic treatment for cGVHD with the exception of corticosteroids administered for cGVHD within the 72 hours prior to signing the informed consent form.
- •Inability to begin a prednisone dose ≥0.5 mg/kg/d for the treatment of cGVHD
- •Any uncontrolled infection or active infection requiring ongoing systemic treatment
- •Progressive underlying malignant disease or any post-transplant lymphoproliferative disease
- •Known bleeding disorders
- •Active hepatitis C virus (HCV) or hepatitis B virus (HBV)
研究组 & 干预措施
Ibrutinib + Prednisone
Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for cytochrome P450 [CYP] inhibitors or hepatic dysfunction as applicable.
Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
干预措施: ibrutinib (Drug)
Ibrutinib + Prednisone
Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for cytochrome P450 [CYP] inhibitors or hepatic dysfunction as applicable.
Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
干预措施: Prednisone (Drug)
Placebo + Prednisone
Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity.
Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
干预措施: Placebo (Drug)
Placebo + Prednisone
Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity.
Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
干预措施: Prednisone (Drug)
结局指标
主要结局
Primary Analysis: Response Rate at 48 Weeks
时间窗: 48 weeks (Cumulatively up to 30 March 2020)
Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.
Final Analysis: Response Rate at 48 Weeks
时间窗: 48 weeks (Cumulatively up to 12 July 2021)
Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.
次要结局
- Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD(Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 30 March 2020))
- Primary Analysis: Response Rate at 24 Weeks(24 weeks (Cumulatively up to 30 March 2020))
- Final Analysis: Response Rate at 24 Weeks(24 weeks (Cumulatively up to 12 July 2021))
- Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD(Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021))
- Primary Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days(24 weeks (Cumulatively up to 30 March 2020))
- Primary Analysis: Overall Survival (OS)(Median time on study (cumulatively up to 30 March 2020) was 19.8 months and 18.4 months for the Ibrutinib + Prednisone and Placebo + Prednisone arms, respectively.)
- Final Analysis: OS(Median time on study (cumulatively up to 12 July 2021) was 33.1 months and 32.5 months for the Ibrutinib + Prednisone and Placebo + Prednisone arms, respectively.)
- Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants(Months 3, 6, 9, 12, 15, 18, 21, 24 (cumulatively up to 30 March 2020))
- Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants(Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021))
- Primary Analysis: Duration of Response (DOR) for Participants Who Had PR or CR at Any Time(Response was assessed every 4 weeks from Week 5 through Week 25, Week 37, Week 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 30 March 2020))
- Primary Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits(Assessed at Weeks 5, 13, 25, 37, 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 30 March 2020))
- Final Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days(24 weeks (Cumulatively up to 12 July 2021))
- Final Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits(Assessed at Weeks 5, 13, 25, 37, 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 12 July 2021))
- Final Analysis: DOR for Participants Who Had PR or CR at Any Time(Response was assessed every 4 weeks from Week 5 through Week 25, Week 37, Week 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 12 July 2021))
- Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone(From first dose of study drug through the end of treatment plus 30 days. As of data cutoff (cumulatively up to 30 March 2020), median ibrutinib treatment duration was 5.4 months and the median placebo treatment duration was 6.4 months.)
- Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone(From first dose of study drug through the end of treatment plus 30 days. As of data cutoff (cumulatively up to 12 July 2021), median ibrutinib treatment duration was 5.4 months and the median placebo treatment duration was 6.4 months.)