A Phase III Randomized Open-label Multi-center Study of Ruxolitinib Versus Best Available Therapy in Patients With Corticosteroid-refractory Acute Graft vs. Host Disease After Allogeneic Stem Cell Transplantation
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 310
- 试验地点
- 1
- 主要终点
- Overall Response Rate (ORR) at Day 28
研究概览
简要总结
Assess the efficacy and safety of ruxolitinib compared to Best Available Therapy (BAT) in patients with corticosteroid-refractory acute graft vs. host disease (aGvHD) after allogeneic stem cell transplantation.
详细描述
This randomized, phase III, open-label study investigated the efficacy and safety of ruxolitinib vs. BAT added to the patient's immunosuppressive regimen in adults and adolescents (≥ 12 years old) with grade II-IV Steroid-refractory Acute Graft vs. Host Disease (SR-aGvHD). During the screening period, patients were monitored for a diagnosis of SR-aGvHD, which was defined as patients who had high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with CNI, who either:
- Progressed based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR
- Failed to achieve at a minimum a partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR
- Failed corticosteroid taper defined as fulfilling either one of the following criteria:
- Requirement for an increase in the corticosteroid dose to methylprednisolone ≥ 2 mg/kg/day (or equivalent prednisone dose ≥ 2.5 mg/kg/day) OR
- Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone dose <0.6 mg/kg/day) for a minimum 7 days.
Patients meeting eligibility criteria were randomized 1:1 to receive either ruxolitinib or BAT stratifying on aGvHD grade at the time of randomization (Grade II vs III vs IV).
Study treatment began on Day 1 (no later than 72 hours after randomization) followed by regular visits for assessments of efficacy and safety. Study treatment was administered until the patient met any of the criteria for discontinuation of study treatment or, in responders (i.e. patients achieving PR or CR) until the dosing schedule for ruxolitinib or BAT was completed.
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
- None
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
- •Have undergone Allogeneic Stem Cell Transplanttaion (alloSCT) from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of non- myeloablative, myeloablative, and reduced intensity conditioning are eligible
- •Clinically diagnosed Grades II to IV acute GvHD as per standard criteria occurring after alloSCT requiring systemic immune suppressive therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening.
- •Confirmed diagnosis of steroid refractory aGvHD defined as patients administered high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) and either:
- •Progressing based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR
- •Failure to achieve at a minimum partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,OR
- •Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria:
- •Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 mg/kg/day (or equivalent prednisone dose ≥2.5 mg/kg/day) , OR
- •Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone dose <0.6 mg/kg/day) for a minimum 7 days.
排除标准
- •Has received more than one systemic treatment for steroid refractory aGvHD.
- •Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
- •Evidence of uncontrolled viral infection including Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Human Herpes Virus-6 (HHV-6), Hepatitis Virus (HBV), or Hepatitis C Virus (HCV) based on assessment by the treating physician.
- •Presence of relapsed primary malignancy, or who have been treated for relapse after the alloHSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.
研究组 & 干预措施
Ruxolitinib
These patients were administered Ruxolitinib orally twice per day (b.i.d) at a dose of 10 mg bid, as two 5-mg tablets. Ruxolitinib was taken without regards to food.
干预措施: Ruxolitinib (RUX) (Drug)
Best Available Therapy (BAT)
These patients were administered BAT per the Investigator's best judgement based on a specific list of BAT.
干预措施: Best Available Therapy (BAT) (Drug)
结局指标
主要结局
Overall Response Rate (ORR) at Day 28
时间窗: Day 28
Overall response rate at Day 28 after randomization was defined as the percentage participants in each arm demonstrating a complete response (CR) or partial response (PR), based on investigator assessment \& according to standard criteria, without requirement for additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response was relative to the organ stage at the time of randomization. CR was defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs \& symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD.
次要结局
- Durable Overall Response Rate (DORR) (Key Secondary Endpoint) at Day 56(Day 56)
- Cumulative Steroid Dosing Until Day 56(up to Day 56)
- Cumulative Probability of Malignancy Relapse/Progression (MR)(1, 2, 6, 12 , 18 & 24 months)
- Cumulative Probability of Chronic Graft Versus Host Disease (cGvHD)(1, 2, 6, 12, 18 & 24 months)
- Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC) (AUCinf, AUClast, AUCtau) of Ruxolitinib(pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose)
- Kaplan Meier Estimates of Probability of Overall Survival (OS) by Time Interval(1, 2, 6, 12, 18 & 24 months)
- Overall Response Rate (ORR) at Day 14(Day 14)
- Duration of Response (DOR)(Up to 24 months)
- Pharmacokinetic (PK) Parameter: CL/F of Ruxolitinib(pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose)
- Cumulative Probability of Non Relapse Mortality (NRM)(1, 2, 6, 12, 18 & 24 months)
- Exposure-efficacy Relationship of Ruxolitinib in Corticosteroid Refractory aGvHD: PK-Overall Response Rate(Day 28)
- Best Overall Response Rate (BOR)(up to Day 28)
- Pharmacokinetic (PK) Parameter: T1/2 of Ruxolitinib(pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose)
- Kaplan Meier Estimates of Probability of Event-free Survival (EFS) by Time Interval(1, 2, 6, 12, 18 & 24 months)
- Cumulative Incidence Rate of Failure-Free Survival (FFS)(1, 2, 6, 12, 18, & 24 Months)
- Exposure-efficacy Relationship of Ruxolitinib in Corticosteroid Refractory aGvHD: PK- Durable Overall Response Rate (DORR)(Day 56)
- Exposure-efficacy Relationship of Ruxolitinib in Corticosteroid Refractory aGvHD: PK-Overall Survival(up to 24 months)
- Patient Reported Outcomes (PROs): Change From Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) Total Score(Baseline, Week 24)
- Patient Reported Outcomes (PROs): Change From Baseline in EuroQol-5D-5L UK Score(Baseline, Week 24)
- Pharmacokinetic (PK) Parameter: Plasma Concentration at Peak (Cmax) of Ruxolitinib(pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose)
- Pharmacokinetic (PK) Parameter: VzF of Ruxolitinib(pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose)
- Pharmacokinetic (PK) Parameter: Lambda_z of Ruxolitinib(pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose)
- Pharmacokinetic (PK) Parameter: Tmax of Ruxolitinib(pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose)
- Pharmacokinetic (PK) Parameter: Racc of Ruxolitinib(pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose)
- Pharmacokinetic (PK) Parameter: Ctrough of Ruxolitinib(pre-dose)