A Phase III Randomized Open-label Multi-center Study of Ruxolitinib vs. Best Available Therapy in Patients With Corticosteroid-refractory Chronic Graft vs Host Disease After Allogeneic Stem Cell Transplantation (REACH3)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 330
- 试验地点
- 3
- 主要终点
- Efficacy of Ruxolitinib Versus Investigator's Choice Best Available Therapy (BAT) in Participants With Moderate or Severe Steroid Refractory Chronic Graft Versus Host Disease (SR-cGvHD) Assessed by Overall Response Rate (ORR) at the Cycle 7 Day 1 Visit
研究概览
简要总结
The purpose of this study is to assess the efficacy of ruxolitinib against best available therapy in participants with steroid-refractory chronic graft-versus-host disease (SR 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
- 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 transplantation (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
- •Evident myeloid and platelet engraftment: Absolute neutrophil count (ANC) > 1000/mm^3 and platelet count > 25,000/ mm^3
- •Participants with clinically diagnosed moderate to severe cGvHD according to NIH Consensus Criteria prior to randomization:
- •Moderate cGvHD: At least one organ (not lung) with a score of 2, 3 or more organs involved with a score of 1 in each organ, or lung score of 1
- •Severe cGvHD: at least 1 organ with a score of 3, or lung score of 2 or 3
- •Participants currently receiving systemic or topical corticosteroids for the treatment of cGvHD for a duration of < 12 months prior to Cycle 1 Day 1 (if applicable), and have a confirmed diagnosis of steroid-refractory cGvHD defined per 2014 NIH consensus criteria irrespective of the concomitant use of a calcineurin inhibitor (CNI), as follows:
- •A lack of response or disease progression after administration of minimum prednisone 1 mg/kg/day for at least 1 week, OR
- •Disease persistence without improvement despite continued treatment with prednisone at > 0.5 mg/kg/day or 1 mg/kg/every other day for at least 4 weeks, OR
- •Increase to prednisolone dose to > 0.25 mg/kg/day after 2 unsuccessful attempts to taper the dose
- •Participant must accept to be treated with only one of the following BAT options on Cycle 1 Day 1 (additions and changes are allowed during the course of the study, but only with BAT from the following BAT options): extracorporeal photopheresis (ECP), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, ibrutinib
排除标准
- •Participants who have received 2 or more systemic treatment for cGvHD in addition to corticosteroids ± CNI for cGvHD
- •Patients that transition from active aGvHD to cGvHD without tapering off corticosteroids ± CNI and any systemic treatment
- •* Patients receiving up to 30 mg by mouth once a day of hydrocortisone (i.e., physiologic replacement dose) of corticosteroids are allowed.
- •Participants who were treated with prior JAK inhibitors for aGvHD; except when the participant achieved complete or partial response and has been off JAK inhibitor treatment for at least 8 weeks prior to Cycle 1 Day 1
- •Failed prior alloSCT within the past 6 months from Cycle 1 Day 1
- •Participants with relapsed primary malignancy, or who have been treated for relapse after the alloSCT was performed
- •Steroid refractory cGvHD occurring after a non-scheduled donor lymphocyte infusion (DLI) administered for preemptive treatment of malignancy recurrence. Participants who have received a scheduled DLI as part of their transplant procedure and not for management of malignancy relapse are eligible
- •Any corticosteroid therapy for indications other than cGvHD at doses > 1 mg/kg/day methylprednisolone or equivalent within 7 days of Cycle 1 Day 1
研究组 & 干预措施
Ruxolitinib
Ruxolitinib for the treatment period and extension period.
干预措施: Ruxolitinib (Drug)
Best Available Therapy
Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.
干预措施: Extracorporeal photopheresis (ECP) (Drug)
Best Available Therapy
Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.
干预措施: Low-dose methotrexate (MTX) (Drug)
Best Available Therapy
Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.
干预措施: Mycophenolate mofetil (MMF) (Drug)
Best Available Therapy
Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.
干预措施: mechanistic Target of Rapamycin (mTOR) inhibitors (everolimus or sirolimus) (Drug)
Best Available Therapy
Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.
干预措施: Infliximab (Drug)
Best Available Therapy
Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.
干预措施: Rituximab (Drug)
Best Available Therapy
Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.
干预措施: Pentostatin (Drug)
Best Available Therapy
Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.
干预措施: Imatinib (Drug)
Best Available Therapy
Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.
干预措施: Ibrutinib (Drug)
结局指标
主要结局
Efficacy of Ruxolitinib Versus Investigator's Choice Best Available Therapy (BAT) in Participants With Moderate or Severe Steroid Refractory Chronic Graft Versus Host Disease (SR-cGvHD) Assessed by Overall Response Rate (ORR) at the Cycle 7 Day 1 Visit
时间窗: Cycle 7 Day 1 (each cycle was comprised of 4 weeks)
ORR was defined as the percentage of participants in each arm demonstrating a complete response (CR) or partial response (PR) based on chronic GvHD (cGvHD) disease assessments (National Institutes of Health Consensus Criteria) without the requirement of additional systemic therapies for an earlier progression, mixed response, or non-response. Scoring of response was relative to the organ score at the time of randomization. CR: complete resolution of all signs and symptoms of cGVHD in all evaluable organs without the initiation or addition of new systemic therapy. PR: improvement in at least one organ (e.g., improvement of 1 or more points on a 4- to 7-point scale, or an improvement of 2 or more points on a 10- to 12-point scale) without progression in other organs or sites, initiation, or addition of new systemic therapies.
次要结局
- Rate of Participants With Clinically Relevant Improvement of the Modified Lee cGvHD Symptom Scale Score(Baseline; Cycle 7 Day 1 (each cycle was comprised of 4 weeks))
- Rate of Failure-free Survival (FFS)(Baseline to when the last participant reached Cycle 7 Day 1 (each cycle was comprised of 4 weeks))
- BOR During Cross-over Treatment With Ruxolitinib(from Crossover Cycle 1 Day 1 to any time point up to and including Crossover Cycle 7 Day 1 (each cycle was comprised of 4 weeks))
- ORR at the End of Cycle 3(Cycle 4 Day 1 (each cycle was comprised of 4 weeks))
- Rate of FFS at Study Completion(From Baseline to Last Participant Last Visit (LPLV) (approximately 5 years))
- Best Overall Response (BOR) at Cycle 7 Day 1(up to Cycle 7 Day 1 (each cycle was comprised of 4 weeks))
- Cumulative Incidence of Non-relapse Mortality (NRM)(Months 3, 6, 12, 18, 24, 30, and 36)
- Duration of Response Through Study Completion(from first response to LPLV (approximately 5 years))
- Overall Survival (OS)(from the date of randomization to the date of death due to any cause up to LPLV (approximately 5 years))
- Percentage of Participants With a ≥ 50% Reduction in Daily Corticosteroid Dose(from Day 15 up to Day 182)
- Percentage of Participants Successfully Tapered Off of All Corticosteroids(up to Day 179)
- Cumulative Incidence of Malignancy Relapse/Recurrence (MR)(Months 3, 6, 12, 18, 24, 30, and 36)
- Change From Baseline in Functional Assessment of Cancer Therapy - Bone Marrow Transplantation (FACT-BMT)(Baseline; up to Cycle 39 Day 1 (each cycle was comprised of 4 weeks))
- Number of Participants With Any Treatment-emergent Adverse Event (TEAE)(from Baseline to LPLV (approximately 5 years))
- AUClast of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses(Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose)
- AUCinf of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses(Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose)
- Change From Baseline in EQ-5D-5L(Baseline; up to Cycle 39 Day 1 (each cycle was comprised of 4 weeks))
- Cmax of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses(Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose)
- CL/F of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses(Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose)
- Vz/F of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses(Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose)
- Tmax of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses(Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose)
- t1/2 of Ruxolitinib After Single (Cycle 1 Day 1) and Multiple (Cycle 1 Day 15) Doses(Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose)
- Utilization of Medical Resources(from Baseline to LPLV (approximately 5 years))