Initial Systemic Treatment of Acute GVHD: A Phase II Randomized Trial Evaluating Etanercept, Mycophenolate Mofetil (MMF), Denileukin Diftitox (ONTAK), and Pentostatin in Combination With Corticosteroids (BMT CTN #0302)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 180
- 试验地点
- 19
- 主要终点
- Number of Complete Response (CR) at Day 28 of Therapy
研究概览
简要总结
The study is a randomized Phase II, four arm treatment trial. The primary purpose of the study is to define new agents with promising activity against acute graft-versus-host disease (GVHD) suitable for testing against corticosteroids alone in a subsequent Phase III trial.
详细描述
BACKGROUND:
Acute graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell (HSC) transplantation. Acute GVHD produces significant morbidity and complicates patient management resulting in organ toxicity, frequent infections, malnutrition, and substantial delay in recovery from transplantation. Corticosteroids have been the primary therapy for acute GVHD for over three decades. Various additional immunosuppressive strategies have been tested as GVHD therapy but neither anti-thymocyte globulin (ATG), CD5-immunotoxins, IL-1 antagonists nor other agents have been demonstrably helpful in either control of GVHD symptoms or improvement in survival. Published response rates of complete response (CR) to acute GVHD therapy with corticosteroids range from 25-41%. These rates will be used as benchmarks for assessing efficacy of promising new agents. New immunosuppressive agents and strategies are required to improve the management of GVHD and decrease the toxicities of the immunosuppressive regimens.
DESIGN NARRATIVE:
In this trial, patients with newly diagnosed acute GVHD will be randomly assigned to receive corticosteroids plus one of four new agents (etanercept, MMF, denileukin diftitox [Ontak], and pentostatin). A control arm of only corticosteroids will not be employed. Each agent will be assessed for safety and efficacy (at least 35% complete remission [CR] rate at Day 28 of therapy can be expected from previously untreated patients).
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
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Prior allogeneic hematopoietic stem cell transplant using either bone marrow, peripheral blood stem cells, or cord blood
- •De novo acute GVHD diagnosed within 48 hours prior to enrollment; biopsy confirmation of GVHD is strongly recommended but not required; enrollment should not be delayed awaiting biopsy or pathology results; the patient must have had no previous systemic immune suppressive therapy given for treatment of acute GVHD except for a maximum 48 hours of prior corticosteroid therapy (at least 1 mg/kg/day methylprednisolone)
- •Patients that have undergone a scheduled donor lymphocyte infusion (DLI) as part of their original transplant therapy plan
- •Absolute neutrophil count (ANC) greater than 500/µL
- •Clinical status at enrollment to allow tapering of steroids to not less than 1 mg/kg/day methylprednisolone (1.4 mg/kg/day prednisone) at Day 28 of therapy (e.g., persisting malignant disease suggesting the need for accelerated taper of immunosuppression)
- •Estimated creatinine clearance greater than 30 mL/minute
- •Assent and educational materials provided to, and reviewed with, patients under the age of 18
排除标准
- •ONTAK, pentostatin, or etanercept given within 7 days of enrollment
- •Active uncontrolled infection
- •Patients that have undergone an unscheduled DLI, or DLI that was not part of their original transplant therapy plan
- •If any prior steroid therapy (for indication other than GVHD), treatment at doses of at least 0.5 mg/kg/day methylprednisolone within 7 days prior to onset of GVHD
- •Patients unlikely to be available at the transplant center on Day 28 and 56 of therapy
- •A clinical syndrome resembling de novo chronic GVHD developing at any time after allotransplantation (see Chapter 2 of the BMT CTN Manual of Procedures for details of de novo chronic GVHD)
- •Other investigational therapeutics for GVHD within 30 days, including agents used for GVHD prophylaxis
- •Patients who are pregnant, breast feeding, or if sexually active, unwilling to use effective birth control for the duration of the study
- •Adults unable to provide informed consent
- •Patients with a history of intolerance to any of the study drugs
研究组 & 干预措施
Etanercept
Enroll within 48 hours of new onset acute GVHD and randomize to Etanercept
干预措施: Etanercept (Drug)
Mycophenolate Mofetil
Enroll within 48 hours of new onset acute GVHD and randomize to Mycophenolate Mofetil
干预措施: Mycophenolate Mofetil (Drug)
Denileukin Diftitox
Enroll within 48 hours of new onset acute GVHD and randomize to Denileukin Diftitox
干预措施: Denileukin Diftitox (Drug)
Pentostatin
Enroll within 48 hours of new onset acute GVHD and randomize to Pentostatin
干预措施: Pentostatin (Drug)
结局指标
主要结局
Number of Complete Response (CR) at Day 28 of Therapy
时间窗: Measured at Day 28
Complete response at day 28 after randomization. CR was defined as resolution of all signs and symptoms of Graft-Versus-Host Disease (GVHD) in all evaluable organs in comparison to Day 1 scoring.
次要结局
- Number of Patients With Chronic Graft-versus-host Disease (GVHD)(Measured at 9 months)
- Cumulative Incidence of Systemic Infections(Measured at Day 270)
- Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90(Measured at Day 90)
- Number of Partial Response (PR), Mixed Response (MR), and Progression(Measured at Day 28)
- Number of Patients Surviving at 6 and 9 Months Post Randomization(Measured at 6 and 9 months)
- Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma(Measured at 9 months)
- Proportion of Treatment Failure(Measured at Day 56)
- Number of Patients Discontinuing Immune Suppression Without Flare(Measured at Days 90, 180, and 270 post-treatment)