Phase I-II Study Using Tocilizumab for Treatment of Steroid Refractory Acute Graft-versus-Host Disease
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 14
- 试验地点
- 1
- 主要终点
- Number of Subjects Achieving Complete or Partial Response at Day 56 After Administration of Tocilizumab
研究概览
简要总结
This trial designed to evaluate the toxicity and efficacy of tocilizumab in the treatment of steroid refractory acute graft versus host disease (GVHD).
详细描述
Patients who underwent an allogeneic hematopoietic stem cell transplantation, with biopsy proven GVHD, active acute GVHD requiring systemic immune suppressive therapy and that failed or did not respond to first line of therapy (corticosteroids ± other agent).
Tocilizumab will be administered intravenously at a dose of 8 mg/kg once every three weeks. Patients with documented responses will continue to receive treatment at 8 mg/kg once every 3 weeks for at least two months (day 56). Patients that have some degree of response but without complete resolution of signs and symptoms of acute GVHD may continue to receive 8 mg/kg on a 3-week cycle until complete response is achieved or lack of further improvement. In patients who are beyond day 56 and whose GVHD has resolved, the dose of Tocilizumab will be reduced to 4 mg/kg every 3 weeks. Subsequent discontinuation of Tocilizumab will occur once patients are off other immune suppressive medications (including extracorporeal photopheresis, ECP) or are receiving sub therapeutic levels of immunosuppression (i.e., Tacrolimus (FK) levels <5 ng/mL) or prednisone dose <20 mg/day (or equivalent) and are free of acute GVHD signs or symptoms for at least one month.
Patients who fulfill criteria of progression of GVHD not in the setting of immunosuppressive taper, no response of GVHD or require initiation of other immune suppressive treatment for GVHD will have Tocilizumab discontinued.
Tocilizumab shall be discontinued and not re-instituted if any one of the following criteria is met. The patient will be taken off study drug therapy at that point, but still followed for primary and secondary study endpoints. A response assessment will be made at the time of therapy discontinuation and at subsequent defined study endpoints. The patient will not be replaced on study. Follow-up data will be required unless consent for data collection is withdrawn:
- Additional systemic GVHD therapy is added for disease progression or non-response
- Steroid dose is escalated to ≥ 2.5 mg/kg/day of prednisone (or methylprednisolone equivalent of 2 mg/kg/day) for GVHD progression or no response
- Development of toxicity that requires withholding of study medication for more then 14 days
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
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
- •Patients age 18 and older who underwent an allogeneic hematopoietic stem cell transplantation.
- •Patients are required to have biopsy proven GVHD.
- •Patients must have active acute GVHD requiring systemic immune suppressive therapy and that failed or did not respond to first line of therapy.
- •First line therapy needs to be a minimum of corticosteroids, methylprednisolone of 1.6mg/kg/day or prednisone of 2mg/kg/day, alone or combined to other agent.
- •Failure of GVHD therapy is defined as flare of signs and symptoms of acute GVHD or progression of GVHD grade after at least 72 hours from starting therapy.
- •No response to GVHD treatment (corticosteroids ± other agent) after a minimum of 7 days of treatment.
- •Patient must be able to give informed consent.
排除标准
- •Intolerance or allergy to Tocilizumab
- •Active uncontrolled infection requiring ongoing treatment with antifungals, antibiotics or anti-viral drugs.
- •Relapsed/persistent malignancy requiring rapid immune suppression withdrawal.
- •Liver enzymes: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 3x upper limit of normal.
- •Patients with severe sinusoidal obstruction syndrome who in the judgment of the treating physician are not expected to have normalized bilirubin by day 56 after enrollment.
- •Serum bilirubin > 2x upper limit of normal.
研究组 & 干预措施
Tocilizumab
Drug: Tocilizumab
Other Names:
Actemra
Tocilizumab will be administered intravenously at a dose of 8 mg/kg once every three weeks for three doses. After Day 56 doses may be decreased to 4mg/kg once every three weeks depending on GVHD response.
干预措施: Tocilizumab (Drug)
结局指标
主要结局
Number of Subjects Achieving Complete or Partial Response at Day 56 After Administration of Tocilizumab
时间窗: Day 56
Number of subjects achieving Center for International Blood and Marrow Transplant Research (CIBMTR) score of 0 (complete response); or achieving improvement in one or more organs involved in GVHD without progression in other organs (partial response). CIBMTR score of 0 means no evidence of rash or diarrhea and bilirubin less than 2.0 mg/dl. CIBMTR score of 4 means rash with bullae desquamation, lower gastrointestinal diarrhea more than 1,500 ml, and bilirubin greater than 15.1 mg/dl. Higher score means worse disease.
次要结局
- Disease-free Survival(6 and 12 months)
- Number of Patients With Partial, Mixed or no GVHD Responses(Day 56)
- GVHD Flares(Day 90)
- Discontinuation of Immunosuppression(Day 56, Day 180 and Day 365)
- Overall Survival(1 year)
- Non-relapse Mortality(6 months)
- Number of Subjects Experiencing at Least One Serious Adverse Event or Grade 3 Non-serious Adverse Event(Day 56)
研究者
William R. Drobyski, MD
Professor of Medicine
Medical College of Wisconsin