A Phase 2, Open-label Study to Evaluate Graft-vs-host Disease Prophylaxis With High Dose Thymoglobulin, Methotrexate, and Low-dose Cyclosporine in Comparison to Historical/Concurrent Controls Who Received Low Dose Thymoglobulin, Methotrexate, and High-dose Cyclosporine
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 68
- 试验地点
- 1
- 主要终点
- moderate/severe chronic GVHD- and relapse-free survival (cGFRS) at 2 years post transplant
研究概览
简要总结
The purpose of this study is to find out whether compared to our standard low dose ATG with CSA, the high dose ATG with low-dose CSA minimizes the chances of relapse and chronic GVHD, without increasing the chances of other transplant complications.
详细描述
There are a number of complications of allogeneic hematopoietic cell transplantation.
The main complications are:
- Relapse (leukemia or leukemia-like disease returning). This usually leads to death.
- Acute graft-versus-host disease (GVHD). This may lead to death.
- Chronic GVHD. This may lead to poor quality of life long-term.
This study is being done to minimize the chances of patients getting relapse and chronic GVHD, without increasing the chances of getting acute GVHD.
At this time, the standard of care approach to treat this condition would be with:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •First allogeneic HCT, performed for a hematologic malignancy, using filgrastim-mobilized peripheral blood stem cells (PBSC).
- •Conditioning with fludarabine 50 mg/m2 daily on day -6 to -2, busulfan approximately 3.2 mg/kg daily on day -5 to -2 with PK adjustment (target AUC of 3750 uM*min/L) and total body irradiation (TBI) 2 Gy x 2 given typically on day -1 and/or day 0 (before graft infusion), ie, our standard myeloablative conditioning.79 Dose and schedule adjustments per Investigator discretion are permitted.
- •Planned GVHD prophylaxis with our standard of low-dose ATG (4.5 mg/kg) + MTX + high-dose CSA.
- •HLA matched sibling donor, or ≥7/8 HLA allele-matched unrelated donor (maximum 1 allele mismatch at HLA-A, B, C, or DRB1).
- •Age >17 years.
排除标准
- •Nonmyeloablative conditioning.
- •Cord blood or marrow graft.
- •Myelofibrosis being the primary indication for HCT.
- •Previous autologous or allogeneic HCT.
- •Total Bilirubin >1.5-fold above upper normal limit (UNL), ALT >2.0-fold above UNL, or alkaline phosphatase >2.5-fold above UNL.
- •HIV positive by a serologic test that includes detection of both antibody and antigen)
- •Increased risk of tuberculosis, defined as patient requiring an anti-tuberculosis drug peritransplant. All patients with a history of tuberculosis (active or latent) or contact with a person with active tuberculosis will be evaluated by an infectious disease specialist to determine whether treatment or prophylaxis of tuberculosis with an anti-tuberculosis drug peritransplant is needed. The infectious disease specialist will order tests (eg, Mantoux tuberculin skin test or interferon gamma release test) as needed to arrive at the decision on whether an anti-tuberculosis drug peritransplant is needed.
- •High risk of cytomegalovirus (CMV) disease or recurrent CMViremia based on donor negative AND recipient positive CMV serostatus.2 If recipient serostatus was determined since the presentation of his/her hematologic malignancy more than once and the results are discrepant, the determination performed >4 weeks after a transfusion of platelets or plasma (or before transfusions of platelets or plasma were initiated) is considered valid. If unclear, the CMV serostatus determination will be at the discretion of the treating Investigator
- •High risk of PTLD based on donor positive AND recipient negative Epstein-Barr virus (EBV) serostatus (EBNA1 or VCA IgG)80
- •Hypersensitivity to rabbit blood protein, Thymoglobulin or a Thymoglobulin excipient.
- •Severe obesity, defined as body mass index ≥40 kg/m2.81 The reason is that obese patients are at risk of achieving a high ATG area under the time vs concentration curve (AUC).82 This could lead to substantial toxicity (e.g., death due to an infection) when using the studied high dose (10 mg/kg) of ATG.
- •Contraindication to methotrexate:
- •Hypersensitivity to methotrexate or to any ingredient in the formulation or component of the container.
- •Females of childbearing potential who are pregnant, breastfeeding or unwilling to use adequate contraception from the time of enrolment until at least day 100 posttransplant.
研究组 & 干预措施
Treatment Arm - High dose ATG, Low dose CSA
High dose ATG will be infused on days -4, -3, -2, -1 and 0. Before each infusion of ATG (thymoglobulin), patient will receive medications preventing side effects from the ATG, including diphenhydramine (Benadryl), an antipyretic (ibuprofen or acetaminophen) and methylprednisolone (Solumedrol). The high dose ATG will be given into patient's vein via central venous catheter. Each infusion of ATG will take 4-8 hours. CSA (cyclosporine A) will be given from day 21. Standard dose methotrexate will be given.
干预措施: Treatment Arm - high dose ATG (Drug)
Control Arm - Standard of care
Low dose ATG (thymoglobulin) will be infused on days -2, -1 and 0, and CSA (cyclosporine A) will be given from day -1 through day 84. Standard dose methotrexate will also be given.
干预措施: Control Arm - standard of care (Drug)
结局指标
主要结局
moderate/severe chronic GVHD- and relapse-free survival (cGFRS) at 2 years post transplant
时间窗: 2 years
cGRFS will be compared between the study patients and the historical/concurrent controls using a Cox proportional hazards model to determine if administering high dose ATG + MTX and low dose CSA will be associated with improved cGRFS compared to historical/concurrent controls (4.5 mg/kg ATG + MTX + CSA).
次要结局
- quality of life(approximately 2 years (21 to 27 months) post transplant)