A Prospective Study of Tocilizumab for the Prevention of Graft Failure and Graft-versus-Host Disease in Haplo-Cord Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Percentage of Subjects With Successful Haplo-derived Neutrophil Engraftment
研究概览
简要总结
The purpose of this study is to evaluate the safety of reducing and ultimately eliminating anti-thymocyte globulin (ATG) from the haplo-cord transplant conditioning regimen and replacing it with tocilizumab, an IL-6 receptor monoclonal antibody, to improve immune reconstitution and reduce relapse while preserving low rates of graft failure and graft versus host disease (GVHD).
详细描述
This study is a prospective phase II non-inferiority study investigating tocilizumab as a potential alternative to anti-thymocyte globulin (ATG) in haplo-cord transplantation. It is a single-center study based at Weill Cornell Medicine/NewYork Presbyterian Hospital.
The hypothesis is that tocilizumab is a safe and effective alternative to ATG in haplo-cord transplantation, facilitating transient engraftment of the haplo-identical stem cell graft without prolonged neutropenia or second nadir prior to durable cord engraftment while also preventing graft versus host disease (GVHD).
This study plans to enroll patients with hematologic malignancies in need of alternate donor transplant. All subjects will be conditioned with fludarabine, melphalan and total body irradiation (TBI), followed by a single dose of tocilizumab 8 mg/kg on Day -1. Patients will be enrolled into 4 successive cohorts, initially administering the current standard 3 doses of ATG 1.5 mg/kg (total 4.5 mg/kg). In the absence of safety signals, we will drop one dose of ATG in successive cohorts until the drug ultimately has been eliminated.
The primary endpoint of the study is successful haplo-derived neutrophil engraftment. Treatment will only be of interest if there is evidence that this rate is greater than 60%. If there are 4 or fewer successes, that dose group will be deemed unacceptable and the next higher ATG dose for which there were 5 or more success will be expanded.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Subject must have a confirmed diagnosis of one of the following:
- •Relapsed or refractory acute leukemia (myeloid or lymphoid)
- •Acute leukemia in first remission at high-risk for recurrence
- •Chronic myelogenous leukemia in chronic, accelerated phase or blast-crisis
- •Myelodysplastic syndromes
- •Chronic myeloproliferative disease
- •Recurrent, refractory or high-risk malignant lymphoma
- •Chronic lymphocytic leukemia, relapsed or with poor prognostic features
- •Multiple myeloma
- •Other hematological disorder in need of allogeneic transplant (e.g. blastoid dendritic cell neoplasm)
- •Age ≥ 18 years.
- •Likely to benefit from allogeneic transplant in the opinion of the transplant physician.
- •An HLA-identical related or unrelated donor cannot be identified within an appropriate time frame.
- •Karnofsky Performance Status (KPS) of ≥ 70%.
- •Acceptable organ function as defined below:
- •Serum bilirubin: <2.0 mg/dL
- •ALT (SGPT) <3x upper limit of normal (ULN)
- •Creatinine Clearance: >50 mL/min/1.73m2 (eGFR as estimated by the modified MDRD equation)
- •Left ventricular ejection fraction >40%
- •Pulmonary diffusion capacity >40% predicted
- •Ability to understand and the willingness to sign a written informed consent document.
排除标准
- •Life expectancy is severely limited by concomitant illness or uncontrolled infection.
- •Evidence of chronic active hepatitis or cirrhosis
- •Uncontrolled HIV disease.
- •Pregnancy or lactation.
- •History of complicated diverticulitis, including fistulae, abscess formation or gastrointestinal perforation
- •History of allergic reactions attributed to compounds of similar chemical or biological composition as tocilizumab, including known allergies to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
研究组 & 干预措施
ATG Group I
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5, Day -3 and Day -1 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Tocilizumab (Drug)
ATG Group I
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5, Day -3 and Day -1 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Fludarabine (Drug)
ATG Group I
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5, Day -3 and Day -1 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Melphalan (Drug)
ATG Group I
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5, Day -3 and Day -1 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Anti-thymocyte globulin (rabbit) (Drug)
ATG Group I
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5, Day -3 and Day -1 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Total Body Irradiation (Radiation)
ATG Group II
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5, and Day -3 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Tocilizumab (Drug)
ATG Group II
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5, and Day -3 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Fludarabine (Drug)
ATG Group II
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5, and Day -3 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Melphalan (Drug)
ATG Group II
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5, and Day -3 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Anti-thymocyte globulin (rabbit) (Drug)
ATG Group II
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5, and Day -3 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Total Body Irradiation (Radiation)
ATG Group III
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Tocilizumab (Drug)
ATG Group III
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Fludarabine (Drug)
ATG Group III
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Melphalan (Drug)
ATG Group III
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Anti-thymocyte globulin (rabbit) (Drug)
ATG Group III
Anti-thymocyte Globulin (ATG) 1.5 mg/kg administered on Day -5 of the transplant conditioning regimen.
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Total Body Irradiation (Radiation)
ATG Group IV
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Tocilizumab (Drug)
ATG Group IV
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Fludarabine (Drug)
ATG Group IV
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Melphalan (Drug)
ATG Group IV
- Fludarabine 30mg/m2 administered on Day -7 through Day -3 of transplant conditioning regimen (if under 60 years old), or on Day -5 through Day -3 of transplant conditioning regimen (if over 60 years old)
- Melphalan 140 mg/m2 administered on Day -2 of transplant conditioning regimen.
- Total Body Irradiation 2 Gray administered on Day -4, Day -3 of transplant conditioning regimen.
- Tocilizumab 8 mg/kg administered on Day -1 of transplant conditioning regimen.
干预措施: Total Body Irradiation (Radiation)
结局指标
主要结局
Percentage of Subjects With Successful Haplo-derived Neutrophil Engraftment
时间窗: 21 days post-transplant
This is defined as: 1. Achieve an absolute neutrophil count (ANC) of 500 cells/microL for three consecutive days with the first on or prior to Day +21 post-transplant, AND 2. Absence of a second nadir - a drop in the ANC to \<300 cells/microL for five consecutive days - after initial neutrophil recovery.
次要结局
- Progression-Free Survival(5 years post-transplant)
- Overall Survival(5 years post-transplant)
- Transplant-Related Mortality(5 years post-transplant)
- Proportion of Platelet Engraftment Success(6 months post-transplant)
- Proportion of Failure of the Haplo-Graft(21 days post-transplant)
- Proportion of Acute Graft-versus-Host Disease(1 year post-transplant)
- Percentage of Chronic Graft-versus-Host Disease(5 years post-transplant)