A Phase 1 Safety and Tolerability Study of Infused Donor T Regulatory Cells in Steroid Dependent/Refractory Chronic Graft Versus Host Disease
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 14
- 试验地点
- 2
- 主要终点
- The frequency of adverse events related to the donor Treg infusions (e.g., grade III-IV aGVHD by the modified Keystone criteria and grade 3 or higher infusional toxicities graded according to the CTCAE v. 4)
研究概览
简要总结
Chronic graft versus host disease (cGVHD) is a common complication of bone marrow or hematopoietic cell transplant from another person (allogeneic transplant). This study will determine if subjects with steroid dependent/refractory cGVHD can tolerate infusion of donor regulatory T cells and whether their cGVHD responds to the infusion.
详细描述
PRIMARY OBJECTIVES:
Determine the safety and tolerability of donor T regulatory (Treg) cell infusions in subjects with steroid dependent/refractory chronic graft versus host disease.
SECONDARY OBJECTIVES:
-
Determine the quantitative blood Treg cell changes following the cell infusions
-
Determine clinical efficacy of donor Treg cells as failure-free survival (FFS) defined by the absence of a new immunosuppressive therapy added, non-relapse mortality, and recurrent malignancy at Day 180 after the first Treg infusion
-
In addition to FFS, the study will measure the change in:
-
cGVHD symptom burden measured by the Lee cGVHD Symptom Scale by increase in >7 points
-
NIH organ-specific cGVHD scale
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The reduction in daily corticosteroid requirement of prednisone to <=0.25 mg/kg-day at Day 180 after the first Treg infusion
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
- •Steroid dependent/refractory cGVHD defined as:
- •Steroid dependent disease: Persistent cGVHD manifestations requiring a glucocorticoid dose >= prednisone 0.25 mg/kg/day (0.5 mg/kg orally [po] every other day) for at least 12 weeks
- •Steroid refractory disease: Progressive cGVHD manifestations despite treatment with a glucocorticoid dose >= prednisone 0.5 mg/kg/day (1 mg/kg po every other day) for at least 4 weeks
- •Participants must be receiving systemic glucocorticoid therapy for cGVHD; all immunosuppressive therapy may include but not be limited to tacrolimus, sirolimus, CellCept, cyclosporine, and systemic corticosteroid must be at stable doses for 28 days prior to the first cell infusion
- •Chronic GVHD manifestations that can be followed on physical or laboratory exam; these include but are not necessarily limited to:
- •Skin changes
- •Oral mucosa changes
- •Bronchiolitis obliterans
- •Ocular changes
- •Karnofsky performance status >= 60
- •Serum creatinine =< 2 mg/dL
- •Absolute neutrophil count (ANC) > 1 x 10^9/L
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 20 x upper limit of normal (ULN) or
- •Total bilirubin =< 10 x ULN
- •Allogeneic hematopoietic cell transplant recipient
- •Transfusion independent
- •Oxygen saturation during exertion is maintained at >= 88% on room air
- •Does not have clinically significant, symptomatic uncontrolled heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension)
- •DONOR: Age >= 18 to =< 75 years old
- •DONOR: Karnofsky performance status of >= 70% defined by institutional standards
- •DONOR: Must be the same sibling donor from whom the recipient's blood and marrow graft was collected for the original allogeneic transplant that is human leukocyte antigen (HLA) 7/8 or 8/8 matched at the HLA-A, B,C, DRB1
- •DONOR: Serologies for human immunodeficiency virus (HIV) antigen (Ag), HIV 1 and HIV 2 antibody (Ab), human T-lymphotropic virus type I (HTLV 1) and HTLV 2 Ab, hepatitis B surface antigen (sAg) or polymerase chain reaction positive (PCR+), or hepatitis C Ab or PCR+, Syphilis (Treponema) screen and HIV 1 and hepatitis C by nucleic acid testing (NAT) have been collected prior to apheresis
- •DONOR: Female donors of child-bearing potential must have a negative serum or urine beta-human chorionic gonadotropin (HCG) test within three weeks of apheresis
- •DONOR: Capable of undergoing leukapheresis, have adequate venous access, and be willing to undergo insertion of a central catheter should leukapheresis via peripheral vein be inadequate
- •DONOR: Donor selection will be in compliance with 21 Code of Federal Regulations (CFR) 1271
排除标准
- •Original transplant utilized an unrelated donor graft
- •Uncontrolled infections that are not responsive to antimicrobial therapy
- •Progressive malignant disease, including post-transplant lymphoproliferative disease unresponsive to therapy
- •Second malignancy except for skin cancer within the last 5 years
- •Received any investigational agent =< 28 days before Treg infusions
- •Received filgrastim (GCSF) treatment within one month of enrollment
- •Received a donor lymphocyte infusion (DLI) or hematopoietic cell transplantation (HCT) within 3 months of enrollment
- •DONOR: Evidence of active infection or viral hepatitis
- •DONOR: HIV positive
- •DONOR: Pregnant donor
研究组 & 干预措施
Regulatory T Cells
Cohort 1 at 1x105 Treg cells/kg, Cohort 2 at 5x105 Treg cells/kg and Cohort 3 at 1.5x106 Treg cells/kg with an extension phase at the MTD (or maximum administered dose if the MTD is not reached).
干预措施: Regulatory T Cells (Biological)
结局指标
主要结局
The frequency of adverse events related to the donor Treg infusions (e.g., grade III-IV aGVHD by the modified Keystone criteria and grade 3 or higher infusional toxicities graded according to the CTCAE v. 4)
时间窗: Up to day 180
For infusion-related toxicities, recipients will be monitored for 1 hour after the Treg infusion. Additional toxicities which may occur during the first 28 days after the Treg infusions will count towards the assessment of safety and tolerability (DLT assessment) (e.g., development of aGVHD). Acute GVHD will be assessed using the modified Keystone criteria on Days 14, 28, 42, 56, 84 and 180 after the Treg infusion (or if the subject is exhibiting signs of aGVHD in-between study visits). Dose limiting toxicities are defined in Section 8. Only toxicities which occur during the first 28 days after the cell infusion will count towards the assessment of DLTs. A dose of Treg will be considered safe if DLTs occur in only 1/6 or 0/3 members of the cohort during the dose-escalation phase.
次要结局
- Change in >7 points on the Lee cGVHD Symptom scale relates to improvement in quality of life(Baseline to day 180)
- Successful achievement of cGVHD partial response or Complete response by the NIH consensus criteria(Up to day 180)
- Change in absolute blood Treg levels(Baseline to day 42)
- Improvement in Failure Free Survival (FFS) over cGVHD(At day 180)
- The ability to reduce steroid requirements to <0.25 mg/kg-day(At day 180)
研究者
Laura Johnston
Associate Professor
Stanford University