Phase I Study of Ex Vivo Expanded/Activated Gamma Delta T-cell Infusion Following Haploidentical Hematopoietic Stem Cell Transplantation and Post-transplant Cyclophosphamide
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 38
- 试验地点
- 2
- 主要终点
- Phase I - Dose-limiting toxicity (DLT)
研究概览
简要总结
Gamma delta T-cells are part of the innate immune system with the ability to recognize malignant cells and kill them. This study uses gamma delta T-cells to maximize the anti-tumor response and minimize graft versus host disease (GVHD) in leukemic and myelodysplastic patients who have had a partially mismatched bone marrow transplant (haploidentical).
详细描述
Many patients with hematological malignancies require a bone marrow transplant for curative treatment. A matched sibling donor is optimal but may not be available. Therefore, a partially matched family member (haploidentical) may be a viable alternative. The incidence of graft vs. host disease, however, can become more of a significant, even fatal, factor with partial matches.
T-cells have been shown to be the key player in the post-transplant immune phenomena. The majority of T-cells are composed of alpha beta T-cells with a small minority of gamma delta T-cells, which are known to have the unique ability to kill malignant cells without antigen recognition.
This study proposes to extract, concentrate, and activate gamma delta T-cells from the peripheral blood to provide innate anti-tumor effect with minimal risk of GVHD. Safety and impact and/or the rate of GVHD will be evaluated.
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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The following criteria are used to enroll patients in the study before transplant.
- •Patients with neoplastic hematological disorders with indication of allogeneic transplant according to the National Comprehensive Cancer Network (NCCN) or other standard guidelines as follows:
- •Acute myeloid leukemia [AML] in morphologic complete remission with intermediate/high-risk features (per NCCN criteria) or relapsed disease
- •Chronic myeloid leukemia [CML] in any chronic phase.
- •Myelodysplastic syndrome [MDS] with intermediate/high risk features or refractory disease (with bone marrow blast count <10%).
- •Acute lymphoblastic leukemia [ALL] in morphologic complete remission with high-risk features or relapsed disease.
- •Negative test for donor-specific antibody within 28 days of starting conditioning regimen.
- •Age Criteria: 19-65 years.
- •Organ Function Criteria: The following organ function testing should be done within 35 days before study registration.
- •Cardiac: Normal left ventricular ejection fraction (LVEF) (50% or above) as measured by MUGA or Echocardiogram.
- •Pulmonary: FVC, FEV1 and DLCO (corrected) should be 50% or above of expected.
- •Renal: serum creatinine level to be <2 mg/dl AND estimated (Cockcroft-Gault formula) or measured (takes priority if done) creatinine clearance (CrCl) must be equal or greater than 70 mL/min/1.73 m
- •Hepatic: serum bilirubin 1.5 upper limit of normal (ULN), Aspartate transaminase (AST)/alanine transaminase (ALT) 2.5 ULN, and alkaline phosphatase 2.5 ULN.
- •Performance status: Karnofsky performance score (KPS) or Lansky score: ≥
- •Hematopoietic cell transplant comorbidity index (HCT-CI) <
- •Exception may be made on individual cases after discussion with the primary investigator.
- •Consent: All patients must be informed of the investigational nature of this study and given written informed consent in accordance with institutional and federal guidelines.
- •The following criteria are required within 48 hours prior to infusion of the EAGD T cell product.
- •Absence of uncontrolled infection with sepsis syndrome (e.g persistent positive blood culture).
- •NO hemodynamic instability (due to sepsis or organ dysfunction) or circulatory volume overload.
- •NO clinically significant organ toxicity that are defined as follows:
- •Heart failure with subnormal LVEF or clinical fluid overload.
- •Elevated serum creatinine or subnormal creatinine clearance (either estimated or measured).
- •Elevated total bilirubin ≥1.5 upper normal level (unless indirect hyperbilirubinemia attributed to non-hepatic pathology), or elevated liver enzymes (ALT, AST, ALP) >5 x ULN.
- •Hypoxemia requiring oxygen therapy
- •NO acute graft versus host disease (any grade).
- •Neutrophil engraftment.
排除标准
- •Non-compliant patients.
- •No appropriate caregivers identified.
- •Uncontrolled medical or psychiatric disorders which may preclude patients to undergo clinical studies (Discretion of the attending physician).
- •Active central nervous system (CNS) neoplastic involvement.
- •Morbid obesity with body mass index >35 (borderline cases may be considered on case-by-case basis after discussion with the primary investigator).
- •Patients with known allergy to DMSO.
- •HIV1 (Human Immunodeficiency Virus-1) or HIV2 positive.
- •Pregnant or breastfeeding women.
研究组 & 干预措施
EAGD T-cell infusion (Phase I)
Peripheral blood is collected by leukapheresis from the donor, expanded and activated on CliniMACS-Prodigy, further depleted of alpha beta T-cells using the CliniMACS Alpha Beta T-Cell Depletion System, which leaves a gamma delta T-cell rich product. This product is then infused into the recipient at either 1, 3, or 10 x 1,000,000 cells/kg concentrations depending upon the cohort.
干预措施: EAGD T-cell infusion (Phase I) (Drug)
EAGD T-cell infusion (Expansion)
Peripheral blood is collected by leukapheresis from the donor, expanded and activated on CliniMACS-Prodigy, further depleted of alpha beta T-cells using the CliniMACS Alpha Beta T-Cell Depletion System, which leaves a gamma delta T-cell rich product. This product is then infused into the recipient at the maximum tolerated dose as determined from Phase I.
干预措施: EAGD T-cell infusion (Expansion) (Drug)
结局指标
主要结局
Phase I - Dose-limiting toxicity (DLT)
时间窗: Baseline to Day 30
The dose escalation strategy will follow the Food and Drug Administration Guideline for design of early phase clinical trials of cellular therapy products.
Phase I - Severe acute adverse events following infusion of EAGD T-cells
时间窗: Baseline to Day 100
Safety of the infusion will be based on the risk of treatment-related severe adverse events as identified in the National Cancer Common Terminology Criteria for Adverse Events (CTCAE) version 4.
Expansion phase - Rate of acute GVHD
时间窗: Baseline to Day 100
Monitoring for GVHD is assessed with Grade II-IV adverse events as identified by the National Cancer Common Terminology Criteria for Adverse Events (CTCAE) version 4.
次要结局
- Expansion phase - Overall survival following haploidentical HCT and PTCy with EAGD T-cell infusion(Baseline to 100 days)
- Rate of one-year relapse-free survival (RFS)(Baseline to one year)
- Rate of one-year overall survival (OS)(Baseline to one year)
- Rate of one-year non-relapse mortality (NRM)(Baseline to one year)
- Proportion of subjects with chronic GVHD at one year(Baseline to one year)
- Expansion phase - Non-relapse mortality following haploidentical HCT and PTCy with EAGD T-cell infusion(Baseline to 100 days)
- Expansion phase - Relapse following haploidentical HCT and PTCy with EAGD T-cell infusion(Baseline to 100 days)
研究者
Joseph McGuirk
Professor & Division Director
University of Kansas Medical Center