Phase I/II Study to Determine the Safety, Tolerability, Biological Activity and Efficacy of Universal CRISPR-Cas9 Gene-Editing CAR-T Cells Targeting CD19(UCART019) in Patients With Relapsed or Refractory CD19+ Leukemia and Lymphoma
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Number of Participants with Severe/Adverse Events as a Measure of Safety and Tolerability
研究概览
简要总结
Autologous T cells engineered to express chimeric antigen receptors (CARs) against leukemia antigens such as CD19 on B cells have shown promising results for the treatment of relapsed or refractory B-cell malignancies. However, a subset of cancer patients especially heavily pretreated cancer patients could be unable to receive this highly active therapy because of failed expansion. Moreover, it is still a challenge to manufacture an effective therapeutic product for infant cancer patients due to their small blood volume. On the other hand, the inherent characters of autologous CAR-T cell therapy including personalized autologous T cell manufacturing and widely "distributed" approach result in the difficulty of industrialization of autologous CAR-T cell therapy. Universal CD19-specific CAR-T cell(UCART019),derived from one or more healthy unrelated donors but could avoid graft-versus-host-disease (GVHD) and minimize their immunogenicity, is undoubtedly an alternative option to address above-mentioned issues. We have generated gene-disrupted allogeneic CD19-directed BBζ CAR-T cells (termed UCART019) by combining the lentiviral delivery of CAR and CRISPR RNA electroporation to disrupt endogenous TCR and B2M genes simultaneously and will test whether it can evade host-mediated immunity and deliver antileukemic effects without GVHD.
The main goal of the phase 1 portion of this phase 1/2 trial is to evaluate the safety and tolerability of several doses of UCART019 in patients with relapsed or refractory CD19+ leukemia and lymphoma, so as to establish the recommended dose and/or schedule of UCART019 for phase 2 portion. The recommended Phase 2 dose will be defined as the highest dose level of UCART019 that induced DLT in fewer than 33% of patients (i.e., one dose level below that which induced DLT in at least two of six patients). Phase 2 portion of the trial will not be initiated until the recommended Phase 2 dose is determined. In the phase 2 portion of this trial, we will mainly determine if UCART019 help the body's immune system eliminate malignant B-cells. Safety of UCART019 and impact of this treatment on survival will also be observed.
详细描述
PRIMARY OBJECTIVES:
- To evaluate the feasibility and safety of UCART019 in patients with relapsed or refractory CD19+ leukemia and lymphoma.
- To evaluate the duration of in vivo persistence of adoptively transferred T cells, and the phenotype of persisting T cells. Real Time polymerase chain receptor (RT-PCR) analysis of peripheral blood(PB), bone marrow(BM) and lymph node will be used to detect and quantify survival of UCART019 over time.
SECONDARY OBJECTIVES:
- For patients with detectable disease, measure anti-tumor response due to UCART019 cell infusions.
- Determine if cellular or humoral host immunity develops against the murine anti-CD19, and assess correlation with loss of detectable UCART019 (loss of engraftment).
OUTLINE: This is a phase I, dose-escalation study of allogeneic CD19 CAR-T-cells followed by a phase II study.
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
- 12 Years 至 75 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female participant
- •12 Years to 75 Years (Infant, Child, Adult, Senior)
- •Patient with relapsed or refractory CD19 positive B-cell leukemia or lymphoma
- •Estimated life expectancy ≥ 12 weeks (according to investigator's judgement)
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- •Adequate organ function
排除标准
- •Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease
- •Diagnosis of Burkitt's leukemia/lymphoma according to WHO classification or chronic myelogenous leukemia lymphoid blast crisis
- •Richter's syndrome
- •Presence of Grade II-IV (Glucksberg) or B-D (IBMTR) acute or extensive chronic GVHD at the time of screening
- •Subjects with any autoimmune disease or any immune deficiency disease or other disease in need of immunosuppressive therapy
- •Severe active infection (uncomplicated urinary tract infections, bacterial pharyngitis is allowed), Prophylactic antibiotic, antiviral and antifungal treatment is permissible
- •Active hepatitis B, active hepatitis C, or any human immunodeficiency virus (HIV) infection at the time of screening
- •Patient has an investigational medicinal product within the last 30 days prior to screening
- •Previous treatment with investigational gene or cell therapy medicine products
- •Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary
- •Pregnant or nursing women
结局指标
主要结局
Number of Participants with Severe/Adverse Events as a Measure of Safety and Tolerability
时间窗: 24 weeks
Highest dose of UCART019 that is estimated to result in defined DLT with the exception of allowable UCART019 infusion related 'expected' AEs, using CTCAE 4.0, in less than 1/3 patients
时间窗: 8 weeks
Copy numbers of UCAR019 in PB, BM and lymph nodes
时间窗: 24 weeks
次要结局
- Progression free survival.Descriptive statistics will be used(24 weeks)
- Overall survival.Descriptive statistics will be used(24 weeks)
- Objective response rate of complete remission and partial remission.Descriptive statistics will be used(24 weeks)
研究者
Han weidong
Director of Molecular & Immunological Department, Bio-therapeutic Department
Chinese PLA General Hospital