Evaluation of the Safety and Efficacy of CD19 CAR-T Combined With Autologous T Cells Engineered to Express CD19 (CD19+ Feeding T Cells, FTCs) for Consolidation Treatment for Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Phase 1 Incidence of adverse events (AEs) and abnormal laboratory test results
研究概览
简要总结
This is a single-arm, open-label, single-center, phase I/II study to determine the safety and efficacy of CD19 CAR-T(ssCART-19) combined with autologous T cells engineered to express CD19, namely CD19+ feeding T cells (FTCs), as consolidation therapy in patients diagnosed with de novo Philadelphia chromosome-positive CD19+ B-ALL.
The study will contain the following sequential phases: screening, lymphocyte apheresis, induction, and consolidation chemotherapies combined with tyrosine kinase inhibitors. Once in complete response, patients will receive two to four cycles of ssCART-19s, namely one cycle of ssCART-19 infusion (CAR-T1) followed by one to three cycles of ssCART-19 and CD19+ FTC infusion (CAR-T2-4). The role of CD19+ FTCs is to mimic leukemia cells. Therefore, they are expected to stimulate in vivo expansion and persistence of ssCART-19.
Considering the limited number of lymphocytes obtained by a single apheresis from patients and cost-efficacy, in addition to safety, we will explore the range of biologically active doses of FTCs in a phase I study. Based on preclinical data, FTCs' stimulation of ssCART-19 at a ratio of 1:1 could achieve the best activation response, so a 5×10^6/kg dosage of FTCs was set as the initial dosage in the study, and lower doses were also evaluated. In phase I, FTCs will be administered at the dose of 5×10^6/kg, 3.25×10^6/kg, or 2×10^6/kg two hours after ssCART-19 infusion on day 1 and once again administered at the same dose on day 8. After ssCART-19 and FTCs infusion, adverse events (AEs) as the primary endpoints will be recorded for 6 months; efficacy as the secondary endpoint will be assessed by detecting molecular response for 6 months, PFS, and OS for 2 years.
In phase II, we will expand the study at optimal biological doses of FTCs and further evaluate the efficacy and safety of the innovative combination therapy of ssCART-19 and FTCs. The primary endpoint was the complete molecular response (CMR). The secondary endpoints were RFS, OS, and adverse events (AEs) of the patients.
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
- 15 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •15-65 years of age at the time of signing informed consent
- •Diagnosed as de novo Philadelphia chromosome-positive CD19+ B-ALL
- •Karnofsky performance status ≥ 60 or Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- •Unable to find a suitable donor or for other reasons to undergo allogeneic hematopoietic stem cell transplantation during the study
- •Ability and willingness to adhere to the study visit schedule and all protocol requirements
- •Voluntarily sign informed consent forms
排除标准
- •Unable to tolerate any kind of TKIs (including the first- and second-generation tyrosine kinase inhibitors) for a long period.
- •Subjects who have positive mutation(s) of the ABL kinase domain and require the third-generation tyrosine kinase inhibitors for long-term therapies.
- •Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 × upper limit of normal (ULN) and direct bilirubin > 1.5 × ULN
- •Inadequate renal function defined by serum creatinine > 1.6 mg/dL
- •International ratio (INR) or partial thromboplastin time (PTT) > 1.5 x ULN
- •Left ventricular ejection fraction < 50%
- •Ongoing treatment with chronic immunosuppressants
- •Significant comorbid conditions or diseases which, in the judgment of the investigator, would place the subject at undue risk or interfere with the study; examples include, but are not limited to, cirrhotic liver disease, sepsis, recent significant traumatic injury, and other conditions
- •Known human immunodeficiency virus (HIV) positivity
- •Subjects with a history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control
- •Subjects with second malignancies in addition to ALL
- •Pregnant or lactating women, or subjects refusing to take effective contraception measures
- •Other contraindications that are considered inappropriate to participate in this trial
研究组 & 干预措施
FTCs: High dose (Phase 1)
干预措施: ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion (Biological)
FTCs: Medium dose (Phase 1)
干预措施: ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion (Biological)
FTCs: Low dose (Phase 1)
干预措施: ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion (Biological)
FTCs: High dose (Phase 2)
干预措施: ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion (Biological)
结局指标
主要结局
Phase 1 Incidence of adverse events (AEs) and abnormal laboratory test results
时间窗: 6 months after ssCART-19 consolidation termination (CAR-T4; each cycle is 3 months)
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 5.0 (CTCAE5.0).
Phase 2 Molecular response after CD19 CAR-T consolidation therapy combined with CD19+ feeding T cells
时间窗: 3 months after each cycle of ssCART-19 consolidation termination (each cycle is 3 months)
Complete molecular response (CMR) was defined as the absence of a detectable BCR-ABL1 transcript with a sensitivity of 0.01%.
次要结局
- Phase 1 Molecular response after CD19 CAR-T consolidation therapy combined with CD19+ feeding T cells.(3 months after each cycle of ssCART-19 consolidation termination (each cycle is 3 months))
- Phase 1 The range of biologically active doses and optimal biological doses of CD19+ feeding T cells.(6 months after ssCART-19 consolidation termination (CAR-T4; each cycle is 3 months))
- Phase 1 Overall survial (OS)(2 years)
- Phase 1 Relapse free survival（RFS）(2 years)
- Phase 2 Incidence of adverse events (AEs) and abnormal laboratory test results(6 months after ssCART-19 consolidation termination (the specific date depending how many cycles the participants received; each cycle is 3 months))
- Phase 2 Overall survial (OS)(2 years)
- Phase 2 Relapse free survival（RFS）(2 years)
研究者
Sheng-Li Xue, MD
Professor
The First Affiliated Hospital of Soochow University