Treatment of patients with relapsed or refractory CD19+ lymphoid disease with T lymphocytes transduced by RV-SFG.CD19.CD28.4-BBzeta retroviral vector – A unicenter Phase I/II clinical trial [HD-CAR-1]
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 63
- 试验地点
- 1
- 主要终点
- Assessment of toxicities according to the CTCAEv5.0
研究概览
简要总结
The main purpose of the study is to evaluate the safety and feasibility of escalating doses of autologous activated peripheral blood T lymphocytes (ATLs) genetically modified to express third-generation CARs (comprising the CD28 and CD137 (4-1BB) costimulatory domain) that target the CD19 molecule in patients with refractory or relapsed CD19+ lymphoid disease such as ALL or NHL including CLL, DLBCL, FL and/or MCL.
研究设计
- 研究类型
- Interventional
入排标准
- 年龄范围
- 0 years 至 65+ years（0-17 Years, 65+ Years, 18-64 Years）
- 接受健康志愿者
- 否
入选标准
- •Stratum 1-2 (Adults): Confirmed CD19+ ALL, CLL, DLBCL, FL or MCL in patients ≥ 18 years
- •Stratum 3: Renal function defined as serum creatinine-clearance ≥ 30 mL/min/1.73 m²
- •Stratum 3: Absolute lymphocyte count (ALC) ≥ 100/mm³
- •Stratum 1-2 (Adults): Relapsed or refractory disease (including “molecular relapse” with minimal residual disease (MRD)
- •Stratum 1-2 (Adults): Renal function defined as: serum creatinine of ≤ 2 x ULN or eGFR ≥ 30 mL/min/1.73 m²
- •Stratum 1-2 (Adults): Absolute lymphocyte count (ALC) ≥ 100/mm³
- •Stratum 3: Age of > 3 years until < 18 years at the time of screening
- •Stratum 3: CD19+ ALL (Ph+ and Ph-) confirmed by cytology and flow cytometry (FACS) AND Relapsed or refractory disease
- •Stratum 3: Measurable disease/MRD at time of enrollment
- •Stratum 3: Life expectancy ≥ 12 weeks
- •Stratum 3: ECOG performance status ≤ 2 (age ≥ 16 years) or Lansky performance status ≥ 50 (age < 16 years) at the time of screening
排除标准
- •Stratum 1-2 (Adults): Immunosuppressive medication with the exception of ≤ 30 mg prednisolone/d or equivalent at the time of CAR TC transfusion
- •Stratum 3: Uncontrolled acute life-threatening bacterial, viral or fungal infection
- •Stratum 1-2 (Adults): Any donor lymphocyte infusions (DLI) must be completed > 6 weeks prior to CD19.CAR TC transfusion
- •Stratum 1-2 (Adults): Florid/acute or chronic Graft-versus-Host disease (GvHD)
- •Stratum 1-2 (Adults): Uncontrolled acute life-threatening bacterial, viral or fungal infection
- •Stratum 1-2 (Adults): A primary malignancy which is in complete remission for ≥ 5 years
- •Stratum 1-2 (Adults): Pregnant or nursing (lactating) women
- •Stratum 3: immunosuppressive medication with the exception of < 0.5 mg/d*kg BW prednisolone-equivalent at the time of CD19.CAR TC transfusion
- •Stratum 3: Any donor lymphocyte infusions (DLI) must be completed > 6 weeks prior to CD19.CAR TC transfusion
- •Stratum 3: Florid/acute or chronic Graft-versus-Host disease (GvHD)
结局指标
主要结局
Assessment of toxicities according to the CTCAEv5.0
Assessment of toxicities according to the CTCAEv5.0
Assessment of frequency and grade of CRS and/or ICANS
Assessment of frequency and grade of CRS and/or ICANS
Assessment of dose-limiting toxicity (DLT) and maximum tolerated dose (MTD)
Assessment of dose-limiting toxicity (DLT) and maximum tolerated dose (MTD)
Yield of sufficient NCs by leukapheresis
Yield of sufficient NCs by leukapheresis
Successful transduction (>15%) of CD3+ TCs
Successful transduction (>15%) of CD3+ TCs
Yield of the respective dose of transduced TCs (1 to 20x106 transduced CD3+TCs/m2) in the first three dose levels (I-III)
Yield of the respective dose of transduced TCs (1 to 20x106 transduced CD3+TCs/m2) in the first three dose levels (I-III)
Yield of the respective dose of transduced TCs (5 to 20x107 transduced CD3+ TCs/m2) in the second three dose levels (IV-VI)
Yield of the respective dose of transduced TCs (5 to 20x107 transduced CD3+ TCs/m2) in the second three dose levels (IV-VI)
次要结局
- Characterization of in vivo cellular pharmakokinetics
- Correlation of clinical response and number of circulating gene modified cells
- Reduction of disease burden with CD19.CAR TC transfusions
- Evaluation of survival and function of chimeric antigen receptor (CAR) TCs directed against CD19 (CD19.CAR TC) in vivo
- Anti-tumor efficacy of CD19.CAR TCs in patients with CD19+ lymphoid disease (overall response rate (ORR), complete response (CR), partial response (PR)) at day 90 (EOS) after CD19.CAR TC transfusion)
- Time to response (at least PR) after the CD19.CAR TC transfusion
- Duration of overall response (DOR) after the CD19.CAR TC transfusion
- Progression-free survival (PFS) after the CD19.CAR TC transfusion
- Overall survival (OS) after the CD19.CAR TC transfusion
- Correlation of B-cell depletion in vivo and response to CD19.CAR TC treatment
研究者
Prof. Dr. Michael Schmitt
Scientific
Universitaetsklinikum Heidelberg AöR