NCT03676504招募中1 期
Treatment of Patients With Relapsed or Refractory CD19+ Lymphoid Disease With T Lymphocytes Transduced by RV-SFG.CD19.CD28.4-1BBzeta Retroviral Vector - a Unicenter Phase I/II Clinical Trial
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 68
- 试验地点
- 1
- 主要终点
- Safety of CD19.CAR T cell administration assessing grade and frequency of toxicities including cytokine release syndrome (CRS) and neurotoxicity according to Common Toxicity Criteria for Adverse Events (CTCAE)
研究概览
简要总结
Adult patients with r/r acute lymphoblastic leukemia (ALL) (stratum I), r/r Non-Hodgkin's lymphoma (NHL) including chronic lymphocytic leukaemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) or mantle cell lymphoma (MCL) (stratum II) as well as paediatric patients with r/r ALL (stratum III) will be treated with autologous T-lymphocytes transduced by the third-generation RV-SFG.CD19.CD28.4-1BBzeta retroviral vector. The main purpose of this study is to evaluate safety and feasibility of escalating CD19.CAR T cell doses (0,1-20×20^7 transduced cells/m^2) after lymphodepletion with fludarabine and cyclophosphamide.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Stratum I/II (Adults):
- •Confirmed CD19+ ALL, CLL, DLBCL, FL or MCL in patients ≥ 18 years
- •ALL (Ph+ and Ph-): Confirmed CD19+ ALL by cytology and flow cytometry (FACS) AND
- •Relapsed or refractory disease (including "molecular relapse" with minimal residual disease (MRD) levels > 10^-3 at two occasions > 2 weeks apart) with confirmed CD19 expression on malignant cells in relapse
- •Any relapse after allogeneic stem cell transplantation (alloSCT) (≥ 6 months from alloSCT at time of CAR T cell infusion) OR
- •Any relapse failing to achieve an MRD level of < 10^-3 after ≥ 2 lines of treatment OR
- •Primary refractory as defined by not achieving a complete remission (CR) after ≥ 2 lines of treatment
- •CLL/NHL: Confirmed CD19+ CLL/NHL (including CLL, DLBCL, FL or MCL) with
- •CLL in need of treatment with:
- •Early relapse (within 2 years) after end of chemoimmunotherapy or chemoimmunotherapy refractoriness plus failure or intolerance of both Bruton's tyrosine kinase Inhibitor (BTKi) and B-cell lymphoma 2 inhibitors (BCL-2i) OR
- •Relapse after alloSCT, ineligible for or refractory to standard interventions (donor lymphocyte infusions (DLI), CD20 antibodies, chemoimmunotherapy)
- •DLBCL with:
- •Refractoriness to a 2nd or later line of chemoimmunotherapy OR
- •Relapse after autologous stem cell transplantation (autoSCT) plus ineligibility for alloSCT (including refractoriness to one line of salvage chemoimmunotherapy) OR
- •Relapse after alloSCT
- •FL in need of treatment with:
- •Relapse <2 years after chemoimmunotherapy AND ineligibility for or failure of autologous stem cell transplantation (autoSCT) AND ineligibility for or failure of idelalisib OR
- •Relapse after alloSCT, ineligible for or refractory to standard interventions (DLI, CD20 antibodies, chemoimmunotherapy)
- •MCL with:
- •Relapse after standard first-line therapy AND ineligibility for or failure to BTKi salvage therapy OR
- •Relapse after alloSCT AND ineligibility for or failure to BTKi salvage therapy
- •Measurable disease/MRD at time of enrollment
- •Life expectancy ≥ 12 weeks
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at the time of screening
- •Adequate organ function:
- •Renal function defined as: serum creatinine of ≤ 2 x ULN or estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m^2
- •Liver function defined as:
- •ALT ≤ 5 times the ULN for the respective age
- •Bilirubin ≤ 2.0 mg/dl with the exception of patients with hyperbilirubinemia explained by Gilbert-Meulengracht syndrome (may be included if total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN) or extrahepatic disease (e.g. chronic hemolytic anemia)
- •minimum level of pulmonary reserve defined as ≤ grade 1 dyspnea and pulse oxygenation > 90% on room air
- •Hemodynamic stability and left ventricular ejection fraction (LVEF) ≥ 40% as confirmed by echocardiogram
- •Absolute neutrophil count (ANC) ≥ 500/mm3
- •Absolute lymphocyte count (ALC) ≥ 100/mm3
- •Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for one year following CD19.CAR T cell therapy
- •Ability to understand the nature of the trial and the trial related procedures
- •Written informed consent must be obtained prior to any screening procedures
- •Stratum III (Children and Adolescents with ALL):
- •Age of > 3 years until < 18 years at the time of screening
- •CD19+ ALL (Ph+ and Ph-) confirmed by cytology and flow cytometry (FACS) AND
- •Relapsed or refractory disease (including "molecular relapse" with polymerase chain reaction (PCR) MRD > 10^-3 at two occasions > 2 weeks apart) with confirmed CD19 expression on malignant cells in relapse
- •Any relapse after alloSCT (≥ 6 months from alloSCT at time of CAR T cell infusion) OR
- •Any relapse failing to achieve an MRD level of < 10^-3 after ≥ 2 lines of treatment OR
- •Primary refractory as defined by not achieving a CR after ≥ 2 lines of treatment
- •Measurable disease/MRD at time of enrollment
- •Life expectancy ≥ 12 weeks
- •ECOG performance status ≤ 2 (age ≥ 16 years) or Lansky performance status ≥ 50 (age < 16 years) at the time of screening
- •Adequate organ function:
- •Renal function defined as serum creatinine-clearance ≥ 30 mL/min/1.73 m^2
- •Liver function defined as:
- •ALT ≤ 5 times the ULN for the respective age
- 另有 7 项未显示
排除标准
- •Stratum I/II (Adults):
- •The following medications are excluded:
- •Immunosuppressive medication with the exception of ≤ 30 mg prednisolone/d or equivalent at the time of CAR T cell transfusion
- •Bridging/maintenance therapy including chemo- and immunotherapy must be stopped ≥ 2 weeks prior to leukapheresis, but can be continued between leukapheresis and lymphodepletion
- •Intrathecal chemotherapy is possible at any time, but not during lymphodepletion until 14 days after CD19.CAR T cell transfusion
- •Any DLI must be completed > 6 weeks prior to CD19.CAR T cell infusion
- •Florid/acute or chronic Graft-versus-Host disease (GvHD)
- •Uncontrolled active hepatitis B or C
- •HIV-positivity
- •Uncontrolled acute life-threatening bacterial, viral or fungal infection
- •Severe concomitant disease (e.g. uncontrolled arterial hypertension, heart failure New York Heart Association (NYHA) III-IV, uncontrolled diabetes mellitus, uncontrolled hyperlipidemia)
- •Unstable angina and/or myocardial infarction within 3 months prior to screening
- •Any previous or concurrent malignancy.
- •The following exceptions do NOT constitute exclusion criteria:
- •Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
- •In situ carcinoma of the cervix or breast, treated curatively without evidence of recurrence ≥ 3 years prior to the study
- •CLL or FL transformed into an aggressive B cell lymphoma
- •A primary malignancy which is in complete remission for ≥ 5 years
- •Pregnant or nursing (lactating) women
- •Intolerance to the excipients of the cell product
- •Active central nervous System (CNS) involvement in ALL patient at the time of screening is not an exclusion criterion, but patients with CNS 3 status at clinical screening (d-14) are not eligible for CD19.CAR T cell transfusion
- •Participation in another clinical trial at the time of screening
- •Stratum III (Children and Adolescents with ALL):
- •The following medications are excluded:
- •immunosuppressive medication with the exception of < 0.5 mg/d*kg body weight (BW) prednisolone-equivalent at the time of CD19.CAR T cell transfusion
- •Bridging/Maintenance therapy including chemo- and immunotherapy must be stopped ≥ 2 weeks prior to leukapheresis, but can be continued between leukapheresis and lymphodepletion
- •Intrathecal chemotherapy is possible at any time, but not during lymphodepletion until 14 days after CD19.CAR T cell transfusion
- •Any DLI must be completed > 6 weeks prior to CD19.CAR T cell infusion
- •Florid/acute or chronic GvHD
- •Uncontrolled active hepatitis B or C
- •HIV-positivity
- •Uncontrolled acute life-threatening bacterial, viral or fungal infection
- •Severe concomitant disease (e.g. any life-limiting genetic disorder). Patients with Down Syndrome will not be excluded.
- •Any previous or concurrent malignancy.
- •The following exceptions do not constitute exclusion criteria:
- •Lymphoblastic lymphoma transformed into a CD19+ acute lymphoblastic leukemia
- •A primary malignancy which is in complete remission for ≥ 5 years
- •Pregnant or nursing (lactating) women
- •Intolerance to the excipients of the cell product
- •Active CNS involvement at the time of screening is not an exclusion criterion, but patients with CNS 3 status at clinical screening (d-14) are not eligible for CD19.CAR T cell transfusion
- •Participation in another clinical trial at the time of screening
研究组 & 干预措施
Stratum I
Experimental
Adult patients with relapsed or refractory ALL
干预措施: CD19.CAR T Cells (Biological)
Stratum I
Experimental
Adult patients with relapsed or refractory ALL
干预措施: Fludarabine (Drug)
Stratum I
Experimental
Adult patients with relapsed or refractory ALL
干预措施: Cyclophosphamide (Drug)
Stratum II
Experimental
Adult patients with relapsed or refractory CLL, DLBCL, FL or MCL
干预措施: CD19.CAR T Cells (Biological)
Stratum II
Experimental
Adult patients with relapsed or refractory CLL, DLBCL, FL or MCL
干预措施: Fludarabine (Drug)
Stratum II
Experimental
Adult patients with relapsed or refractory CLL, DLBCL, FL or MCL
干预措施: Cyclophosphamide (Drug)
Stratum III
Experimental
Pediatric patients with relapsed or refractory ALL
干预措施: CD19.CAR T Cells (Biological)
Stratum III
Experimental
Pediatric patients with relapsed or refractory ALL
干预措施: Fludarabine (Drug)
Stratum III
Experimental
Pediatric patients with relapsed or refractory ALL
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Safety of CD19.CAR T cell administration assessing grade and frequency of toxicities including cytokine release syndrome (CRS) and neurotoxicity according to Common Toxicity Criteria for Adverse Events (CTCAE)
时间窗: Up to 90 days after CD19.CAR T cell administration
Feasibility of CD19.CAR T cell manufacturing assessing the number of transduced T cells
时间窗: Within 45 days prior to CD19.CAR T cell administration
次要结局
未报告次要终点
研究者
Prof. Dr. Michael Schmitt
Head of the GMP Core Facility University Hospital Heidelberg, Principal Investigator, Clinical Professor for Cellular Immunotherapy
University Hospital Heidelberg
研究点 (1)
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