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]
- Conditions
- Accute lymphoblastic leukemia recurrent, Non-Hodgkin´s lymphoma NOS refractory
- Registration Number
- 2024-516832-82-00
- Lead Sponsor
- Universitaetsklinikum Heidelberg AöR
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing, recruiting
- Sex
- Not specified
- Target Recruitment
- 63
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
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)
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 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)
- Secondary Outcome Measures
Name Time Method Characterization of in vivo cellular pharmakokinetics Characterization of in vivo cellular pharmakokinetics
Correlation of clinical response and number of circulating gene modified cells Correlation of clinical response and number of circulating gene modified cells
Reduction of disease burden with CD19.CAR TC transfusions 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 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) 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 Time to response (at least PR) after the CD19.CAR TC transfusion
Duration of overall response (DOR) 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 Progression-free survival (PFS) after the CD19.CAR TC transfusion
Overall survival (OS) 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 Correlation of B-cell depletion in vivo and response to CD19.CAR TC treatment
Trial Locations
- Locations (1)
Universitaetsklinikum Heidelberg AöR
🇩🇪Heidelberg, Germany
Universitaetsklinikum Heidelberg AöR🇩🇪Heidelberg, GermanyAndreas KulozikSite contact+496221564500Andreas.Kulozik@med.uni-heidelberg.deMichael SchmittSite contact+496221566614Michael.Schmitt@med.uni-heidelberg.de