Treatment of Patients With Relapsed or Refractory CD19+ Lymphoid Disease With T Cells Expressing a Third-generation CAR

A vizsgálat adatai

Ki végzi

University Hospital Heidelberg

Azonosító

NCT03676504EU 2024-516832-82-00

A regiszteradat frissítve

2024. július 29.

Eredeti leírás

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.A teljes eredeti leírásKevesebb

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

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.

Bevonási feltételek: 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; Bilirubin ≤ 2.0 mg/dl with the exception of patients with hyperbilirubinemia explained by Gilbert-Meulengracht syndrome 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 LVEF ≥ 40% or shortening fraction > 29% as confirmed by echocardiogram; ANC) ≥ 500/mm3; ALC ≥ 100/mm3; Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and postpubertal male participants must agree to use highly effective methods of contraception for one year following CD19.CAR T cell therapy; Written informed consent of the study patient and/or the legal representative must be obtained prior to any screening procedures.

Kizáró feltételek: 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; 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; 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; 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:; 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; Uncontrolled active hepatitis B or C; HIV-positivity; Uncontrolled acute life-threatening bacterial, viral or fungal infection; 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):; 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; Stratum I/II (Adults):; CLL or FL transformed into an aggressive B cell lymphoma; Florid/acute or chronic GvHD; Lymphoblastic lymphoma transformed into a CD19+ acute lymphoblastic leukemia.

ClinicalTrials.gov NCT03676504 · EU CTIS 2024-516832-82-00