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

Korábbi kezelés

• 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:

Más betegség

• 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

Életkor

• 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

Egyéb

• 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

• 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