Treatment for relapsed or refractory CD19+ lymphoid diseases using engineered T cells

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

This study is testing a new treatment using specially modified immune cells to help adults and children with certain types of blood cancers that haven't responded to other therapies.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 68 (estimated)
• Ages: 3 Years and up
• Sex: All
• Sponsor: University Hospital Heidelberg (Academic / other)
• Drugs / interventions: CAR T, chemotherapy, immunotherapy, cyclophosphamide, fludarabine
• Locations: 2 sites (Heidelberg and 1 other locations)
• Trial ID: NCT03676504 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to treat patients with relapsed or refractory CD19+ lymphoid diseases, including acute lymphoblastic leukemia and various types of non-Hodgkin's lymphoma, using autologous T-lymphocytes that have been genetically modified to express a third-generation CAR targeting CD19. The study will evaluate the safety and feasibility of administering escalating doses of these CAR T cells after patients undergo lymphodepletion with fludarabine and cyclophosphamide. The trial includes both adult and pediatric patients, with specific eligibility criteria based on their disease status and previous treatments.

Who should consider this trial

Good fit: Ideal candidates include adults and pediatric patients with confirmed CD19+ relapsed or refractory acute lymphoblastic leukemia or non-Hodgkin's lymphoma.

Not a fit: Patients with CD19-negative lymphoid diseases or those who have not undergone prior treatment may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with difficult-to-treat relapsed or refractory lymphoid malignancies.

How similar studies have performed: Other studies using CAR T cell therapy have shown promising results in treating similar conditions, indicating a potential for success in this approach.

Eligibility criteria

Inclusion Criteria:

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:

    1. 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
    2. Relapse after alloSCT, ineligible for or refractory to standard interventions (donor lymphocyte infusions (DLI), CD20 antibodies, chemoimmunotherapy)
  * DLBCL with:

    1. Refractoriness to a 2nd or later line of chemoimmunotherapy OR
    2. Relapse after autologous stem cell transplantation (autoSCT) plus ineligibility for alloSCT (including refractoriness to one line of salvage chemoimmunotherapy) OR
    3. Relapse after alloSCT
  * FL in need of treatment with:

    1. Relapse \<2 years after chemoimmunotherapy AND ineligibility for or failure of autologous stem cell transplantation (autoSCT) AND ineligibility for or failure of idelalisib OR
    2. Relapse after alloSCT, ineligible for or refractory to standard interventions (DLI, CD20 antibodies, chemoimmunotherapy)
  * MCL with:

    1. Relapse after standard first-line therapy AND ineligibility for or failure to BTKi salvage therapy OR
    2. 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

Exclusion Criteria:

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

Where this trial is running

Heidelberg and 1 other locations

• University Hospital Heidelberg — Heidelberg, Germany (Recruiting)
• University Hospital Heidelberg — Heidelberg, Germany (Recruiting)

Study contacts

• Principal investigator: Prof. Dr. Michael Schmitt — University Hospital Heidelberg, Department V
• Study coordinator: Prof. Dr. Michael Schmitt

Conditions Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Pediatric; Chronic Lymphocytic Leukemia; Diffuse Large B Cell Lymphoma; Follicular Lymphoma; Mantle Cell Lymphoma