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

• ClinicalTrials.gov Identifier: NCT03676504
• Recruitment Status: Recruiting
• First Posted: September 18, 2018
• Last Update Posted: November 20, 2020
• Sponsor: University Hospital Heidelberg
• Information provided by (Responsible Party): Prof. Dr. Michael Schmitt, University Hospital Heidelberg

Tracking Information

• First Submitted Date: September 7, 2018
• First Posted Date: September 18, 2018
• Last Update Posted Date: November 20, 2020
• Actual Study Start Date: September 7, 2018
• Estimated Primary Completion Date: April 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 16, 2018)

• 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) [ Time Frame: Up to 90 days after CD19.CAR T cell administration ]
• Feasibility of CD19.CAR T cell manufacturing assessing the number of transduced T cells [ Time Frame: Within 45 days prior to CD19.CAR T cell administration ]

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Treatment of Patients With Relapsed or Refractory CD19+ Lymphoid Disease With T Cells Expressing a Third-generation CAR
• Official Title: 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
• Brief Summary: 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 (1-20×20^7 transduced cells/m^2) after lymphodepletion with fludarabine and cyclophosphamide.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Biological: CD19.CAR T Cells
  Dose Level 1: 1×10^6 transduced cells/m^2; Dose Level 2: 5×10^6 transduced cells/m^2; Dose Level 3: 20×10^6 transduced cells/m^2; Dose Level 4: 5x10^7 transduced cells/m^2; Dose Level 5: 10x10^7 transduced cells/m^2; Dose Level 6: 20x10^7 transduced cells/m^2
• Drug: Fludarabine
  3 days of fludarabine 30 mg/m^2/day
• Drug: Cyclophosphamide
  3 days of cyclophosphamide 500 mg/m^2/day

Study Arms

• Experimental: Stratum I
  Adult patients with relapsed or refractory ALL
  Interventions:

  • Biological: CD19.CAR T Cells
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
• Experimental: Stratum II
  Adult patients with relapsed or refractory CLL, DLBCL, FL or MCL
  Interventions:

  • Biological: CD19.CAR T Cells
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
• Experimental: Stratum III
  Pediatric patients with relapsed or refractory ALL
  Interventions:

  • Biological: CD19.CAR T Cells
  • Drug: Fludarabine
  • Drug: Cyclophosphamide

• Publications *: Schubert ML, Schmitt A, Sellner L, Neuber B, Kunz J, Wuchter P, Kunz A, Gern U, Michels B, Hofmann S, Huckelhoven-Krauss A, Kulozik A, Ho AD, Muller-Tidow C, Dreger P, Schmitt M. Treatment of patients with relapsed or refractory CD19+ lymphoid disease with T lymphocytes transduced by RV-SFG.CD19.CD28.4-1BBzeta retroviral vector: a unicentre phase I/II clinical trial protocol. BMJ Open. 2019 May 19;9(5):e026644. doi: 10.1136/bmjopen-2018-026644.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 16, 2018): 48
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 1, 2023
• Estimated Primary Completion Date: April 1, 2023 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 3 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Prof. Dr. Michael Schmitt; +49-6221-566614; michael.schmitt@med.uni-heidelberg.de

• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT03676504
• Other Study ID Numbers: HD-CAR-1
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Prof. Dr. Michael Schmitt, University Hospital Heidelberg
• Original Responsible Party: Same as current
• Current Study Sponsor: University Hospital Heidelberg
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Prof. Dr. Michael Schmitt; University Hospital Heidelberg, Department V
• Principal Investigator: Prof. Dr. Andreas Kulozik; University Hospital Heidelberg, University Medical Center for Children and Adolescents

• PRS Account: University Hospital Heidelberg
• Verification Date: November 2020