JOURNAL ONKOLOGIE – STUDIE

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

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

Studienbeginn:
September 2018

Letztes Update:
08.06.2023

Wirkstoff:
CD19.CAR T Cells, Fludarabine, Cyclophosphamide

Indikation (Clinical Trials):
Lymphoma, Leukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Lymphoid, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Mantle-Cell, Lymphoma, Large B-Cell, Diffuse

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
University Hospital Heidelberg

Collaborator:
-

Studienleiter

Prof. Dr. Michael Schmitt
Principal Investigator
University Hospital Heidelberg, Department V

Prof. Dr. Andreas Kulozik
Principal Investigator
University Hospital Heidelberg, University Medical Center for Children and Adolescents

Kontakt

Prof. Dr. Michael Schmitt
Kontakt:
Phone: +49-6221-566614
E-Mail: michael.schmitt@med.uni-heidelberg.de» Kontaktdaten anzeigen

Studienlocations
(2 von 2)

University Hospital Heidelberg
Heidelberg
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Prof. Dr. Michael Schmitt
Phone: +49-6221-566614
E-Mail: michael.schmitt@med.uni-heidelberg.de» Ansprechpartner anzeigen

Studien-Informationen

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 (0,1-20×20^7 transduced cells/m^2) after lymphodepletion with fludarabine and

cyclophosphamide.

Ein-/Ausschlusskriterien

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

Studien-Rationale

Primary outcome:

1. 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)

2. 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)

Studien-Arme

Experimental: Stratum I
Adult patients with relapsed or refractory ALL
Experimental: Stratum II
Adult patients with relapsed or refractory CLL, DLBCL, FL or MCL
Experimental: Stratum III
Pediatric patients with relapsed or refractory ALL

Geprüfte Regime

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
Fludarabine:
3 days of fludarabine 30 mg/m^2/day
Cyclophosphamide:
3 days of cyclophosphamide 500 mg/m^2/day

Quelle: ClinicalTrials.gov

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