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TisaGenlecleucel in Elderly Patients With First-Relapsed or Primary Refractory Aggressive B-cell Non-Hodgkin Lymphoma



A phase II trial of TisaGenlecleucel (CTL019) in Elderly Patients with First-Relapsed or Primary Refractory Aggressive B-cell Non-Hodgkin Lymphoma

Related Conditions:
  • ALK-Positive Large B-Cell Lymphoma
  • B-Cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma Associated with Chronic Inflammation
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Double-Hit Lymphoma
  • Grade 3b Follicular Lymphoma
  • HHV8-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • High Grade B-Cell Lymphoma, Not Otherwise Specified
  • Intravascular Large B-Cell Lymphoma
  • Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
  • T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
  • Transformed Non-Hodgkin Lymphoma
  • Triple-Hit Lymphoma
Recruiting Status:

Not yet recruiting


Phase 2

Trial Eligibility



  • Brief Title: Phase II Trial of TisaGenlecleucel (Kymriah®) in Elderly Patients With First-Relapsed or Primary Refractory Agressive B-cell Non-Hodgkin Lymphoma
  • Official Title: Phase II Trial of TisaGenlecleucel (Kymriah®) in Elderly Patients With First-Relapsed or Primary Refractory Agressive B-cell Non-Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: Uni-Koeln-3903
  • NCT ID: NCT04161118


  • Non Hodgkin Lymphoma


KymriahTisagenlecleucel (Kymriah®)


A phase II trial of TisaGenlecleucel (Kymriah®) in Elderly Patients with First-Relapsed or Primary Refractory Agressive B-cell Non-Hodgkin Lymphoma

Detailed Description

      This is a single-arm, prospective, multicenter phase-II trial for elderly patients with aNHL
      failing 1st-line treatment with immunochemotherapy containing rituximab and anthracycline,
      who are not eligible for either autologous or allogeneic stem cell transplantation, defined
      as age > 65 years, or > 60 years old with HCT-CI score >2. This trial evaluates the CMR rate
      12 weeks after tisagenlecleucel (Kymriah®) infusion, the incidence and severity of adverse
      events, progression-free survival, and overall survival after one and two years after
      tisagenlecleucel (Kymriah®).

Trial Arms

Tisagenlecleucel (Kymriah®)ExperimentalAll patients will receive a single target dose of 0.6 to 6.0 × 108 of autologous tisagenlecleucel (Kymriah®) transduced T-cells with a viability of at least 70% administered via IV infusion after optional bridging with chemo- or immunotherapy and lymphodepleting (LD) chemotherapy with cyclophosphamide and fludarabine.
  • Kymriah

Eligibility Criteria

        Inclusion Criteria:

          1. Written, signed and dated informed consent must be obtained prior to participation in
             the study

          2. Patients with first relapse of aggressive B-cell Non-Hodgkin Lymphoma (aNHL) within
             365 days after rituximab- and anthracycline-containing first-line immunochemotherapy
             or aNHL refractory to first-line therapy (not achieving a CR or PR), who are
             ineligible for either autologous or allogeneic stem cell transplantation, defined by
             age > 65 years, or > 60 years with a HCT-CI score > 2
             -comorbidity-index-hct-ci) and not older than 80 years.

          3. Histologically confirmed (by local histopathological assessment) aNHL at relapse or
             progression due to refractory disease after front line therapy. aNHL is defined by the
             following list of subtypes:

               1. DLBCL, NOS (GCB, ABC, centroblastic, immunoblastic, anaplastic)

               2. FL grade 3B

               3. T-cell-rich/histiocyte-rich large B-cell lymphoma (T/HRBCL)

               4. DLBCL associated with chronic inflammation

               5. Intravascular large B-cell lymphoma

               6. ALK+ large B-cell lymphoma

               7. B-cell lymphoma, unclassifiable, (with features intermediate between DLBCL and
                  classical HL)

               8. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements

               9. High-grade B-cell lymphoma, NOS

              10. HHV8+ DLBCL, NOS

              11. DLBCL transformed from follicular lymphoma

              12. DLBCL transformed from marginal zone lymphoma

              13. DLBCL, leg type

          4. Measurable disease:

               1. Nodal lesions >15 mm in the long axis, regardless of the length of the short
                  axis, and/or

               2. Extranodal lesions (outside lymph node or nodal mass, but including liver and
                  spleen) >10 mm in long AND short axis

          5. ECOG performance status 0-2

          6. Adequate organ function:

             a. Kidney function defined as: i. Serum creatinine estimated glomerular filtration
             rate GFR ≥ 30mL/min b. Hepatic function defined as: i. ALT and AST ≤ 5 × ULN, except
             for aNHL-related functional impairment. ii. Bilirubin ≤2.0 mg/dl except for patients
             with Gilbert syndrome, who may be included if their total bilirubin is ≤3.0 × ULN and
             direct bilirubin ≤1.5 × ULN OR for aNHL-related functional impairment c. Adequate bone
             marrow function (regardless of transfusion) defined as: i. WBC ≥2500/µL ii. Absolute
             neutrophil count (ANC) >1000/µL iii. Platelets ≥50,000/µL iv. Hemoglobin >8.0 g/dl d.
             Minimum level of pulmonary function defined as: i. No or mild dyspnea (≤ Grade 1) ii.
             pulse oxygenation ≥ 91% on room air

          7. Life expectancy of more than six months

          8. Women have to be in menopausal or post-menopausal status or confirmed as not having
             potential on childbearing

          9. Male participants with female partners of childbearing potential are eligible to
             participate if they agree to contraceptive methods as described in the study protocol

        Exclusion Criteria:

          1. Patients with Richter's transformation, Burkitt lymphoma, or primary CNS lymphoma

          2. Prior treatment with anti-CD19 therapy, adoptive T-cell therapy, or any prior gene
             therapy product

          3. Treatment with any lymphoma-directed second-line anticancer therapy prior to
             enrollment with the exception of intermittent steroid therapy. After enrollment,
             bridging therapy is permitted for disease control.

          4. Patients with active CNS involvement are excluded, except if the CNS involvement has
             been effectively treated (i.e. patient is asymptomatic) and local treatment was >4
             weeks before enrollment

          5. Prior allogeneic bone marrow transplantation (HSCT)

          6. Active hepatitis B, hepatitis C, or hepatitis E infection

          7. HIV-positive patients

          8. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood
             culture positive ≤ 72 hours prior to infusion)

          9. Any of the following cardiovascular conditions:

               1. Unstable angina, myocardial infarction, coronary artery bypass graft (CABG), or
                  stroke within 6 months prior to screening,

               2. LVEF <45% as determined by ECHO at screening except for aNHL-related functional

               3. NYHA functional class III or IV (Chavey et al. 2001) at screening,

               4. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia),
                  complete left bundle branch block, high-grade AV block (e.g., bifascicular block,
                  Mobitz type II) and third degree AV block, unless adequately controlled by
                  pacemaker implantation,

               5. Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening or inability to
                  determine the QTcF interval,

               6. Risk factors for Torsades de Point (TdP), including uncorrected hypokalemia or
                  hypomagnesemia, history of cardiac failure, or history of clinically
                  significant/symptomatic bradycardia, or any of the following:

               7. Long QT syndrome, family history of idiopathic sudden death or congenital long QT
                  syndrome, or

               8. Concomitant medication(s) with a "Known Risk of Torsades de Point" per
         that cannot be discontinued or replaced by safe alternative

         10. Previous or concurrent malignancy with the following exceptions:

               1. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing
                  is required prior to study entry)

               2. In situ carcinoma of the cervix or breast, treated curatively and without
                  evidence of recurrence for at least 3 years prior to the study

               3. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               4. Adequately treated carcinoma in situ without evidence of of recurrence for at
                  least 3 years prior to the study

               5. A primary malignancy which has been completely resected and in complete remission
                  for ≥ 3 years

         11. Pregnant or nursing (lactating) women and women who are not confirmed to be
             menopausal/post-menopausal. Or women who are capable of giving birth.

         12. Intolerance to the excipients of the tisagenlecleucel cell product

         13. Active or history of inflammatory disorders or autoimmune disease that required
             systemic steroids or immunosuppressive medications, with exception of vitiligo or
             resolved childhood asthma

         14. Active tuberculosis

         15. Exposure to any investigational agent(s) within 4 weeks prior to study entry

         16. Chemotherapy less than 2 weeks before leukapheresis

         17. Simultaneous radiotherapy to tisagenlecleucel infusion (radiotherapy between
             leukapheresis and day -6 before tisagenlecleucel infusion is permitted)

         18. Ongoing necessity for systemic corticosteroids >10mg daily prednisone equivalent.
             Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily
             prednisone equivalent are permitted in the absence of active autoimmune disease.

         19. History of active primary immunodeficiency

         20. Major surgery (defined as opening at least one body cavity) within 4 weeks prior to
             study entry

         21. History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, idiopathic
             pneumonitis, or evidence of active pneumonitis on screening CT scan

         22. Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PDL2,
             anti-CTLA-4 antibodies, other immune checkpoint inhibitors

         23. Prior treatment with any anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy.

         24. Current treatment within another therapeutic clinical trial with experimental and not
             approved drugs and treatment combinations

         25. Patient's lack of accountability and inability to appreciate the nature, meaning and
             consequences of the trial and to formulate his/her own wishes correspondingly

         26. Non-compliance, e.g. due to

               1. Drug dependency or substance abuse that would interfere with cooperation with
                  requirements of the trial

               2. Refusal of blood products during treatment

               3. Change of residence to abroad

               4. any similar circumstances that appear to make protocol treatment or long-term
                  follow-up impossible

         27. Patients who have a relationship of dependence or employer-employee relationship to
             the sponsor or the investigator

         28. Committal to an institution on judicial or official order
Maximum Eligible Age:80 Years
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The primary objective is to estimate efficacy of treatment with tisagenlecleucel (Kymriah®) in elderly patients with r/r aNHL: Complete metabolic response (CMR) rate
Time Frame:12 weeks after tisagenlecleucel (Kymriah®) infusion
Safety Issue:
Description:Complete metabolic response (CMR) rate 12 weeks after tisagenlecleucel (Kymriah®) infusion

Secondary Outcome Measures

Measure:Incidence and severity of adverse events (AEs)
Time Frame:From study start to study end (44 months)
Safety Issue:
Description:Incidence and severity of adverse events (AEs)
Measure:Progression-free survival (PFS) rates at 1 and 2 year(s)
Time Frame:Up to two years from study start
Safety Issue:
Description:Progression-free survival (PFS) rates at 1 and 2 year(s)
Measure:Overall survival (OS) rates at 1 and 2 year(s)
Time Frame:Up to two years from study start
Safety Issue:
Description:Overall survival (OS) rates at 1 and 2 year(s)


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Cologne

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