Clinical Trials /

Tisagenlecleucel in Adult Patients With Aggressive B-cell Non-Hodgkin Lymphoma

NCT03570892

Description:

This is a randomized, open label, multicenter phase III trial comparing the efficacy, safety, and tolerability of tisagenlecleucel to Standard Of Care in adult patients with aggressive B-cell Non-Hodgkin Lymphoma after failure of rituximab and anthracycline containing frontline immunochemotherapy.

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
  • High Grade B-Cell Lymphoma, Not Otherwise Specified
  • Intravascular Large B-Cell Lymphoma
  • Mediastinal Large B-Cell Lymphoma
  • Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
  • T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
  • Transformed Lymphoma
  • Triple-Hit Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Tisagenlecleucel in Adult Patients With Aggressive B-cell Non-Hodgkin Lymphoma
  • Official Title: Tisagenlecleucel Versus Standard of Care in Adult Patients With Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphoma: A Randomized, Open Label, Phase III Trial (BELINDA)

Clinical Trial IDs

  • ORG STUDY ID: CCTL019H2301
  • SECONDARY ID: 2016-002966-29
  • NCT ID: NCT03570892

Conditions

  • Non-Hodgkin Lymphoma

Interventions

DrugSynonymsArms
Tisagenlecleucel after optional bridging and lymphodepleting chemotherapyTisagenlecleucel treatment strategy
Platinum-based immunochemotherapy followed in responding patients with high dose chemotherapy and HSCTStandard of care treatment strategy

Purpose

This is a randomized, open label, multicenter phase III trial comparing the efficacy, safety, and tolerability of tisagenlecleucel to Standard Of Care in adult patients with aggressive B-cell Non-Hodgkin Lymphoma after failure of rituximab and anthracycline containing frontline immunochemotherapy.

Trial Arms

NameTypeDescriptionInterventions
Tisagenlecleucel treatment strategyExperimentalPatients will receive investigator's choice of optional platinum-based immunochemotherapy followed by lymphodepleting chemotherapy and a single dose of tisagenlecleucel
  • Tisagenlecleucel after optional bridging and lymphodepleting chemotherapy
Standard of care treatment strategyActive ComparatorPatients will receive investigator's choice of platinum-based immunochemotherapy followed in responding patients by high dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT). Patients who do not respond to initial immunochemotherapy may switch to a different regimen or to lenalidomide or ibrutinib
  • Platinum-based immunochemotherapy followed in responding patients with high dose chemotherapy and HSCT

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically confirmed, aggressive B-cell NHL at relapse/progression after front
             line therapy. Aggressive B-cell NHL is heretofore defined by the following list of
             subtypes (Swerdlow et al 2016):

               1. DLBCL, NOS,

               2. FL grade 3B,

               3. Primary mediastinal B cell lymphoma (PMBCL),

               4. T cell rich/histiocyte rich large B cell lymphoma (T/HRBCL),

               5. DLBCL associated with chronic inflammation,

               6. Intravascular large B-cell lymphoma,

               7. ALK+ large B-cell lymphoma,

               8. B-cell lymphoma, unclassifiable, (with features intermediate between DLBCL and
                  classical Hodgkin's Lymphoma (HL)),

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

              10. High-grade B-cell lymphoma, NOS

              11. HHV8+ DLBCL, NOS

              12. DLBCL transforming from follicular lymphoma

              13. DLBCL transforming from marginal zone lymphoma

              14. DLBCL, leg type

          2. Relapse or progression within 365 days from last dose of rituximab and anthracycline
             containing first line immunochemotherapy or refractory (have not achieved a CR or PR).

          3. Patient is considered eligible for autologous stem cell transplant (ASCT) as per local
             investigator assessment. Note: Intention to transplant and type of high dose
             chemotherapy (HDCT) regimen will be documented at the time of study entry

          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. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

          6. Adequate organ function:

             Renal function defined as:

               1. Serum creatinine of ≤1.5 x upper limit of normal (ULN), OR estimated glomerular
                  filtration rate (eGFR) ≥ 60 mL/min/1.73 m2

                  Hepatic function defined as:

               2. Alanine Transaminase (ALT) and Aspartate Transiminase (AST) ≤ 5 × ULN

               3. Bilirubin ≤2.0 mg/dL with the exception of patients with Gilbert syndrome who may
                  be included if their total bilirubin is ≤3.0 × ULN and direct bilirubin ≤1.5 ×
                  ULN

                  Hematologic Function (regardless of transfusions) defined as:

               4. Absolute neutrophil count (ANC) >1000/mm3

               5. Absolute lymphocyte count (ALC) >300/mm3 and absolute number of CD3+ T cells
                  >150/mm3

               6. Platelets ≥50000/mm3

               7. Hemoglobin >8.0 g/dl

                  Adequate pulmonary function defined as:

               8. No or mild dyspnea (≤ Grade 1) I. Oxygen saturation measured by pulse oximetry >
                  91% on room air

             j. Forced expiratory volume in 1 s (FEV1) <50% and/or carbon monoxide diffusion test
             (DLCO) <50% of predicted level

          7. Must have a leukapheresis material of non-mobilized cells available for manufacturing.

        Exclusion Criteria:

          1. Prior treatment with anti-CD19 therapy or any prior gene therapy product

          2. Patients with active central nervous system (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 randomization

          3. Prior allogeneic HSCT

          4. Uncontrolled acute life threatening infection

          5. Any of the following cardiovascular conditions:

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

               -  Left ventricle ejection fraction (LVEF) <45% as determined by echocardiogram
                  (ECHO) or magnetic resonance angiography (MRA) or multigated acquisition (MUGA)
                  within the past 12 months including the screening assessment.

               -  New York Heart Association (NYHA) functional class III or IV (Chavey et al 2001),
                  within the past 12 months.

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

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

               -  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:

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

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

          6. Patients with active neurological autoimmune or inflammatory disorders (e.g.,
             Guillain-Barré Syndrome (GBS), Amyotrophic Lateral Sclerosis (ALS))

        Other protocol-defined inclusion and exclusion criteria may apply.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival (EFS)
Time Frame:5 years
Safety Issue:
Description:Event-free survival (EFS) is defined as the time from the date of randomization to the date of the first documented disease progression or stable disease at or after the week 12 assessment, as assessed by Blinded Independent Review Committee (BIRC) per Lugano criteria, or death due to any cause, at any time.

Secondary Outcome Measures

Measure:EFS as assessed by local investigator
Time Frame:5 years
Safety Issue:
Description:EFS as assessed by local investigator
Measure:Overall Survival (OS)
Time Frame:5 years
Safety Issue:
Description:Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause
Measure:Overall Response Rate (ORR)
Time Frame:5 years
Safety Issue:
Description:Overall Response Rate (ORR) as per the Lugano criteria as per BIRC review and local investigator assessment
Measure:Duration of Response (DOR)
Time Frame:5 years
Safety Issue:
Description:Duration of response: time from the date of first documented response of CR or PR to the date of first documented progression (SD or PD at or after the week 12 (±1w) assessment will be considered progression) or death due to aggressive B-cell NHL. DOR will be summarized by BIRC and local response
Measure:SF-36v2
Time Frame:5 years
Safety Issue:
Description:Time to definitive deterioration in SF-36v2
Measure:FACT-Lym
Time Frame:5 years
Safety Issue:
Description:Time to definitive deterioration in FACT-Lym
Measure:EQ-VAS
Time Frame:5 years
Safety Issue:
Description:Time to definitive deterioration in EQ-VAS
Measure:Tisagenlecleucel transgene concentrations
Time Frame:5 years
Safety Issue:
Description:qPCR will be used to measure tisagenlecleucel transgene concentrations in peripheral blood and bone marrow
Measure:Tisagenlecleucel immunogenicity (humoral and cellular)
Time Frame:5 years
Safety Issue:
Description:Pre-existing and treatment related immunogenicity (humoral and cellular) of tisagenlecleucel will be characterized.
Measure:Presence of replication competent lentivirus (RCL)
Time Frame:5 years
Safety Issue:
Description:The presence of RCL will be assessed by VSV-qPCR in patients receiving tisagenlecleucel

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • Non-Hodgkin's Lympoma
  • B-Cell Lymphoma
  • Diffuse Large B-cell Lymphoma
  • High Grade B-cell Lymphoma
  • Follicular Lymphoma grade 3B
  • CAR-T
  • Tisagenlecleucel
  • Kymriah
  • Immunotherapy
  • Cellular therapy
  • CTL019

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