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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Tisagenlecleucel after optional bridging and lymphodepleting chemotherapy
* Drug: Platinum-based immunochemotherapy followed in responding patients with high dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, aggressive B-cell NHL at relapse/progression or PR after front line therapy. Aggressive B-cell NHL is heretofore defined by the following list of subtypes (Swerdlow et al 2016): DLBCL, NOS, FL grade 3B, Primary mediastinal large B cell lymphoma (PMBCL), T cell rich/histiocyte rich large B cell lymphoma (T/HRBCL), DLBCL associated with chronic inflammation, Intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, B-cell lymphoma, unclassifiable, (with features intermediate between DLBCL and classical Hodgkin's Lymphoma (HL)), High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, High-grade B-cell lymphoma, NOS HHV8+ DLBCL, NOS DLBCL transforming from follicular lymphoma DLBCL transforming from marginal zone lymphoma DLBCL, leg type Relapse or progression within 365 days from last dose of anti CD20 antibody and anthracycline containing first line immunochemotherapy or refractory (have not achieved a CR). Patient is considered eligible for autologous HSCT 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 Disease that is both active on PET scan (defined as 5-Deauville scorepoint-scale of 4 or 5) and measurable on CT scan, defined as:: Nodal lesions >15 mm in the long axis, regardless of the length of the short axis, and/or Extranodal lesions (outside lymph node or nodal mass, but including liver and spleen) >10 mm in long AND short axis Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Adequate organ function: Renal function defined as: 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: Alanine Transaminase (ALT) and Aspartate Transiminase (AST) ≤ 5 × ULN Total bilirubin ≤ 1.5 x ULN 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: Absolute neutrophil count (ANC) >1000/mm3 Absolute lymphocyte count (ALC) >300/mm3 OR Absolute number of CD3+ T cells >150/mm3 (only for patients with non-historical apheresis) Platelets ≥50000/mm3 Hemoglobin >8.0 g/dl Adequate pulmonary function defined as: No or mild dyspnea (≤ Grade 1) Oxygen saturation measured by pulse oximetry > 90% on room air Forced expiratory volume in 1 s (FEV1) ≥ 50% and/or carbon monoxide diffusion test (DLCO) ≥50% of predicted level Must have a leukapheresis material of non-mobilized cells available for manufacturing. Exclusion Criteria: Prior treatment with anti-CD19 therapy, T cell therapy, or any prior gene therapy product Treatment with any systemic lymphoma-directed second line anticancer therapy prior to randomization. Only steroids and local irradiation are permitted for disease control Patients with active central nervous system (CNS) involvement by disease under study are excluded, except if the CNS involvement has been effectively treated and local treatment was >4 weeks before randomization Prior allogeneic HSCT Clinically significant active infection 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) at 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 Pointes (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 Pointes per crediblemeds.org that cannot be discontinued or replaced by safe alternative medication. Patients with active neurological autoimmune or inflammatory disorders (e.g., Guillain-Barré Syndrome (GBS), Amyotrophic Lateral Sclerosis (ALS)) and clinically significant active cerebrovascular disorders (e.g. cerebral edema, posterior reversible encephalopathy syndrome (PRES)) Other protocol-defined inclusion and exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, Open-Label
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tisagenlecleucel treatment strategy<br>Patients will receive investigator's choice of optional platinum-based immunochemotherapy followed by lymphodepleting chemotherapy and a single dose of tisagenlecleucel | Drug: Tisagenlecleucel after optional bridging and lymphodepleting chemotherapy<br>* Investigator's choice of optional platinum-based immunochemotherapy (ie. R-ICE, R-GemOx, R-GDP, R-DHAP) + Lymphodepleting chemotherapy (fludarabine with cyclophosphamide or bendamustine) + Tisagenlecleucel (a second generation CAR-T composed of a CD19 antigen-binding domain, a 4-1BB costimulatory domain and a CD3-ζ signaling domain)<br>|
| Active Comparator: Standard of care treatment strategy<br>Patients will receive investigator's choice of platinum-based immunochemotherapy followed in responding patients by high dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT) | Drug: Platinum-based immunochemotherapy followed in responding patients with high dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT)<br>* Investigator's choice of platinum-based immunochemotherapy (ie. R-ICE, R-GemOx, R-GDP, R-DHAP)+ High dose chemotherapy (ie. BEAM) + autologous HSCT. *Ibrutinib or lenalidomide may be used in patients who are no longer eligible for autologous HSCT after 2 cycles of immunochemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | 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 (+/- 1 week) assessment, as assessed by Blinded Independent Review Committee (BIRC) per Lugano criteria, or death due to any cause, at any time. | 5 years | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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