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

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)

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.

Study Overview

• Status: Completed
• Conditions: Non-Hodgkin Lymphoma
• Intervention / Treatment: 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)

Detailed Description

Approximately 318 subjects were planned to be randomized; 322 subjects were analyzed (Full analysis set): 162 subjects in the tisagenlecleucel arm and 160 subjects in the SOC arm.

The target population consisted of adult participants with aggressive B-cell non-Hodgkin lymphoma (NHL) who were relapsed/refractory within 365 days of their last dose of first line immunochemotherapy and eligible for autologous hematopoietic stem cell transplantation (HSCT).

The duration of treatment in the tisagenlecleucel treatment strategy is from the start of bridging chemotherapy (if applicable) until the infusion of tisagenlecleucel (expected on average at approximately 6 weeks from randomization). The duration of the treatment in the SOC treatment strategy is from the start of salvage chemotherapy until autologous HSCT. In either treatment arm, if infusion of tisagenlecleucel or autologous HSCT is not possible, the duration of treatment is until the last dose of study treatment prior to discontinuation of the treatment strategy.

• Study Type: Interventional
• Enrollment (Actual): 330
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Novartis Investigative Site
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Novartis Investigative Site
• Austria
  • Salzburg, Austria, 5020
    • Novartis Investigative Site
  • Vienna, Austria, 1090
    • Novartis Investigative Site
• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Brazil
  • São Paulo, Brazil, 05651-901
    • Novartis Investigative Site
  • Estado de Bahia
    • Salvador, Estado de Bahia, Brazil, 41253-190
      • Novartis Investigative Site
• China
  • Beijing, China, 100191
    • Novartis Investigative Site
  • Beijing, China, 100036
    • Novartis Investigative Site
  • Shanghai, China, 200065
    • Novartis Investigative Site
• France
  • Lille, France, 59037
    • Novartis Investigative Site
  • Montpellier, France, 34295
    • Novartis Investigative Site
  • Nantes, France, 44093
    • Novartis Investigative Site
  • Paris, France, 75475
    • Novartis Investigative Site
  • Pierre-Bénite, France, 69495
    • Novartis Investigative Site
  • Toulouse, France, 31059
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
  • Bavaria
    • Munich, Bavaria, Germany, 81377
      • Novartis Investigative Site
    • Regensburg, Bavaria, Germany, 93053
      • Novartis Investigative Site
  • North Rhine-Westphalia
    • Cologne, North Rhine-Westphalia, Germany, 50937
      • Novartis Investigative Site
  • Saxony
    • Leipzig, Saxony, Germany, 04103
      • Novartis Investigative Site
• Hong Kong
  • Hong Kong, Hong Kong, 999077
    • Novartis Investigative Site
• Italy
  • MI
    • Milan, MI, Italy, 20133
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00168
      • Novartis Investigative Site
• Japan
  • Fukuoka, Japan, 8128582
    • Novartis Investigative Site
  • Fukuoka
    • Fukuoka, Fukuoka, Japan, 812-8582
      • Kyushu University Hospital
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060 8648
      • Hokkaido University Hospital
    • Sapporo, Hokkaido, Japan, 060-8648
      • Novartis Investigative Site
  • Miyagi
    • Sendai, Miyagi, Japan, 980 8574
      • Tohoku University Hospital
    • Sendai, Miyagi, Japan, 9808574
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam UMC, locatie AMC
  • Utrecht, Netherlands, 3584 CX
    • Novartis Investigative Site
  • Utrecht, Netherlands, 3584CX
    • UMC Utrecht Cancer Center
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1081 HV
      • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0310
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119074
    • Novartis Investigative Site
  • Singapore, Singapore, 169608
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08035
    • Novartis Investigative Site
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Salamanca, Spain, 37007
    • Novartis Investigative Site
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Novartis Investigative Site
• Switzerland
  • Zurich, Switzerland, 8091
    • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, NW1 2BU
    • Novartis Investigative Site
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2TH
      • Novartis Investigative Site
• United States
  • California
    • La Jolla, California, United States, 92093
      • Moores UC San Diego Cancer Center
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • San Francisco, California, United States, 94143
      • UCSF Medical Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Sarah Cannon Research Institute
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Uni of Chi Medi Ctr Hema and Onco
  • Kansas
    • Kansas City, Kansas, United States, 66205
      • University of Kansas Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University-Karmanos Cancer Institute
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Uni of Nebraska Med Ctr
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack Uni Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45236
      • Jewish Hospital
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences Univ
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Uni Pennsylvania Abramson Cncr Ctr
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • MUSC Hollings Cancer Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Tennessee Oncology PLLC
  • Texas
    • Austin, Texas, United States, 78704
      • St Davids South Austin Medical Ctr
    • Dallas, Texas, United States, 75231
      • Texas Oncology-Baylor Scott and White
    • Houston, Texas, United States, 77030
      • Uni of Texas MD Anderson Ca Center
    • San Antonio, Texas, United States, 78229
      • Methodist Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-6164
      • Uni of Wisconsin Carbone Cancer Ctr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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))

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tisagenlecleucel treatment strategy; Patients received 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; 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)
Active Comparator: Standard of care treatment strategy; Patients received 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); 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free Survival (EFS) Per Blinded Independent Review Committee (BIRC) Assessment	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.	appro. 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	24 Months
FACT-Lym	Time to definitive deterioration in FACT-Lym	24 Months
EQ-VAS	Time to definitive deterioration in EQ-VAS	24 Months
Event Free Survival (EFS) as Assessed by Local Investigator	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.	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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
• Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, Sureda A, Greil R, Thieblemont C, Morschhauser F, Janz M, Flinn I, Rabitsch W, Kwong YL, Kersten MJ, Minnema MC, Holte H, Chan EHL, Martinez-Lopez J, Muller AMS, Maziarz RT, McGuirk JP, Bachy E, Le Gouill S, Dreyling M, Harigae H, Bond D, Andreadis C, McSweeney P, Kharfan-Dabaja M, Newsome S, Degtyarev E, Awasthi R, Del Corral C, Andreola G, Masood A, Schuster SJ, Jager U, Borchmann P, Westin JR. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):629-639. doi: 10.1056/NEJMoa2116596. Epub 2021 Dec 14.
• Thiruvengadam SK, Hunter B, Varnavski A, Fakhri B, Kaplan L, Ai WZ, Pampaloni M, Huang CY, Martin T 3rd, Damon L, Andreadis CB. Ofatumumab, Etoposide, and Cytarabine Intensive Mobilization Regimen in Patients with High-risk Relapsed/Refractory Diffuse Large B-Cell Lymphoma Undergoing Autologous Stem Cell Transplantation. Clin Lymphoma Myeloma Leuk. 2021 Apr;21(4):246-256.e2. doi: 10.1016/j.clml.2020.11.005. Epub 2020 Nov 11.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): May 9, 2019
• Primary Completion (Actual): May 6, 2021
• Study Completion (Actual): February 3, 2026

Study Registration Dates

• First Submitted: June 18, 2018
• First Submitted That Met QC Criteria: June 18, 2018
• First Posted (Actual): June 27, 2018

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: CAR-T; Immunotherapy; CTL019; Diffuse Large B-cell Lymphoma; Cellular therapy; B-Cell Lymphoma; Kymriah; Non-Hodgkin's Lympoma; High Grade B-cell Lymphoma; Follicular Lymphoma grade 3B; Tisagenlecleucel
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Therapeutics; Drug Therapy
• Other Study ID Numbers: CCTL019H2301; 2016-002966-29 (EudraCT Number); 2023-508343-48-00 (Registry Identifier: EU CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No