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

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)

ClinicalTrials.gov Identifier: NCT03570892

Novartis Reference Number: CCTL019H2301

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All compounds are either investigational or being studied for (a) new use(s). Efficacy and safety have not been established. There is no guarantee that they will become commercially available for the use(s) under investigation. 

Study 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.

Condition 
Non-Hodgkin Lymphoma
Phase 
Phase 3
Overall status 
Recruiting
Enrollment count 
318 participants
Start date 
May 07, 2019
Completion date 
Mar 31, 2026
Gender 
All
Age(s)
18 Years and older (Adult, Older Adult)

Interventions

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)
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

Eligibility Criteria

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.

Study Locations

United States
Moores UC San Diego Cancer Center
Recruiting
La Jolla, 92093
California
United States
University of California Los Angeles University of California LA
Recruiting
Los Angeles, 90095
California
United States
UCSF Medical Center
Recruiting
San Francisco, 94143
California
United States
Sarah Cannon Research Institute
Recruiting
Denver, 80218
Colorado
United States
Yale Cancer Center
Recruiting
New Haven, 06520
Connecticut
United States
Mayo Clinic Jacksonville
Recruiting
Jacksonville, 32224
Florida
United States
Emory University School of Medicine/Winship Cancer Institute SC
Recruiting
Atlanta, 30322
Georgia
United States
University of Chicago Medical Center Hematology and Oncology
Recruiting
Chicago, 60637
Illinois
United States
University of Kansas Cancer Center SC
Recruiting
Kansas City, 66205
Kansas
United States
Wayne State University - Karmanos Cancer Institute SC
Recruiting
Detroit, 48201
Michigan
United States
University of Nebraska Medical Center
Recruiting
Omaha, 68198
Nebraska
United States
Hackensack University Medical Center
Recruiting
Hackensack, 07601
New Jersey
United States
Duke University Medical Center
Recruiting
Durham, 27705
North Carolina
United States
Jewish Hospital
Recruiting
Cincinnati, 45236
Ohio
United States
The Ohio State University SC
Recruiting
Columbus, 43210
Ohio
United States
Oregon Health Sciences Univ SC
Recruiting
Portland, 97239
Oregon
United States
University of Pennsylvania, Abramson Cancer Center
Recruiting
Philadelphia, 19104
Pennsylvania
United States
MUSC Hollings Cancer Center
Recruiting
Charleston, 29425
South Carolina
United States
Sarah Cannon Research Institute
Recruiting
Nashville, 37203
Tennessee
United States
St Davids South Austin Medical Ctr
Recruiting
Austin, 78704
Texas
United States
Baylor Scott and White Research Institute
Recruiting
Dallas, 75231
Texas
United States
University of Texas MD Anderson Cancer Center MD Anderson Cancer Center
Recruiting
Houston, 77030
Texas
United States
Methodist Hospital
Recruiting
San Antonio, 78229
Texas
United States
University of Wisconsin Carbone Cancer Center
Recruiting
Madison, 53792-6164
Wisconsin
United States
Australia
Novartis Investigative Site
Recruiting
Darlinghurst, 2010
New South Wales
Australia
Novartis Investigative Site
Recruiting
Melbourne, 3000
Victoria
Australia
Novartis Investigative Site
Recruiting
Murdoch, 6150
Western Australia
Australia
Austria
Novartis Investigative Site
Recruiting
Innsbruck, A-6020
-
Austria
Novartis Investigative Site
Recruiting
Salzburg, 5020
-
Austria
Novartis Investigative Site
Recruiting
Vienna, A-1090
-
Austria
Brazil
Novartis Investigative Site
Recruiting
Salvador, 41253-190
BA
Brazil
Novartis Investigative Site
Recruiting
Sao Paulo, 05651-901
-
Brazil
China
Novartis Investigative Site
Recruiting
Beijing, 100036
-
China
France
Novartis Investigative Site
Recruiting
Lille Cedex, 59037
-
France
Novartis Investigative Site
Recruiting
Montpellier cedex 5, 34295
-
France
Novartis Investigative Site
Recruiting
Nantes Cedex 1, 44093
-
France
Novartis Investigative Site
Recruiting
Paris, 75010
-
France
Novartis Investigative Site
Recruiting
Pierre Benite Cedex, 69495
-
France
Novartis Investigative Site
Recruiting
Toulouse, 31059
-
France
Germany
Novartis Investigative Site
Recruiting
Regensburg, 93053
Bavaria
Germany
Novartis Investigative Site
Recruiting
Berlin, 13353
-
Germany
Novartis Investigative Site
Recruiting
Hamburg, 20246
-
Germany
Novartis Investigative Site
Recruiting
Koeln, 50937
-
Germany
Novartis Investigative Site
Recruiting
Leipzig, 04103
-
Germany
Novartis Investigative Site
Recruiting
Muenchen, 81377
-
Germany
Novartis Investigative Site
Recruiting
Ulm, 89081
-
Germany
Hong Kong
Novartis Investigative Site
Recruiting
Hong Kong,
-
Hong Kong
Italy
Novartis Investigative Site
Recruiting
Milano, 20133
MI
Italy
Novartis Investigative Site
Recruiting
Rozzano, 20089
MI
Italy
Novartis Investigative Site
Recruiting
Roma, 00168
RM
Italy
Japan
Kyushu University Hospital
Recruiting
Fukuoka city, 812-8582
Fukuoka
Japan
Hokkaido University Hospital
Recruiting
Sapporo city, 060 8648
Hokkaido
Japan
Tohoku University Hospital
Recruiting
Sendai city, 980 8574
Miyagi
Japan
Netherlands
Amsterdam UMC, locatie AMC
Recruiting
Amsterdam, 1105 AZ
-
Netherlands
UMC Utrecht Cancer Center
Recruiting
Utrecht, 3584CX
-
Netherlands
Norway
Novartis Investigative Site
Recruiting
Oslo, NO-0424
-
Norway
Singapore
Novartis Investigative Site
Recruiting
Singapore, 119228
-
Singapore
Novartis Investigative Site
Recruiting
Singapore, 169608
-
Singapore
Spain
Novartis Investigative Site
Recruiting
Salamanca, 37007
Castilla Y Leon
Spain
Novartis Investigative Site
Recruiting
Barcelona, 08035
Catalunya
Spain
Novartis Investigative Site
Recruiting
Hospitalet de LLobregat, 08907
Catalunya
Spain
Novartis Investigative Site
Recruiting
Madrid, 28009
-
Spain
Novartis Investigative Site
Recruiting
Madrid, 28041
-
Spain
Switzerland
Novartis Investigative Site
Recruiting
Zurich, 8091
-
Switzerland
Taiwan
Novartis Investigative Site
Recruiting
Taipei, 10002
-
Taiwan
United Kingdom
Novartis Investigative Site
Recruiting
Birmingham, B15 2TH
-
United Kingdom
Novartis Investigative Site
Recruiting
London, WC1E 6HX
-
United Kingdom

Contacts

Name: 
Novartis Pharmaceuticals
Phone: 
1-888-669-6682
Name: 
Novartis Pharmaceuticals
Phone: 
+41613241111
Email: 

Have a question?

Call 1-999-669-6682 or email [email protected]