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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03570892




Registration number
NCT03570892
Ethics application status
Date submitted
18/06/2018
Date registered
27/06/2018

Titles & IDs
Public title
Tisagenlecleucel in Adult Patients With Aggressive B-cell Non-Hodgkin Lymphoma
Scientific 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)
Secondary ID [1] 0 0
2016-002966-29
Secondary ID [2] 0 0
CCTL019H2301
Universal Trial Number (UTN)
Trial acronym
BELINDA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-Hodgkin Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tisagenlecleucel after optional bridging and lymphodepleting chemotherapy
Treatment: Drugs - Platinum-based immunochemotherapy followed in responding patients with high dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT)

Experimental: Tisagenlecleucel treatment strategy - Patients received investigator's choice of optional platinum-based immunochemotherapy followed by lymphodepleting chemotherapy and a single dose of tisagenlecleucel

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)


Treatment: Drugs: 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-? signaling domain)

Treatment: Drugs: 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
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event-free Survival (EFS) Per Blinded Independent Review Committee (BIRC) Assessment
Timepoint [1] 0 0
appro. 24 months
Secondary outcome [1] 0 0
Event Free Survival (EFS) as Assessed by Local Investigator
Timepoint [1] 0 0
5 years
Secondary outcome [2] 0 0
Overall Survival (OS)
Timepoint [2] 0 0
5 years
Secondary outcome [3] 0 0
Overall Response Rate (ORR)
Timepoint [3] 0 0
5 years
Secondary outcome [4] 0 0
Duration of Response (DOR)
Timepoint [4] 0 0
5 years
Secondary outcome [5] 0 0
Time to Response (TTR)
Timepoint [5] 0 0
5 years
Secondary outcome [6] 0 0
SF-36v2
Timepoint [6] 0 0
24 Months
Secondary outcome [7] 0 0
FACT-Lym
Timepoint [7] 0 0
24 Months
Secondary outcome [8] 0 0
EQ-VAS
Timepoint [8] 0 0
24 Months
Secondary outcome [9] 0 0
Tisagenlecleucel Transgene Concentrations
Timepoint [9] 0 0
5 years
Secondary outcome [10] 0 0
Tisagenlecleucel Immunogenicity (Humoral and Cellular)
Timepoint [10] 0 0
5 years
Secondary outcome [11] 0 0
Presence of Replication Competent Lentivirus (RCL)
Timepoint [11] 0 0
5 years

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
7/05/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
14/02/2026
Actual
Sample size
Target
Accrual to date
Final
331
Recruitment in Australia
Recruitment state(s)
NSW,VIC,WA
Recruitment hospital [1] 0 0
Novartis Investigative Site - Darlinghurst
Recruitment hospital [2] 0 0
Novartis Investigative Site - Melbourne
Recruitment hospital [3] 0 0
Novartis Investigative Site - Murdoch
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 0 0
3000 - Melbourne
Recruitment postcode(s) [3] 0 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Kansas
Country [7] 0 0
United States of America
State/province [7] 0 0
Michigan
Country [8] 0 0
United States of America
State/province [8] 0 0
Nebraska
Country [9] 0 0
United States of America
State/province [9] 0 0
New Jersey
Country [10] 0 0
United States of America
State/province [10] 0 0
Ohio
Country [11] 0 0
United States of America
State/province [11] 0 0
Oregon
Country [12] 0 0
United States of America
State/province [12] 0 0
Pennsylvania
Country [13] 0 0
United States of America
State/province [13] 0 0
South Carolina
Country [14] 0 0
United States of America
State/province [14] 0 0
Tennessee
Country [15] 0 0
United States of America
State/province [15] 0 0
Texas
Country [16] 0 0
United States of America
State/province [16] 0 0
Wisconsin
Country [17] 0 0
Austria
State/province [17] 0 0
Salzburg
Country [18] 0 0
Austria
State/province [18] 0 0
Vienna
Country [19] 0 0
Belgium
State/province [19] 0 0
Leuven
Country [20] 0 0
Brazil
State/province [20] 0 0
BA
Country [21] 0 0
Brazil
State/province [21] 0 0
Sao Paulo
Country [22] 0 0
China
State/province [22] 0 0
Beijing
Country [23] 0 0
China
State/province [23] 0 0
Shanghai
Country [24] 0 0
France
State/province [24] 0 0
Lille
Country [25] 0 0
France
State/province [25] 0 0
Montpellier
Country [26] 0 0
France
State/province [26] 0 0
Nantes
Country [27] 0 0
France
State/province [27] 0 0
Paris 10
Country [28] 0 0
France
State/province [28] 0 0
Pierre Benite
Country [29] 0 0
France
State/province [29] 0 0
Toulouse
Country [30] 0 0
Germany
State/province [30] 0 0
Bavaria
Country [31] 0 0
Germany
State/province [31] 0 0
Berlin
Country [32] 0 0
Germany
State/province [32] 0 0
Hamburg
Country [33] 0 0
Germany
State/province [33] 0 0
Koeln
Country [34] 0 0
Germany
State/province [34] 0 0
Leipzig
Country [35] 0 0
Germany
State/province [35] 0 0
Muenchen
Country [36] 0 0
Germany
State/province [36] 0 0
Ulm
Country [37] 0 0
Hong Kong
State/province [37] 0 0
Hong Kong
Country [38] 0 0
Italy
State/province [38] 0 0
MI
Country [39] 0 0
Italy
State/province [39] 0 0
RM
Country [40] 0 0
Japan
State/province [40] 0 0
Fukuoka
Country [41] 0 0
Japan
State/province [41] 0 0
Hokkaido
Country [42] 0 0
Japan
State/province [42] 0 0
Miyagi
Country [43] 0 0
Netherlands
State/province [43] 0 0
Amsterdam
Country [44] 0 0
Netherlands
State/province [44] 0 0
Utrecht
Country [45] 0 0
Norway
State/province [45] 0 0
Oslo
Country [46] 0 0
Singapore
State/province [46] 0 0
Singapore
Country [47] 0 0
Spain
State/province [47] 0 0
Castilla Y Leon
Country [48] 0 0
Spain
State/province [48] 0 0
Catalunya
Country [49] 0 0
Spain
State/province [49] 0 0
Madrid
Country [50] 0 0
Switzerland
State/province [50] 0 0
Zurich
Country [51] 0 0
Taiwan
State/province [51] 0 0
Taipei
Country [52] 0 0
United Kingdom
State/province [52] 0 0
Birmingham
Country [53] 0 0
United Kingdom
State/province [53] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
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.
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://www.clinicalstudydatarequest.com


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT03570892