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

Non-Hodgkin Lymphoma Clinical Trial

— BELINDA  

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03570892
• Other study ID #: CCTL019H2301
• Secondary ID: 2016-002966-29
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: May 7, 2019
• Est. completion date: February 14, 2026

Study information

• Verified date: March 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 331
• Est. completion date: February 14, 2026
• Est. primary completion date: February 13, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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):

1. DLBCL, NOS,

2. FL grade 3B,

3. Primary mediastinal large 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 anti CD20 antibody and anthracycline containing first line immunochemotherapy or refractory (have not achieved a CR).

3. 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

4. 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::

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. 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:

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

5. Absolute lymphocyte count (ALC) >300/mm3 OR Absolute number of CD3+ T cells >150/mm3 (only for patients with non-historical apheresis)

6. Platelets =50000/mm3

7. Hemoglobin >8.0 g/dl

Adequate pulmonary function defined as:

8. No or mild dyspnea (= Grade 1)

9. Oxygen saturation measured by pulse oximetry > 90% on room air

10. 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, T cell therapy, or any prior gene therapy product

2. Treatment with any systemic lymphoma-directed second line anticancer therapy prior to randomization. Only steroids and local irradiation are permitted for disease control

3. 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

4. Prior allogeneic HSCT

5. Clinically significant active infection

6. 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.

7. 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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin
• Non-Hodgkin Lymphoma

Intervention

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-? signaling domain)
• 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

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Darlinghurst	New South Wales
Australia	Novartis Investigative Site	Melbourne	Victoria
Australia	Novartis Investigative Site	Murdoch	Western Australia
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Vienna
Belgium	Novartis Investigative Site	Leuven
Brazil	Novartis Investigative Site	Salvador	BA
Brazil	Novartis Investigative Site	Sao Paulo
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Shanghai
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Montpellier cedex 5
France	Novartis Investigative Site	Nantes Cedex 1
France	Novartis Investigative Site	Paris 10
France	Novartis Investigative Site	Pierre Benite
France	Novartis Investigative Site	Toulouse
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Regensburg	Bavaria
Germany	Novartis Investigative Site	Ulm
Hong Kong	Novartis Investigative Site	Hong Kong
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Rozzano	MI
Japan	Kyushu University Hospital	Fukuoka city	Fukuoka
Japan	Hokkaido University Hospital	Sapporo city	Hokkaido
Japan	Tohoku University Hospital	Sendai city	Miyagi
Netherlands	Amsterdam UMC, locatie AMC	Amsterdam
Netherlands	UMC Utrecht Cancer Center	Utrecht
Norway	Novartis Investigative Site	Oslo
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Salamanca	Castilla Y Leon
Switzerland	Novartis Investigative Site	Zurich
Taiwan	Novartis Investigative Site	Taipei
United Kingdom	Novartis Investigative Site	Birmingham
United Kingdom	Novartis Investigative Site	London
United States	Emory University School of Medicine/Winship Cancer Institute SC	Atlanta	Georgia
United States	St Davids South Austin Medical Ctr	Austin	Texas
United States	MUSC Hollings Cancer Center	Charleston	South Carolina
United States	Uni of Chi Medi Ctr Hema and Onco	Chicago	Illinois
United States	Jewish Hospital	Cincinnati	Ohio
United States	The Ohio State University SC	Columbus	Ohio
United States	Baylor Scott and White Res Inst	Dallas	Texas
United States	Sarah Cannon Research Institute	Denver	Colorado
United States	Wayne State University - Karmanos Cancer Institute SC	Detroit	Michigan
United States	Hackensack Univ Medical Center	Hackensack	New Jersey
United States	University of Texas MD Anderson Cancer Center MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic Jacksonville Main Centre	Jacksonville	Florida
United States	University of Kansas Cancer Center SC	Kansas City	Kansas
United States	Moores UC San Diego Cancer Center	La Jolla	California
United States	University of California Los Angeles University of California LA	Los Angeles	California
United States	Uni of Wisconsin Carbone Cancer Ctr	Madison	Wisconsin
United States	Sarah Cannon Research Institute .	Nashville	Tennessee
United States	Uni of Nebraska Med Ctr	Omaha	Nebraska
United States	University of Pennsylvania, Abramson Cancer Center	Philadelphia	Pennsylvania
United States	Oregon Health Sciences Univ SC	Portland	Oregon
United States	Methodist Hospital	San Antonio	Texas
United States	UCSF Medical Center	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Brazil,  China,  France,  Germany,  Hong Kong,  Italy,  Japan,  Netherlands,  Norway,  Singapore,  Spain,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	EFS as assessed by local investigator	EFS as assessed by local investigator	5 years
Secondary	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
Secondary	Overall Response Rate (ORR)	Overall Response Rate (ORR) as per the Lugano criteria as per BIRC review and local investigator assessment	5 years
Secondary	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
Secondary	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
Secondary	SF-36v2	Time to definitive deterioration in SF-36v2	24 Months
Secondary	FACT-Lym	Time to definitive deterioration in FACT-Lym	24 Months
Secondary	EQ-VAS	Time to definitive deterioration in EQ-VAS	24 Months
Secondary	Tisagenlecleucel transgene concentrations	qPCR will be used to measure tisagenlecleucel transgene concentrations in peripheral blood and bone marrow	5 years
Secondary	Tisagenlecleucel immunogenicity (humoral and cellular)	Pre-existing and treatment related immunogenicity (humoral and cellular) of tisagenlecleucel will be characterized.	5 years
Secondary	Presence of replication competent lentivirus (RCL)	The presence of RCL will be assessed by VSV-qPCR in patients receiving tisagenlecleucel	5 years

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