Clinical Trials List
Protocol NumberCCTL019H2301
NCT Number(ClinicalTrials.gov Identfier)NCT03570892
Completed
2020-08-01 - 2021-09-10
Phase III
Recruiting1
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)
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Trial Applicant
NOVARTIS (TAIWAN) CO., LTD.
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Sponsor
Novartis Pharmaceuticals
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Trial scale
Multi-Regional Multi-Center
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Update
2026/02/01
Investigators and Locations
Co-Principal Investigator
- HSIN-AN HOU Division of General Internal Medicine
- Shang-Ju Wu Division of General Internal Medicine
- SONG-CHOU HSIEH 無
- 徐思淳 Division of Others
- Tai-Chung Huang Division of General Internal Medicine
- Huai-Hsuan Huang 無
- Chien-Chin Lin 無
- SHAN-CHI YU 無
- Sheng-chieh Chou 無
- CHENG-HONG TSAI 無
- 林明恩 無
- 袁章祖 無
- Jih-Luh Tang 無
- Chieh-Lung Cheng 無
- 田豐銘 無
- Wen-Chien Chou Division of Others -
- - - 無
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphoma
Objectives
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.
Test Drug
CTL019
Active Ingredient
tisagenlecleucel
Dosage Form
infusion
Dosage
0.6-6.0x10^8 CAR-positive viable T cells, 30-70mL
Endpoints
Primary Outcome Measures :
Event-free survival (EFS) [ Time Frame: 5 years ]
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.
Secondary Outcome Measures :
EFS as assessed by local investigator [ Time Frame: 5 years ]
EFS as assessed by local investigator
Overall Survival (OS) [ Time Frame: 5 years ]
Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause
Overall Response Rate (ORR) [ Time Frame: 5 years ]
Overall Response Rate (ORR) as per the Lugano criteria as per BIRC review and local investigator assessment
Duration of Response (DOR) [ Time Frame: 5 years ]
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
Time to Response (TTR) [ Time Frame: 5 years ]
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
SF-36v2 [ Time Frame: 5 years ]
Time to definitive deterioration in SF-36v2
FACT-Lym [ Time Frame: 5 years ]
Time to definitive deterioration in FACT-Lym
EQ-VAS [ Time Frame: 5 years ]
Time to definitive deterioration in EQ-VAS
Tisagenlecleucel transgene concentrations [ Time Frame: 5 years ]
qPCR will be used to measure tisagenlecleucel transgene concentrations in peripheral blood and bone marrow
Tisagenlecleucel immunogenicity (humoral and cellular) [ Time Frame: 5 years ]
Pre-existing and treatment related immunogenicity (humoral and cellular) of tisagenlecleucel will be characterized.
Presence of replication competent lentivirus (RCL) [ Time Frame: 5 years ]
The presence of RCL will be assessed by VSV-qPCR in patients receiving tisagenlecleucel
Event-free survival (EFS) [ Time Frame: 5 years ]
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.
Secondary Outcome Measures :
EFS as assessed by local investigator [ Time Frame: 5 years ]
EFS as assessed by local investigator
Overall Survival (OS) [ Time Frame: 5 years ]
Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause
Overall Response Rate (ORR) [ Time Frame: 5 years ]
Overall Response Rate (ORR) as per the Lugano criteria as per BIRC review and local investigator assessment
Duration of Response (DOR) [ Time Frame: 5 years ]
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
Time to Response (TTR) [ Time Frame: 5 years ]
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
SF-36v2 [ Time Frame: 5 years ]
Time to definitive deterioration in SF-36v2
FACT-Lym [ Time Frame: 5 years ]
Time to definitive deterioration in FACT-Lym
EQ-VAS [ Time Frame: 5 years ]
Time to definitive deterioration in EQ-VAS
Tisagenlecleucel transgene concentrations [ Time Frame: 5 years ]
qPCR will be used to measure tisagenlecleucel transgene concentrations in peripheral blood and bone marrow
Tisagenlecleucel immunogenicity (humoral and cellular) [ Time Frame: 5 years ]
Pre-existing and treatment related immunogenicity (humoral and cellular) of tisagenlecleucel will be characterized.
Presence of replication competent lentivirus (RCL) [ Time Frame: 5 years ]
The presence of RCL will be assessed by VSV-qPCR in patients receiving tisagenlecleucel
Inclution 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.
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
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))
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))
The Estimated Number of Participants
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Taiwan
4 participants
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Global
318 participants
