Non-Hodgkin Lymphoma
Conditions
Keywords
Non-Hodgkin's Lympoma, B-Cell Lymphoma, Diffuse Large B-cell Lymphoma, High Grade B-cell Lymphoma, Follicular Lymphoma grade 3B, CAR-T, Tisagenlecleucel, Kymriah, Immunotherapy, Cellular therapy, CTL019
Brief 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.
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.
Interventions
DRUGTisagenlecleucel 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)
DRUGPlatinum-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
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Intervention model description
Randomized, Open-Label
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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))
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) Per Blinded Independent Review Committee (BIRC) Assessment | appro. 24 months | 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
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival (EFS) as Assessed by Local Investigator | 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. |
| Overall Survival (OS) | 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) | 5 years | Overall Response Rate (ORR) as per the Lugano criteria as per BIRC review and local investigator assessment |
| Duration of Response (DOR) | 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) | 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 | 24 Months | Time to definitive deterioration in SF-36v2 |
| FACT-Lym | 24 Months | Time to definitive deterioration in FACT-Lym |
| EQ-VAS | 24 Months | Time to definitive deterioration in EQ-VAS |
| Tisagenlecleucel Transgene Concentrations | 5 years | qPCR will be used to measure tisagenlecleucel transgene concentrations in peripheral blood and bone marrow |
| Tisagenlecleucel Immunogenicity (Humoral and Cellular) | 5 years | Pre-existing and treatment related immunogenicity (humoral and cellular) of tisagenlecleucel will be characterized. |
| Presence of Replication Competent Lentivirus (RCL) | 5 years | The presence of RCL will be assessed by VSV-qPCR in patients receiving tisagenlecleucel |
Countries
Australia, Austria, Belgium, Brazil, China, France, Germany, Hong Kong, Italy, Japan, Netherlands, Norway, Singapore, Spain, Switzerland, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
The study was conducted in 18 countries and 65 sites. Approximately 318 subjects were planned to be randomized; 322 subjects were analyzed.
Pre-assignment details
During the screening period, no lymphoma-specific therapy was allowed prior to randomization. During randomization, subjects were stratified by: Remission duration, international prognostic index (IPI) score and region.
Participants by arm
| Arm | Count |
|---|---|
| Tisagenlecleucel Treatment Strategy Patients received investigator's choice of optional platinum-based immunochemotherapy followed by lymphodepleting chemotherapy and a single dose of tisagenlecleucel | 162 |
| 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) | 160 |
| Total | 322 |
Baseline characteristics
| Characteristic | Tisagenlecleucel Treatment Strategy | Standard of Care Treatment Strategy | Total |
|---|---|---|---|
| Age, Continuous | 56.7 years STANDARD_DEVIATION 13.74 | 55.0 years STANDARD_DEVIATION 12.99 | 55.8 years STANDARD_DEVIATION 13.38 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 20 Participants | 22 Participants | 42 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants | 3 Participants | 11 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown | 4 Participants | 5 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 128 Participants | 128 Participants | 256 Participants |
| Sex: Female, Male Female | 59 Participants | 62 Participants | 121 Participants |
| Sex: Female, Male Male | 103 Participants | 98 Participants | 201 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 52 / 162 | 45 / 160 | 97 / 322 |
| other Total, other adverse events | 159 / 162 | 158 / 160 | 317 / 322 |
| serious Total, serious adverse events | 76 / 162 | 82 / 160 | 158 / 322 |
Outcome results
Primary
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.
Time frame: appro. 24 months
Population: The full analysis set (FAS) comprised all subjects to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tisagenlecleucel Treatment Strategy | Event-free Survival (EFS) Per Blinded Independent Review Committee (BIRC) Assessment | 3.0 months |
| Standard of Care Treatment Strategy | Event-free Survival (EFS) Per Blinded Independent Review Committee (BIRC) Assessment | 3.0 months |
p-value: =0.69495% CI: [0.82, 1.4]Stratified log-rank test one-sided
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
Time frame: 5 years
Secondary
EQ-VAS
Time to definitive deterioration in EQ-VAS
Time frame: 24 Months
Secondary
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.
Time frame: 5 years
Secondary
FACT-Lym
Time to definitive deterioration in FACT-Lym
Time frame: 24 Months
Secondary
Overall Response Rate (ORR)
Overall Response Rate (ORR) as per the Lugano criteria as per BIRC review and local investigator assessment
Time frame: 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
Time frame: 5 years
Secondary
Presence of Replication Competent Lentivirus (RCL)
The presence of RCL will be assessed by VSV-qPCR in patients receiving tisagenlecleucel
Time frame: 5 years
Secondary
SF-36v2
Time to definitive deterioration in SF-36v2
Time frame: 24 Months
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
Time frame: 5 years
Secondary
Tisagenlecleucel Immunogenicity (Humoral and Cellular)
Pre-existing and treatment related immunogenicity (humoral and cellular) of tisagenlecleucel will be characterized.
Time frame: 5 years
Secondary
Tisagenlecleucel Transgene Concentrations
qPCR will be used to measure tisagenlecleucel transgene concentrations in peripheral blood and bone marrow
Time frame: 5 years