Phase III Randomized Open-Label Trial of Tisagenlecleucel Versus Standard of Care in Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma
- Trial ID
- 2023-508343-48-00
- Protocol
- CCTL019H2301
- Sponsor
- Novartis Pharma AG
Trial statistics
Objectives
The primary objective of this study is to compare the **tisagenlecleucel** treatment strategy to the standard of care (SOC) treatment strategy in adult patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. The focus is on delaying the composite event of disease progression or stable disease at or after the Week 12 assessment, or death at any time. This is clinically relevant as it aims to improve patient outcomes by potentially extending the time to disease progression or death, which is critical in managing aggressive B-cell non-Hodgkin lymphoma.
Secondary objectives include:
- Comparing the treatment strategies with respect to event-free survival (EFS) as assessed by local investigators.
- Comparing overall survival (OS) between the treatment strategies.
- Comparing overall response rate (ORR) and duration of response (DOR) by blinded independent review committee (BIRC) and local investigators.
- Comparing time to response (TTR) between the treatment strategies.
- Evaluating the safety and tolerability of the tisagenlecleucel treatment strategy versus SOC.
- Comparing patient-reported outcomes (PROs) of health-related quality of life (HRQoL) in both treatment arms.
- Evaluating efficacy and safety in histological and molecular subgroups.
- Assessing patients treated with tisagenlecleucel for in vivo cellular kinetics, immunogenicity, and presence of replication competent lentivirus (RCL).
Participants
The clinical trial involves a total of **220 participants** diagnosed with **relapsed or refractory aggressive B-cell non-Hodgkin lymphoma**. The study population includes both male and female subjects, aged 18 years and older, who are considered eligible for autologous hematopoietic stem cell transplantation. Participants were selected based on specific inclusion criteria, including histologically confirmed aggressive B-cell non-Hodgkin lymphoma at relapse or progression, and adequate organ function. The trial population is characterized by a generally good health status, as indicated by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Lifestyle considerations such as diet and physical activity are not specified. The study does include a vulnerable population, but specific details regarding this aspect are not provided. Key inclusion criteria require participants to have active disease on PET scan and measurable disease on CT scan, among other health-related parameters.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **tisagenlecleucel** compared to standard of care in adult patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. This is a randomized, open-label, phase III trial. The trial aims to assess the time from randomization to the first documented disease progression or stable disease at or after the week 12 assessment, or death at any time, as the primary endpoint. Secondary endpoints include overall survival, overall response rate, and the type, frequency, and severity of adverse events. The trial is expected to conclude by February 2026, with recruitment having started in May 2019.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, histological confirmation of aggressive B-cell non-Hodgkin lymphoma, and adequate organ function. Following randomization, participants will receive either **tisagenlecleucel** or standard of care treatment. Study visits will include regular assessments to monitor disease progression, response to treatment, and any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected duration of participant involvement is variable, depending on individual response to treatment and disease progression, but the maximum treatment period for **tisagenlecleucel** is one month. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or disease progression that necessitates alternative treatment. The trial will adhere to rigorous scientific and ethical standards to ensure the safety and well-being of all participants.
Treatment
The clinical trial involves the use of **Tisagenlecleucel**, an experimental medication, which is a **dispersion for infusion**. It is administered via **intravenous infusion**. The maximum daily dose is 60,000,000 cells, with a total maximum dose of 600,000,000 cells. The treatment period is limited to one day. Tisagenlecleucel is a cell therapy product, specifically a CAR-expressing T cell therapy, utilizing a replication-deficient lentiviral vector. The product is classified as an orphan drug, and the label text is adapted for clinical trial specificities.
**Tocilizumab** is used as a non-experimental treatment in the study. It is administered intravenously, with a maximum daily dose of 800 mg and a total maximum dose of 3,200 mg over a treatment period of four days. Tocilizumab is a protein-based medication, classified under ATC code L04AC07.
**Etoposide** is another non-experimental treatment, administered intravenously. The maximum daily dose is 200 mg/m², with a total maximum dose of 1,700 mg/m² over a 13-day treatment period. It is categorized as a cytostatic agent, specifically a podophyllotoxin derivative.
**Cytarabine** is administered via intravenous infusion, with a maximum daily dose of 4 g/m² and a total maximum dose of 12.8 g/m² over six days. It is classified as a pyrimidine analog under ATC code L01BC01.
**Fludarabine** is administered intravenously, with a maximum daily dose of 25 mg/m² and a total maximum dose of 75 mg/m² over three days. It is an antineoplastic agent, specifically a purine analog.
**Melphalan** is administered via intravenous infusion, with a maximum daily and total dose of 140 mg/m² over one day. It is an alkylating agent under ATC code L01AA03.
**Cyclophosphamide** is administered intravenously, with a maximum daily dose of 250 mg/m² and a total maximum dose of 750 mg/m² over three days. It is an anticancer alkylating agent.
**Rituximab** is administered intravenously, with a maximum daily dose of 375 mg/m² and a total maximum dose of 1,125 mg/m² over three days. It is a chimeric monoclonal antibody directed against CD-20.
**Carboplatin** is administered via intravenous infusion, with a maximum daily dose of 800 mg and a total maximum dose of 2,400 mg over three days. It is an antineoplastic agent under ATC code L01XA02.
**Ibrutinib** is administered orally, with a maximum daily dose of 420 mg and a total maximum dose of 17,640 mg over 42 days. It is classified as a chemical under ATC code L01EL01.
**Gemcitabine Hydrochloride** is administered via intravenous infusion, with a maximum daily dose of 1,000 mg/m² and a total maximum dose of 6,000 mg/m² over six days. It is a pyrimidine antagonist under ATC code L01BC05.
**Carmustine** is administered via intravenous infusion, with a maximum daily and total dose of 300 mg/m² over one day. It is an alkylating agent under ATC code L01AD01.
**Bendamustine Hydrochloride** is administered intravenously, with a maximum daily dose of 90 mg/m² and a total maximum dose of 180 mg/m² over two days. It is classified as a chemical under ATC code L01AA09.
**Cisplatin** is administered via intravenous infusion, with a maximum daily dose of 100 mg/m² and a total maximum dose of 300 mg/m² over three days. It is an antineoplastic agent, specifically a platinum compound.
**Oxaliplatin** is administered via intravenous infusion, with a maximum daily dose of 100 mg/m² and a total maximum dose of 300 mg/m² over three days. It is a platinum-containing antineoplastic agent under ATC code L01XA03.
**Lenalidomide** is administered orally, with a maximum daily and total dose of 20 mg over 12 weeks. It is an anticancer immunomodulatory agent under ATC code L04AX04.
**Dexamethasone Acetate** is administered orally, with a maximum daily dose of 40 mg and a total maximum dose of 480 mg over 12 days. It is a glucocorticoid under ATC code H02AB02.
**Ifosfamide** is administered via intravenous infusion, with a maximum daily dose of 5,000 mg/m² and a total maximum dose of 15,000 mg/m² over three days. It is an alkylating agent under ATC code L01AA06.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is Event-Free Survival (EFS), defined as the time from the date of randomization to the date of first documented disease progression or stable disease at or after the Week 12 assessment, as assessed by a blinded independent review committee (BIRC) per Lugano criteria, or death at any time. Secondary endpoints include EFS as assessed by local investigators, Overall Survival (OS), and Overall Response Rate (ORR) according to the Lugano criteria. The duration of response will be measured from the date of first documented response of complete response (CR) or partial response (PR) to the date of first documented progression or death due to aggressive B-cell non-Hodgkin lymphoma (NHL). Time to Response (TTR) is defined as the time from the date of randomization to the date a patient first achieves a response of CR or PR on or after the Week 12 assessment.
Additional secondary endpoints include the type, frequency, and severity of serious and non-serious adverse events, laboratory abnormalities, and discontinuations due to adverse events. The trial will also evaluate the time to definitive deterioration in patient-reported outcomes using SF-36v2, FACT-Lym, and EQ-VAS scales. Efficacy will be further assessed through the summary of qPCR detected **tisagenlecleucel** transgene concentrations in peripheral blood and bone marrow, cellular kinetic parameters, and the summary of pre-existing and treatment-induced immunogenicity. The trial will also monitor the levels of pre-existing and treatment-induced immunogenicity, cellular kinetic parameters, and concentration-time profiles by immunogenicity category and efficacy at Month 3 response. The presence of replication-competent lentivirus (RCL) will be assessed by VSV-qPCR.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent must be obtained prior to participation in the study.
- Patients must be ≥18 years of age at the time of informed consent form (ICF) signature.
- Histologically confirmed (by local histopathological assessment), aggressive B-cell NHL at relapse/progression or PR after front line therapy. For patients with relapse/progression if biopsy after relapse/progression is not available or not clinically feasible to obtain a new biopsy, an archival tumor biopsy from the initial diagnosis may be submitted. For patients in PR after at least 6 cycles of first line treatment, a new biopsy must be submitted. 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 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 in the IRT system at the time of study entry
- Disease that is both active on PET scan (defined as Deauville score 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: a. 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 b. Hepatic function defined as: - Alanine Transaminase (ALT) and Aspartate Transaminase (AST) ≤ 5 × ULN - Total Bilirubin ≤1.5 × 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 c. Hematologic Function (regardless of transfusions) defined as: - Absolute neutrophil count (ANC) >1000/mm3 - Platelets ≥50,000/mm3 - Hemoglobin >8.0 g/dl Only for patients with non-historical apheresis: - Absolute lymphocyte count (ALC) >300/mm3 or - Absolute number of CD3+ T cells >150/mm3 d. 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% or carbon monoxide diffusion test (DLCO) ≥50% of predicted level
- Must have a leukapheresis material of non-mobilized cells available for manufacturing
Exclusion Criteria
- Epstein Barr Virus positive (EBV+) DLBCL, NOS, Richter’s transformation, and Burkitt lymphoma, and primary DLBCL of CNS.
- Any of the following cardiovascular conditions: a. Unstable angina, myocardial infarction, coronary artery bypass graft (CABG), or stroke within 6 months prior to screening, b. Left ventricle ejection fraction (LVEF) <45% as determined by echocardiogram (ECHO) or magnetic resonance angiography (MRA) or multigated acquisition (MUGA) at the screening assessment. c. New York Heart Association (NYHA) functional class III or IV (Chavey et al 2001), at screening or within the past 12 months. d. 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. e. Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening or inability to determine the QTcF interval f. 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: i. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome ii. Concomitant medication(s) with a “Known Risk of Torsades de Pointes” per crediblemeds.org that cannot be discontinued or replaced by safe alternative medication
- Previous or concurrent malignancy except for curatively treated non-melanoma skin cancers, in situ carcinoma (e.g. cervix, breast, bladder, prostate), and cancers in complete remission for at least 3 years and without evidence of recurrence
- Hypersensitivity to the excipients of tisagenlecleucel or to any other drug product as advised for administration in the study protocol (e.g. lymphodepleting agents, tocilizumab)
- 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))
- Pregnant or nursing (lactating) women Note: Women of child-bearing potential must have a negative serum pregnancy test performed within 24 hours before leukapheresis
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception starting from the time of informed consent form (ICF) signature and for: - at least 12 months after the tisagenlecleucel infusion and until CART cells are no longer present by qPCR on two consecutive tests for patients in Arm A or patients who crossover. - a duration according to local label and physician recommendations for patients randomized to Arm B (SOC). Furthermore, patients may need to also add barrier contraception methods if required by the local label. Highly effective contraception methods include: - Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception - Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment - Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant - Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. - In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. - Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. Note: If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF. In addition, participants must not donate oocytes.
- Sexually active males who do not use a condom during intercourse starting from the time of ICF signature and for: - at least 12 months after the tisagenlecleucel infusion and until CAR T-cells are no longer present by qPCR on two consecutive tests for patients in Arm A or patients who crossover. - a duration according to local label and physician recommendations for patients randomized to Arm B (SOC) A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, participants must not donate sperm.
- Prior treatment with anti-CD19 therapy, adoptive 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
- Investigational medicinal product (IMP) within the last 30 days prior to screening. Note: IMPs should not be used at any time while on study until the first progression following tisagenlecleucel infusion
- Presence of active hepatitis B or hepatitis C
- HIV positive patients
- Clinically significant active infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)
- Patients who, in the investigator’s judgment and/or according to clinical standards, have a contradiction to any study procedure or have any other medical condition that may put the patient at unacceptable risk.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 07 May 2019 | 17 |
 France | Not Recruiting | 07 May 2019 | 22 |
 Germany | Not Recruiting | 07 May 2019 | 35 |
 Italy | Not Recruiting | 07 May 2019 | 12 |
 The Netherlands | Not Recruiting | 07 May 2019 | — |
 Norway | Not Recruiting | 07 May 2019 | 7 |
 Spain | Not Recruiting | 07 May 2019 | 25 |
| Netherlands | — | — | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DEXAMETHASONE | Comparator | PHF00245MIG | ORAL | 40 | 12 | SCP10332310 |
FLUDARABINE | Other | PHF675 | INTRAVENOUS | 25 | 3 | SCP107125968 |
CISPLATIN | Comparator | PHF00015MIG | INTRAVENOUS INFUSION | 100 | 3 | SCP134220 |
OXALIPLATIN | Comparator | PHF00230MIG | INTRAVENOUS INFUSION | 100 | 3 | SCP128961 |
CARBOPLATIN | Comparator | PHF00230MIG | INTRAVENOUS INFUSION | 800 | 3 | SCP10337134 |
LENALIDOMIDE | Other | PHF00006MIG | ORAL | 20 | 12 | SCP149173 |
RITUXIMAB | Comparator | PHF00230MIG | INTRAVENOUS | 375 | 3 | SCP872361 |
TOCILIZUMAB | Other | PHF00231MIG | INTRAVENOUS USE | 800 | 4 | SCP176238 |
CYCLOPHOSPHAMIDE | Other | PHF00231MIG | INTRAVENOUS | 250 | 3 | SCP106382672 |
BENDAMUSTINE | Other | PHF00230MIG | INTRAVENOUS | 90 | 2 | SCP20211730 |