An Adaptive Phase 3, Randomized, Open-Label, Multicenter Study to Compare the Efficacy and Safety of Axicabtagene Ciloleucel versus Standard of Care Therapy as First-Line Therapy in Subjects with High-Risk Large B-Cell Lymphoma (ZUMA-23)
- Trial ID
- 2022-501489-24-00
- Protocol
- KT-US-484-0136
- Sponsor
- Kite Pharma Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of axicabtagene ciloleucel versus standard of care therapy (SOCT) in patients with high-risk large B-cell lymphoma, as measured by event-free survival (EFS). This is clinically relevant as EFS is a critical endpoint in assessing the effectiveness of first-line treatments in improving patient outcomes in this aggressive form of lymphoma.
Secondary objectives include:
- Comparing the efficacy of axicabtagene ciloleucel versus SOCT, as measured by progression-free survival (PFS) and overall survival (OS).
- Comparing the efficacy of axicabtagene ciloleucel versus SOCT, as measured by PFS and complete remission (CR) rate.
- Comparing the safety of axicabtagene ciloleucel versus SOCT.
- Comparing the quality of life (QOL) of patients receiving axicabtagene ciloleucel versus SOCT.
Participants
The clinical trial involves a total of **177 participants** who are adult subjects diagnosed with high-risk large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), and high-grade B-cell lymphoma (HGBL). The study population includes both **male and female** participants aged 18 years and older. Participants were selected based on specific criteria, including having a high-risk disease defined by an International Prognostic Index (IPI) score of 4 or 5 at initial diagnosis, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of randomization. The trial population is characterized by adequate bone marrow, renal, hepatic, pulmonary, and cardiac function, as well as a baseline oxygen saturation greater than 92% on room air. Participants must have histologically confirmed LBCL based on the 2016 World Health Organization (WHO) classification and have received only one cycle of R-chemotherapy. The trial includes individuals with Ann Arbor Stage III or IV disease and requires at least one measurable lesion per the Lugano Classification on anatomical imaging. The study does not exclude vulnerable populations, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.
Plans and Procedures
The clinical trial is designed as an **adaptive Phase 3, randomized, open-label, multicenter study** to evaluate the efficacy and safety of **axicabtagene ciloleucel** compared to standard of care therapy in subjects with high-risk large B-cell lymphoma (LBCL). The primary objective is to assess event-free survival (EFS) by blinded central assessment, with secondary endpoints including progression-free survival (PFS), overall survival (OS), and complete remission rate, among others. The trial is expected to run from October 2023 to December 2029, with participant involvement lasting up to 147 days, depending on the treatment regimen.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as histologically confirmed LBCL, an International Prognostic Index (IPI) score of 4 or 5, and adequate organ function. Following randomization, participants will receive either the investigational product or standard therapy. Study visits will include regular assessments to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur after the final treatment cycle, where comprehensive evaluations will be conducted to assess the overall outcomes.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure participant safety and data integrity. The study will utilize a combination of intravenous infusions and oral medications, with specific dosing regimens tailored to each participant's treatment plan. The trial's design and methodology aim to provide robust data to support the potential approval and use of axicabtagene ciloleucel as a first-line treatment for high-risk LBCL.
Treatment
The clinical trial involves the administration of **axicabtagene ciloleucel**, a genetically modified autologous cell-based product. This investigational therapy is provided as a dispersion for infusion, with a dosage form of 0.4 – 2 x 108 cells. The route of administration is **intravenous infusion**. Axicabtagene ciloleucel is designed to express an anti-CD19 chimeric antigen receptor (CAR) and is used as a test treatment in the study. The maximum treatment period is one day, and the product is classified as an orphan drug.
**Doxorubicin** is used as a comparator treatment in the study. It is an antineoplastic agent administered via **intravenous infusion**. The dosage is measured in mg/m2, with a maximum daily dose of 50 mg/m2 and a total dose limit of 250 mg/m2. The treatment period can extend up to 105 days.
**Mesna** serves as a detoxifying agent for antineoplastic treatment. It is administered through **intravenous injection** with a maximum daily dose of 540 mg and a total dose limit of 1620 mg over a treatment period of up to 3 days.
**Rituximab** is another antineoplastic agent used in the trial, administered via **intravenous use**. The dosage is 375 mg/m2 per day, with a total dose limit of 2625 mg/m2 over a maximum treatment period of 147 days.
**Cyclophosphamide** is administered as an anti-neoplastic agent through **intravenous infusion**. The maximum daily dose is 750 mg/m2, with a total dose limit of 3750 mg/m2 over 105 days.
**Tocilizumab** is used as an auxiliary treatment, administered via **intravenous infusion**. The maximum daily dose is 2400 mg, with a total dose limit of 3200 mg over a 2-day treatment period.
**Etoposide** is administered as an antineoplastic agent through **intravenous infusion**. The dosage is 50 mg/m2 per day, with a total dose limit of 1000 mg/m2 over 105 days.
**Dexamethasone** is used as a corticosteroid, administered via **intravenous infusion**. The maximum daily dose is 30 mg, with a total dose limit of 360 mg over a 12-day treatment period.
**Methylprednisolone** is another corticosteroid used in the trial, administered through **intravenous use**. The maximum daily dose is 2000 mg, with a total dose limit of 24000 mg over 12 days.
**Prednisone** is administered as a steroid via the **oral** route. The dosage is 120 mg/m2 per day, with a total dose limit of 3000 mg/m2 over 105 days.
**Fludarabine** is used as an antineoplastic agent, administered through **intravenous infusion**. The dosage is 30 mg/m2 per day, with a total dose limit of 90 mg/m2 over a 3-day treatment period.
**Vincristine** is administered as an antineoplastic agent via **intravenous infusion**. The maximum daily dose is 2 mg, with a total dose limit of 10 mg over 105 days.
**Diphenhydramine** is used as an antihistamine, administered orally. The maximum daily dose is 12.5 mg, with a total dose limit of 12.5 mg over a 1-day treatment period.
**Other analgesics and antipyretics** are administered orally, with a maximum daily dose of 650 mg and a total dose limit of 650 mg over a 1-day treatment period.
Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. The trial aims to compare the efficacy of axicabtagene ciloleucel against standard-of-care therapy in subjects with high-risk large B-cell lymphoma.
Efficacy
The efficacy of the clinical trial will be assessed by comparing the performance of **axicabtagene ciloleucel** against standard of care therapy in subjects with high-risk large B-cell lymphoma. The primary endpoint for evaluating efficacy is event-free survival (EFS), which will be measured by blinded central assessment. Secondary endpoints include progression-free survival (PFS) by both blinded central and investigator assessments, overall survival (OS), and complete remission (CR) rate by blinded central assessment. Additionally, the incidence of adverse events (AEs), serious adverse events (SAEs), deaths, and clinically significant changes in safety laboratory values will be monitored.
Patient-reported outcomes (PROs) will also be evaluated using validated instruments such as the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30), the EORTC Quality of Life Questionnaire – Non-Hodgkin Lymphoma High Grade Module (EORTC QLQ-NHL-HG29), and the European Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L). These assessments will provide insights into the quality of life and overall well-being of the participants throughout the trial.
Inclusion and Exclusion Criteria
Inclusion Criteria
- High-risk disease defined as an IPI score of 4 or 5 at initial diagnosis
- Histologically confirmed LBCL based on 2016 World Health Organization (WHO) classification by local pathology lab assessment, including one of the following: a) Diffuse large B-cell lymphoma, NOS b) High-grade B-cell lymphoma (HGBL) (including HGBL with MYC and BCL2 and/or BCL6 rearrangements (DHL/THL) based on FISH analysis, and HGBL-NOS) Note: Transformed DLBCL from follicular lymphoma or from marginal zone lymphoma is eligible if no prior treatment with anthracycline-containing regimen.
- Ann Arbor Stage III or IV disease.
- Have received only 1 cycle of R-chemotherapy
- At least 1 measurable lesion per the Lugano Classification {Cheson 2014} on anatomical imaging such as computed tomography (CT) imaging (functional imaging such as PET may not be used to identify a measurable lesion). A measurable lesion is defined as greater than 1.5 cm LDi for lymph node and greater than 1.0 cm LDi for extranodal lesion
- Adequate tumor biopsy specimen available for central pathology review (detailed sample collection requirement is in central pathology laboratory manual).
- Age 18 years or older.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of randomization. Note: ECOG > 12 at diagnosis is acceptable.
- Adequate bone marrow, renal, hepatic, pulmonary, and cardiac function as indicated by: a) Absolute neutrophil count (ANC) ≥ 1000/μL b) Platelet count ≥ 75,000/μL c) Absolute lymphocyte count ≥ 100/μL d) Creatinine clearance (as estimated by any local institutional method) ≥ 60 mL/minute e) Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 x ULN if documented liver involvement of lymphoma f) Total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert’s Syndrome or documented LBCL liver or pancreatic involvement where ≤ 3.0 times the ULN g) Left ventricular ejection fraction (LVEF) ≥ 50% and no evidence of clinically significant pericardial effusion, and no clinically significant abnormal electrocardiogram (ECG) findings h) No evidence of Grade 2 (per Common Terminology Criteria for Adverse Events [CTCAE] 5.0) or greater pleural effusion or ascites (subjects with Grade 1 ascites or pleural effusion are eligible) i) Baseline oxygen saturation > 92% on room air
- Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential).
Exclusion Criteria
- Any prior treatment for LBCL other than the 1 cycle of R-chemotherapy.
- Presence of cardiac atrial or ventricular lymphoma involvement.
- History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, or other clinically significant cardiac disease within 12 months before enrolment.
- Presence of primary immunodeficiency.
- History of any medical condition including but not limited to autoimmune disease (eg, Crohn’s disease, rheumatoid arthritis, systemic lupus) requiring maintenance systemic immunosuppression/systemic disease modifying agents within the last 2 years. Endocrine conditions that require maintenance with physiologic dose steroids are allowed.
- History of non-line associated, clinically significant (CTCAE 5.0 Grade 2 or greater) deep vein thrombosis or pulmonary embolism requiring therapeutic anticoagulation within 6 months of randomization.
- Any medical condition or residual toxicities from prior therapies per investigator assessment likely to interfere with assessment of safety or efficacy of study treatment
- History of severe immediate hypersensitivity reaction to any of the agents used in this study, including the lymphodepletion chemotherapy (cyclophosphamide or fludarabine).
- Receipt of live vaccine ≤ 6 weeks before randomization and/or anticipation of need for such a vaccine during the subject’s participation in the study.
- Females of childbearing potential who are pregnant or breastfeeding (due to potentially dangerous effects of the preparative chemotherapy on the fetus or infant).
- Not willing to practice birth control from the time of consent through 12 months after the last dose of axicabtagene ciloleucel or SOCT.
- The following WHO 2016 subcategories by local assessment: a) T-cell/histiocyte-rich LBCL b) Primary DLBCL of the CNS c) Primary mediastinal (thymic) LBCL d) B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma e) Burkitt lymphoma f)History of Richter’s transformation of chronic lymphocytic leukemia
- In the investigator’s judgment, the subject is unlikely to complete all study-specific visits or procedures, including follow-up visits, or comply with the study requirements for participation
- History of severe immediate hypersensitivity reaction attributed to aminoglycosides
- Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple bacterial infections are permitted if responding to active treatment. Discussion with the Kite medical monitor is encouraged.
- History of acute or chronic active hepatitis B or C infection. If there is a positive history of treated hepatitis B or hepatitis C, the viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.
- Positive for human immunodeficiency virus (HIV) unless taking appropriate anti-HIV medications, with an undetectable viral load by PCR and with a CD4 count > 200 cells/uL. Note: HIV-positive subjects in Australia are not permitted regardless of active anti-retroviral therapy or undetectable blood viral load (Refer to 12.4.4).
- Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Dedicated central venous access catheters, such as a Port-a-Cath or Hickman catheter, are permitted.
- Presence of detectable cerebrospinal fluid (CSF)-malignant cells, brain metastases, or a history of central nervous system (CNS) involvement of lymphoma.
- Presence of CNS disorder such as dementia, autoimmune disease with CNS involvement, cerebral edema with confirmed structural defects by appropriate imaging, or seizure disorders requiring active anticonvulsive medication. History of stroke, transient ischemic attack, or posterior reversible encephalopathy syndrome (PRES) within 12 months prior to enrollment.
- History of malignancy other than non-melanoma skin cancer or carcinoma in situ (eg, cervix, bladder, breast) unless disease free for at least 3 years
- History of autologous or allogeneic stem cell transplant (SCT)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Oct 2023 | 17 |
 France | Not Recruiting | 01 Oct 2023 | 18 |
 Germany | Not Recruiting | 01 Oct 2023 | 18 |
 Italy | Not Recruiting | 01 Oct 2023 | 30 |
 The Netherlands | Not Recruiting | 01 Oct 2023 | — |
 Portugal | Not Recruiting | 01 Oct 2023 | 9 |
 Spain | Not Recruiting | 01 Oct 2023 | 10 |
| Netherlands | — | — | 15 |
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 |
|---|---|---|---|---|---|---|
- | Other | - | INTRAVENOUS INFUSION, INTRAVENOUS INFUSION | 30 | 12 | SCP18514 |
- | Comparator | - | ORAL | 120 | 105 | SCP21517 |
YESCARTA 0.4 – 2 x 10e8 cells dispersion for infusion | Test | DISPERSION FOR INFUSION | INTRAVENIOUS INFUSION | 0 | 1 | PRD6563420 |
- | Comparator | - | INTRAVENOUS INFUSION | 2 | 105 | SCP14665 |
- | Other | - | INTRAVENOUS USE, INTRAVENOUS USE | 2000 | 12 | SCP20369 |
- | Comparator | - | INTRAVENOUS INFUSION, INTRAVENOUS INFUSION | 50 | 105 | SCP17888 |
- | Other | - | INTRAVENOUS INFUSION | 30 | 3 | SCP19175 |
- | Other | - | ORAL, ORAL | 650 | 1 | N02B |
- | Other | - | INTRAVENOUS INJECTION, INTRAVENOUS INJECTION | 540 | 3 | SCP20281 |
- | Other | - | ORAL USE, ORAL USE | 12.5 | 1 | SCP18708 |