Study to Compare Axicabtagene Ciloleucel With Standard of Care Therapy as First-line Treatment in Participants With High-risk Large B-cell Lymphoma

Study Overview
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Brief Summary
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The goal of this clinical study is to compare the study drug, axicabtagene ciloleucel, versus standard of care (SOC) in first-line therapy in participants with high-risk large B-cell lymphoma.

Detailed Description
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Five years after the last study participant is randomized, participants who have received axicabtagene ciloleucel will transition to a separate long-term follow-up study (study KT-US-982-5968) to complete the remainder of the 15-year follow-up assessments.

Official Title
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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)

Conditions
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High-risk Large B-cell Lymphoma (LBCL)

Intervention / Treatment
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* Biological: Axicabtagene Ciloleucel
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Etoposide
* Drug: Rituximab
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically confirmed large B cell lymphoma (LBCL) based on 2016 World Health Organization (WHO) classification by local pathology lab assessment, including of the following: Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) High-grade B-cell lymphoma (HGBL) Note: Transformed DLBCL from follicular lymphoma or from marginal zone lymphoma is eligible if no prior treatment with anthracycline-containing regimen. High-risk disease defined as an International Prognostic Index (IPI) score of 4 or 5 at initial diagnosis. Have received only 1 cycle of rituximab plus chemotherapy (R-chemotherapy). Adequate bone marrow, renal, hepatic, pulmonary, and cardiac function. Females of childbearing potential must have a negative serum or urine pregnancy test. Key Exclusion Criteria: The following WHO 2016 subcategories by local assessment: T-cell/histiocyte-rich LBCL Primary DLBCL of the central nervous system (CNS) Primary mediastinal (thymic) LBCL B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma Burkitt lymphoma Presence of detectable cerebrospinal fluid (CSF)-malignant cells, brain metastases, or a history of CNS involvement of lymphoma. Presence of cardiac lymphoma involvement. Any prior treatment for LBCL other than the 1 cycle of R-chemotherapy. History of severe immediate hypersensitivity reaction to any of the agents used in this study. Presence of CNS disorder. History of stroke, transient ischemic attack, or posterior reversible encephalopathy syndrome (PRES) within 12 months prior to enrollment. History of acute or chronic active hepatitis B or C infection. Positive for human immunodeficiency virus (HIV) unless taking appropriate anti-HIV medications, with an undetectable viral load by PCR and with a cluster of differentiation 4 (CD4) count > 200 cells/uL. Medical conditions likely to interfere with assessment of safety or efficacy of study treatment. Please refer to protocol for further details. History of clinically significant cardiac disease within 12 months before enrollment. History of any medical condition requiring maintenance systemic immunosuppression/systemic disease modifying agents within the last 2 years. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Axicabtagene Ciloleucel<br>Participants will receive cyclophosphamide 500 mg/m^2/day intravenously (IV) and fludarabine 30 mg/m^2/day IV lymphodepletion chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-cluster of differentiation (CD)19 chimeric antigen receptor (CAR) transduced autologous T cells/kg on Day 0. | Biological: Axicabtagene Ciloleucel<br>* A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells<br>* Other names: Axi-cel;Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Fludarabine<br>* Administered intravenously<br>|
| Active Comparator: Standard of Care Therapy<br>Participants will receive the investigator's choice of one of the following therapies/dosing schedules: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for a total of 6 cycles (21-day cycle) Rituximab 375 mg/m^2 on Day 1 Cyclophosphamide 750 mg/m^2 on Day 1 Doxorubicin 50 mg/m^2 on Day 1 Vincristine 1.4 mg/m^2 (maximum 2 mg) on Day 1 Prednisone 40 mg/m^2 on Day 1 through Day 5 Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) for a total of 6 cycles (21-day cycle) Rituximab 375 mg/m^2 on Day 1 Etoposide 50 mg/m^2 on Days 1 to 4 Doxorubicin 10 mg/m^2 on Days 1 to 4 Vincristine 0.4 mg/m^2 on Days 1 to 4 Cyclophosphamide 750 mg/m^2 on Day 5 Prednisone 60 mg/m^2 twice daily on Days 1 to 5 | Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Etoposide<br>* Administered intravenously<br>Drug: Rituximab<br>* Administered intravenously<br>Drug: Doxorubicin<br>* Administered intravenously<br>Drug: Vincristine<br>* Administered intravenously<br>Drug: Prednisone<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) by Central Assessment | EFS, is defined as the time from randomization to the earliest occurrence of death due to any cause, disease progression/relapse, initiation of any non-protocol specified subsequent new lymphoma therapy for the treatment of residual disease or Biopsy-proven residual disease at the Month 6 disease assessment or later, regardless of whether subsequent new lymphoma therapy is initiated or not. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) by Investigator Assessment | PFS is defined as the time from randomization to disease progression or death due to any cause. | Up to 5 years | 
| Overall Survival | OS is defined as the time from randomization to death due to any cause. | Up to 5 years | 
| PFS by Central Assessment | PFS is defined as the time from randomization to disease progression or death due to any cause. | Up to 5 years | 
| Complete Response (CR) Rate by Central Assessment | CR rate is defined as the proportion of participants who have achieved CR per Lugano classification after treatment completion and prior to subsequent new off protocol anti-lymphoma therapy. | Up to 5 years | 
| Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths |  | First dose date up to 5 years plus 30 days | 
| Percentage of Participants Experiencing Clinically Significant Changes in Safety Laboratory Values |  | First dose date up to 5 years plus 30 days | 
| Change From Baseline in the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire-30 (EORTC QLQ-C30) Score | The EORTC-QLQ-C30 is a multi-item questionnaire measuring the following content: five (5) multi-item functional scales, three (3) multi-item symptom scales, six (6) symptom single-item scales, one (1) global health status scale, and one (1) global health-related quality of life (HRQoL). Each scale is measured from 0 to 100 after a linear transformation. Higher scores for functioning scales and for the Global Health Status or Global HRQoL scales indicate a higher level of functioning and a better HRQoL respectively, whereas higher scores in symptom scales represent a higher level of symptoms. | Baseline, Month 18 | 
| Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Non-Hodgkin Lymphoma High Grade Module (EORTC QLQ-NHL-HG29) Score | The EORTC QLQ-NHL-HG29 is a 29-item patient-reported assessment measuring patients' high-grade NHL-specific symptoms and functioning. The 29 items assess symptom burden due to disease and/or treatment, fatigue/physical condition, neuropathy, emotional impacts, and worries/fears health and functioning. Each scale is measured from 0 to 100 after a linear transformation. Higher scores for functional scales indicate a higher level of functioning and a better HRQoL, whereas higher scores in symptom scales represent a higher level of symptoms. | Baseline, Month 18 | 
| Change From Baseline in the European Quality of Life Five Dimensions Five Levels Questionnaire (EQ-5D-5L) Score | The EQ-5D-5L questionnaire is a generic measure of health status that provides a simple descriptive profile and a single index value. The EQ-5D-5L comprises 2 components: a questionnaire covering 5 dimensions and a tariff of values based upon direct valuations of health states using a visual analog scale (VAS). Rating gets recorded on a vertical VAS in which the endpoints are labeled best imaginable health state is 100 (on the top) and worst imaginable health state is 0 (on the bottom). Higher scores of EQ VAS indicate better health. | Baseline, Month 18 |