Study to Evaluate the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma

Study Overview
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Brief Summary
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The primary objective of this study is to estimate the efficacy of axicabtagene ciloleucel in participants with high-risk large B-cell lymphoma. After the end of KTE-C19-112 (ZUMA-12), participants who received an infusion of axicabtagene ciloleucel will complete the remainder of the 15-year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968.

Official Title
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A Phase 2 Multicenter Study Evaluating the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Subjects With High-Risk Large B-Cell Lymphoma (ZUMA-12)

Conditions
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B-cell Lymphoma

Intervention / Treatment
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* Biological: Axicabtagene Ciloleucel
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically confirmed large B-cell lymphoma High-grade large B-cell lymphoma Individuals must have a positive interim positron emission tomography (PET) per Cheson, 2014 (Deauville PET score of 4 or 5) after 2 cycles (PET2+) of chemoimmunotherapy No evidence, suspicion and/or history of central nervous system (CNS) involvement of lymphoma Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Absolute neutrophil count ≥ 1000/μL Platelet count ≥ 75,000/μL Absolute lymphocyte count ≥ 100/μL Adequate renal, hepatic, pulmonary, and cardiac function defined as: Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 upper limit of normal (ULN) Total bilirubin ≤1.5 mg/dL, except in individuals with Gilbert's syndrome Cardiac ejection fraction ≥ 50% , no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings No clinically significant pleural effusion Baseline oxygen saturation > 92% on room air Key Exclusion Criteria: History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg cervix, bladder, breast) unless disease free for at least 3 years History of Richter's transformation of chronic lymphocytic leukemia or primary mediastinal B-cell lymphoma History of autologous or allogeneic stem cell transplant Prior CD19-targeted therapy Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management History of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection Presence of any indwelling line or drain dedicated central venous access catheters, such as a Port-a-Cath or Hickman catheter, are permitted Individuals with detectable cerebrospinal fluid malignant cells, brain metastases, or active CNS lymphoma History or presence of CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment History of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment 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
Intervention Model: Single Group 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 conditioning 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. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10^8 anti-CD19 CAR T cells will be administered. | Biological: Axicabtagene Ciloleucel<br>* A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells<br>* Other names: Yescarta®;Drug: Fludarabine<br>* Administered according to package insert<br>Drug: Cyclophosphamide<br>* Administered according to package insert<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate Per the Lugano Classification as Determined by Study Investigators | Complete Response Rate (CRR): percentage of participants with CR [complete metabolic response (CMR); complete radiological response (CRR)]. CMR: positron emission tomography (PET) 5-point scale (5-PS) scores of 1 (no uptake above background), 2 (uptake ≤ mediastinum), 3 (uptake > mediastinum but ≤ liver) with/without a residual mass); no new lesions; and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow (BM). CRR: target nodes/nodal masses regressed to ≤ 1.5 cm in longest transverse diameter of lesion (LDi); no extralymphatic sites of disease; absent non-measured lesion (NMLs); organ enlargement regress to normal; no new sites; and bone marrow normal by morphology. | First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (maximum duration: 26.2 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Per the Lugano Classification as Determined by Study Investigators | ORR: percentage of participants with CR [CMR;CRR] or PR [partial metabolic response (PMR); partial radiologic response (PRR)].CMR: PET 5PS scores of 1 (no uptake above background, 2 (uptake ≤ mediastinum), 3 (uptake > mediastinum but ≤ liver) with/without a residual mass; no new lesions; no evidence of FDG-avid disease in BM. CRR:target nodes/nodal masses regressed to ≤ 1.5 cm in LDi;no extralymphatic sites of disease;absent NMLs;organ enlargement regress to normal;no new sites;bone marrow morphology normal. PMR:scores 4 (uptake moderately > liver),5 (uptake markedly > liver, new lesions) with reduced uptake compared with baseline and residual mass;no new lesions;responding disease at interim/residual disease at end of treatment (EOT).PRR: ≥ 50% decrease in sum of the product of perpendicular diameters (SPD) of up to 6 target measurable nodes and extra-nodal sites;absent/normal, regressed, but no increase of NMLs;spleen regressed by > 50% in length beyond normal;no new sites. | First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (maximum duration: 26.2 months) | 
| Duration of Response (DOR) Per the Lugano Classification | DOR is defined only for participants who experience an objective response after axicabtagene ciloleucel infusion and is the time from the first objective response to disease progression or death from any cause. Objective response is defined in outcome measure (OM) 2. | From the date of first confirmed objective response (CR or PR) to disease progression or death regardless of cause (up to approximately 26.2 months) | 
| Event-Free Survival (EFS) | EFS was defined as time from axicabtagene ciloleucel infusion date to earliest date of disease progression (Lugano classification), commencement of subsequent new anti-lymphoma therapy including stem cell transplant, or death from any cause. | First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) | 
| Progression-Free Survival (PFS) | PFS is defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per Lugano classification or death from any cause. | First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) | 
| Overall Survival (OS) | OS is defined as the time from axicabtagene ciloleucel infusion to the date of death from any cause. | First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) | 
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Treatment-Emergent Serious Adverse Events (SAE) | An AE was any untoward medical occurrence in a participant in a clinical trial participant, which did not necessarily have a causal relationship with the treatment. Treatment-emergent adverse events were defined as any adverse event with onset on or after the axicabtagene ciloleucel infusion. Serious adverse event was defined as an event that resulted in the following: death; life-threatening situation; in-patient hospitalization or prolongation of existing hospitalization; persistent or significant disability or incapacity; congenital anomaly or birth defect; and medically important event or reaction. | First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) | 
| Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Value | Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. | First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) | 
| Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Value | Grading categories were determined by CTCAE version 5.0. | First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) | 
| Relapse With Central Nervous Disease (CNS) Disease | Relapse with CNS disease was defined as the time from the axicabtagene ciloleucel infusion date to the earliest date of CNS involvement with lymphoma as determined by typical symptoms, cerebrospinal fluid (CSF) evaluation, and/or diagnostic imaging. | First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) | 
| Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood | Peak was defined as the maximum number of CAR T cells in blood measured after infusion. | From enrollment up to Month 24 | 
| Peak Serum Level of Granzyme B, Interferon-gamma (IFNg), Interleukin (IL)-2, IL-5, IL-6, IL-8 | Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4. | From enrollment up to Week 4 | 
| Peak Serum Level of C-Reactive Protein (CRP) | Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4. | From enrollment up to Week 4 | 
| Peak Serum Level of Ferritin | Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4. | From enrollment up to Week 4 | 
| Time to Peak Serum Level of Granzyme B, Interferon-gamma (IFNg), Interleukin (IL)-2, IL-5, IL-6, IL-8, CRP, and Ferritin | Time to peak is defined as the number of days from axicabtagene ciloleucel infusion to the date when the cytokine first reached the maximum post-baseline level. | From enrollment up to Week 4 |