Study to Evaluate the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma (ZUMA-12)

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)

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.

Study Overview

• Status: Completed
• Conditions: B-cell Lymphoma
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Axicabtagene Ciloleucel

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
• France
  • Paris, France, 75475
    • Hôpital Saint Louis
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner Health MD Anderson Cancer Center
  • California
    • Duarte, California, United States, 91010-3012
      • City of Hope
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center and Research Institute
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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) (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Axicabtagene Ciloleucel; 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. Participants who achieve partial response or complete response and subsequently experience disease progression will have an option to receive second course of conditioning chemotherapy therapy and axicabtagene ciloleucel. Participants will receive the same axicabtagene ciloleucel regimen as the original target dose anytime during the study.

Drug: Cyclophosphamide; Administered according to package insert; Drug: Fludarabine; Administered according to package insert; Biological: Axicabtagene Ciloleucel; A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells; Other Names: Yescarta®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR) Rate Per the Lugano Classification as Determined by Study Investigators	CR Rate is the 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.	Up to 4 years

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.	Up to 4 years
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 (PD) (Lugano classification) or death from any cause. Objective response is defined in outcome measure (OM) 2. PD is defined as a score 4 (uptake moderately > liver) or 5 (uptake markedly >liver and/or new lesions) with an increase in intensity of uptake from baseline; new FDG-avid foci consistent with lymphoma at interim or end of treatment assessment; new FDG-avid foci consistent with lymphoma rather than another etiology (eg, infection, inflammation); new or recurrent FDG-avid foci in bone marrow. Kaplan-Meier (KM) estimates were used for analysis.	Up to 4 years
Event-Free Survival (EFS)	EFS was defined as the 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. PD is defined in OM 3. KM estimates were used for analysis.	Up to 4 years
Progression-Free Survival (PFS)	PFS was defined as the time from axicabtagene ciloleucel infusion date to the date of disease progression per Lugano classification or death from any cause. PD is defined in OM 3. KM estimates were used for analysis.	Up to 4 years
Overall Survival (OS)	OS is defined as the time from axicabtagene ciloleucel infusion to the date of death from any cause. KM estimates were used for analysis.	Up to 4 years
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) 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.	Up to 2 years
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.	Up to 2 years
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.	Up to 2 years
Relapse With Central Nervous System (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.	Up to 4 years
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.	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.	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.	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.	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.	Up to Week 4

Collaborators and Investigators

• Sponsor: Kite, A Gilead Company
• Investigators: Study Director: Kite Study Director, Kite, A Gilead Company

Publications and helpful links

General Publications

• Neelapu SS, Dickinson M, Munoz J, Ulrickson ML, Thieblemont C, Oluwole OO, et al. 739 Primary Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) As First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma (LBCL) [Abstract]. 63rd American Society of Hematology (ASH) Annual Meeting and Exposition; 2021 11-14 December.
• Neelapu SS, Dickinson M, Ulrickson ML, Oluwole OO, Herrera AF, Thieblemont C, et al. 405 Interim Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) as First-Line Therapy in Patients (Pts) With High-Risk Large B-Cell Lymphoma (LBCL) [Abstract]. 62nd American Society of Hematology (ASH) Annual Meeting and Exposition Virtual; 2020 05-08 December.
• Neelapu SS, Chavez JC, Lin Y, Munoz J, Ujjani CS, Riedell P, et al. ZUMA-12: A Phase 2 Multicenter Study of Axicabtagene Ciloleucel (Axi-Cel) as a First-Line Therapy in Patients (Pts) with High-Risk Large B-Cell Lymphoma (LBCL) [Abstract]. J Clin Oncol 2019;37 (15).
• Neelapu SS, Dickinson M, Munoz J, Ulrickson ML, Thieblemont C, Oluwole OO, Herrera AF, Ujjani CS, Lin Y, Riedell PA, Kekre N, de Vos S, Lui C, Milletti F, Dong J, Xu H, Chavez JC. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022 Apr;28(4):735-742. doi: 10.1038/s41591-022-01731-4. Epub 2022 Mar 21.
• Chavez JC, Dickinson M, Munoz JL, Ulrickson ML, Thieblemont C, Oluwole OO, et al. 3-Year Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) As First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma (LBCL). Blood 2023;142 (Supplement 1):894-7

Helpful Links

• Gilead Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2019
• Primary Completion (Actual): October 12, 2023
• Study Completion (Actual): October 12, 2023

Study Registration Dates

• First Submitted: November 29, 2018
• First Submitted That Met QC Criteria: November 29, 2018
• First Posted (Actual): December 3, 2018

Study Record Updates

• Last Update Posted (Actual): December 4, 2024
• Last Update Submitted That Met QC Criteria: November 13, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Axicabtagene ciloleucel; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: KTE-C19-112; 2019-002291-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No