Study of Effectiveness of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Patients With Relapsed/Refractory Diffuse Large B Cell Lymphoma

NCT03391466 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: KTE-C19-1072017-002261-22
• Study Type: interventional
• Target: 359
• Locations: 13 countries
• Sites: 71

Brief Summary

The goal of this clinical study is to assess whether axicabtagene ciloleucel therapy improves the clinical outcome compared with standard of care second-line therapy in participants with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Conditions

Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Outcome Measures

Primary Outcomes (1)

• Event Free Survival (EFS) Per Blinded Central Assessment

  EFS:Time from randomization to disease progression (PD), best response of stable disease (SD) up to Day 150, start of new anti-lymphoma therapy including stem cell transplant, or death from any cause. PD=Score 4 (uptake moderately \> liver) or 5 (uptake markedly \> liver and/or new lesions) with increased uptake from baseline; New fluorodeoxyglucose (FDG)-avid foci consistent with lymphoma rather than another etiology or in bone marrow; Individual node/lesion abnormal with longest diameter \> 1.5 cm, ≥ 50% increase from nadir; Splenic length increase \> 50% of prior increase beyond baseline or ≥ 2 cm increase if no prior splenomegaly; New/recurrent splenomegaly, progression of non-measurable lesions, new lesion, or new/recurrent bone marrow involvement. KM estimates was used for analysis.

  From randomization date up to a median follow-up: 24.9 months

Secondary Outcomes (15)

• Objective Response Rate (ORR) Per Blinded Central Assessment

  From randomization date up to a median follow-up: 24.9 months

• Overall Survival (OS)

  Up to 74.9 months

• Duration of Response (DOR) Per Blinded Central Assessments

  From the date of first confirmed objective response (CR or PR) to disease progression or death regardless of cause (Up to 37.8 months)

• Modified Event Free Survival (mEFS) Per Blinded Central Assessment

  From randomization date up to a median follow-up: 24.9 months

• EFS Per Investigator Disease Assessments

  From randomization date up to a median follow-up: 47.2 months

Study Arms (2)

Axicabtagene Ciloleucel Treatment

EXPERIMENTAL

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 antigen (CD) 19 chimeric antigen receptor (CAR) transduced autologous T cells/kg on Day 0. Participants who will achieve a partial response or complete response and subsequently experience disease progression may have an option to receive a second course of conditioning chemotherapy and axicabtagene ciloleucel.

Biological: Axicabtagene Ciloleucel; Drug: Cyclophosphamide; Drug: Fludarabine

Standard of Care Therapy

ACTIVE COMPARATOR

Participants will receive 2 or 3, 21-day cycles of second-line chemotherapy: * R-ICE:rituximab 375mg/m\^2 before chemotherapy, ifosfamide 5g/m\^2 24 hours continuous infusion (CI) on Day 2+mesna, carboplatin area under the curve (AUC)5 Day 2, maximum dose 800mg, etoposide 100mg/m\^2/day on Days 1-3; * R-ESHAP:rituximab 375mg/m\^2 Day 1, etoposide 40mg/m\^2/day IV on Days 1-4, methylprednisolone 500mg/day IV on Days 1-4 or 5, cisplatin at 25mg/m\^2/day CI Days 1-4, cytarabine 2g/m\^2 on Day 5; * R-GDP:rituximab 375mg/m\^2 Day 1 (or Day 8), gemcitabine 1g/m\^2 on Days 1 and 8, dexamethasone 40mg on Days 1-4, cisplatin 75mg/m\^2 Day 1 or carboplatin area under the curve (AUC)=5; or * R-DHAP:rituximab 375mg/m\^2 before chemotherapy, dexamethasone 40mg/day on Days 1-4, high dose cytarabine 2g/m\^2 every 12 hours for 2 doses on Day 2 following platinum, cisplatin 100mg/m\^2 24 hours CI on Day 1 or oxaliplatin 100mg/m\^2. Responders will receive high-dose therapy and autologous stem cell transplant.

Drug: Platinum-containing Salvage Chemotherapy

Interventions

Axicabtagene Ciloleucel BIOLOGICAL

Administered intravenously

Also known as: KTE-C19, axi-cel, Yescarta ®

Axicabtagene Ciloleucel Treatment

Platinum-containing Salvage Chemotherapy DRUG

Platinum-containing salvage chemotherapy (Rituximab-ifosfamide, carboplatin, etoposide (R-ICE), Rituximab-dexamethasone, cytarabine, cisplatin,oxaliplatin (R-DHAP), Rituximab-etoposide, methylprednisolone, cisplatin, cytarabine (R-ESHAP), or Rituximab-gemcitabine, dexamethasone, cisplatin/carboplatin (R-GDP) as selected by treating investigator).

Standard of Care Therapy

Cyclophosphamide DRUG

Administered intravenously

Axicabtagene Ciloleucel Treatment

Fludarabine DRUG

Administered intravenously

Axicabtagene Ciloleucel Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically proven large B-cell lymphoma (BCL) including the following types defined by World Health Organization (WHO) 2016.
• Diffuse large B-cell lymphoma (DLBCL) not otherwise specified activated B-cell/ germinal center B-cell (ABC/GCB).
• High-grade B-cell lymphoma (HGBL) with or without myelocytomatosis oncogene (MYC) and BCL 2 and/or BCL 6 rearrangement.
• DLBCL arising from follicular lymphoma (FL).
• T-cell/histiocyte rich large B-cell lymphoma.
• DLBCL associated with chronic inflammation.
• Primary cutaneous DLBCL, leg type.
• Epstein-Barr virus (EBV) + DLBCL.
• Relapsed or refractory disease after first-line chemoimmunotherapy.
• Refractory disease defined as no complete remission to first-line therapy; individuals who are intolerant to first-line therapy are excluded.
• Progressive disease (PD) as best response to first-line therapy.
• Stable disease (SD) as best response after at least 4 cycles of first-line therapy (eg, 4 cycles of R-CHOP).
• Partial response (PR) as best response after at least 6 cycles and biopsy-proven residual disease or disease progression ≤ 12 months of therapy.
• Relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven relapse ≤ 12 months of first-line therapy.
• Individuals must have received adequate first-line therapy including at a minimum:

You may not qualify if:

• History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg cervix, bladder, breast) unless disease free for at least 3 years.
• Received more than one line of therapy for DLBCL.
• History of autologous or allogeneic stem cell transplant.
• Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous antimicrobials for management.
• Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or anti-hepatitis C virus (HCV) positive. 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.
• Individuals with detectable cerebrospinal fluid malignant cells or known brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases.
• History or presence of non-malignant central nervous system (CNS) disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
• Presence of any indwelling line or drain. Dedicated central venous access catheter such as a Port-a-Cath or Hickman catheter are permitted.
• 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 diseases within 12 months of enrollment.
• History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment.
• History of autoimmune disease, requiring systemic immunosuppression and/or systemic disease modifying agents within the last 2 years.
• History of anti-Cluster of Differentiation 19 (CD19) or chimeric antigen receptor (CAR)-T therapy or history of prior randomization in ZUMA-7.

Sponsors & Collaborators

• Kite, A Gilead Company: lead

Study Sites (72)

Banner MD Anderson Cancer Center

Gilbert, Arizona, 85234, United States

Location

Mayo Clinic Hospital

Phoenix, Arizona, 85054, United States

Location

UC San Diego Moores Cancer Center

La Jolla, California, 92093, United States

Location

UCLA

Santa Monica, California, 90404, United States

Location

Stanford Cancer Institute

Stanford, California, 94305, United States

Location

University of Miami Hospital and Clinics/Sylvester Comprehensive Cancer Center

Miami, Florida, 33136, United States

Location

Moffitt Cancer Center

Tampa, Florida, 12902, United States

Location

Northwestern University

Chicago, Illinois, 60612, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

University of Iowa Hospitals and Clinincs

Iowa City, Iowa, 52242, United States

Location

The University of Kansas Cancer Center

Kansas City, Kansas, 66160, United States

Location

University of Maryland, Greenbaum Comprehensive Cancer Center

Baltimore, Maryland, 21201, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Mayo Clinic, Patient Location

Rochester, Minnesota, 55905, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63130, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10021, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Henry-Joyce Cancer Center

Nashville, Tennessee, 37232, United States

Location

The University of Texas, MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Utah, Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

Swedish Cancer Institute

Seattle, Washington, 98104, United States

Location

Peter MacCallum Cancer Center

Melbourne, Victoria, 3000, Australia

Location

Universitatsklinikum Graz, Division of Hematology

Graz, 6020, Austria

Location

Medizinische Universitat Innsbruck, Innere Medizin V - Hamatologie und Onkologie

Innsbruck, 6020, Austria

Location

Cliniques Universiaires Saint-Luc

Brussels, Belgium

Location

UZ Gasthuisberg

Leuven, Belgium

Location

Vancouver General Hospital

Vancouver, British Columbia, Canada

Location

CancerCare Manitoba

Winnipeg, Manitoba, R3E 0V9, Canada

Location

Uninversity Health Network - Princess Margaret Cancer Center

Toronto, Ontario, M5G 2M9, Canada

Location

McGill University Health Center

Montreal, Quebec, H4A 3J1, Canada

Location

QEII Health Sciences Centre

Halifax, B3H 2Y9, Canada

Location

Centre Integre Universitaire de Sante et Services Sociaux de l'Est-de-l'lle-de-Montreal / Hopital Maisonneuve-Rosemont

Montreal, H1T 2M4, Canada

Location

The Ottawa Hospital - General Campus

Ottawa, K1H 8L6, Canada

Location

CHU de Quebec-Universite Laval, Hopital de L'Enfante-Jesus

Québec, G1J 1Z4, Canada

Location

CHRU de Lille - Hopital Claude Huriez

Lille, 59037, France

Location

Hopital Saint-Louis

Paris, 75010, France

Location

Centre Hospitalier Lyon-Sud - Service d'Hematologie clinique

Pierre-Bénite, 69495, France

Location

Centre Hospitalier Universitaire de Rennes - Hopital Pontchaillou

Rennes, 35033, France

Location

Universitäts-klinikum Dresden

Dresden, 01307, Germany

Location

Universitatsmedizin Gottingen

Göttingen, 37075, Germany

Location

Universitatsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

Location

Universitäts-klinikum Würzburg

Würzburg, 97080, Germany

Location

Tel Aviv Sourasky Medical Center

Tel Aviv, 6423906, Israel

Location

Instituto di Ematologia "L. e A. Seragnoli" - Dipartimento di Medicina Specialistica Diagnostica e Sperimentale

Bologna, 40138, Italy

Location

IRCCS Ospedale San Raffaele di Milano

Milan, 20132, Italy

Location

Academic Medical Center

Amsterdam, 1105 AZ, Netherlands

Location

University Medical Center Groningen

Groningen, 9700 RB, Netherlands

Location

Erasmus Medical Center

Rotterdam, 3011PL, Netherlands

Location

University Medical Center Utrecht

Utrecht, Netherlands

Location

Hospital Clinic de Barcelona

Barcelona, 08036, Spain

Location

Institut Catala d'Oncologia

Barcelona, 08908, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Clinica Universidad de Navarra

Pamplona, 31008, Spain

Location

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

Location

Uppsala Akademiska Sjukhus

Uppsala, 75185, Sweden

Location

IOSI, OSpedale Regionale Bellinzona e Valli

Bellinzona, 6500, Switzerland

Location

University Hospital Zurich

Zurich, 8091, Switzerland

Location

University Hospitals Birmingham NHS Foundation Trust

Birmingham, B15 2GW, United Kingdom

Location

Barts Health NHS Trust

London, EC1A 7BE, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, NW3 2QG, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (23)

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  PMID: 35839452 BACKGROUND

• Kersten MJ, Qiao Y, Shah R, Solem C, Snider JT, To C, Cheng P, Spooner C, Perales MA. Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma. Transplant Cell Ther. 2023 May;29(5):335.e1-335.e8. doi: 10.1016/j.jtct.2023.01.008. Epub 2023 Jan 14.

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• Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Munoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. doi: 10.1056/NEJMoa2116133. Epub 2021 Dec 11.

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• Westin JR, Locke FL, Dickinson M, Ghobadi A, Elsawy M, van Meerten T, Miklos DB, Ulrickson ML, Perales MA, Farooq U, Wannesson L, Leslie L, Kersten MJ, Jacobson CA, Pagel JM, Wulf G, Johnston P, Rapoport AP, Du L, Vardhanabhuti S, Filosto S, Shah J, Snider JT, Cheng P, To C, Oluwole OO, Sureda A. Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma. Clin Cancer Res. 2023 May 15;29(10):1894-1905. doi: 10.1158/1078-0432.CCR-22-3136.

  PMID: 36999993 BACKGROUND

• Westin JR, Oluwole OO, Kersten MJ, Miklos DB, Perales MA, Ghobadi A, Rapoport AP, Sureda A, Jacobson CA, Farooq U, van Meerten T, Ulrickson M, Elsawy M, Leslie LA, Chaganti S, Dickinson M, Dorritie K, Reagan PM, McGuirk J, Song KW, Riedell PA, Minnema MC, Yang Y, Vardhanabhuti S, Filosto S, Cheng P, Shahani SA, Schupp M, To C, Locke FL; ZUMA-7 Investigators; Kite Members. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N Engl J Med. 2023 Jul 13;389(2):148-157. doi: 10.1056/NEJMoa2301665. Epub 2023 Jun 5.

  PMID: 37272527 BACKGROUND

• Filosto S, Vardhanabhuti S, Canales M, Poiré X, Lekakis LJ, de Vos S, et al. Product attributes of axicabtagene ciloleucel (axi-cel) that associate differentially with efficacy and toxicity in second-line large B-cell lymphoma. Cancer Res. 2022;82(12_Supplement):CT004.

  BACKGROUND

• Ghobadi A, Munoz J, Westin J, Locke FL, Miklos DB, Rapoport AP, et al. Outcomes of Subsequent Anti-Lymphoma Therapies in Patients (Pts) with Large B-Cell Lymphoma (LBCL) Treated with Axicabtagene Ciloleucel (Axi-Cel) or Standard of Care (SOC) in the Second-Line (2L) ZUMA-7 Study. Blood. 2022;140(Supplement 1):1595-1597.

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• Locke FL, Oluwole OO, Kuruvilla J, Thieblemont C, Morschhauser F, Salles G, et al. Association of Metabolic Tumor Volume (MTV) and Clinical Outcomes in Second-Line (2L) Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL) Following Axicabtagene Ciloleucel (Axi-Cel) Versus Standard-of-Care (SOC) Therapy in ZUMA-7. Blood. 2022;140(Supplement 1):638-640.

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• Chartier M, Filosto S, Peyret T, Chiney M, Milletti F, Budka J, Ndi A, Dong J, Vardhanabhuti S, Mao D, Duffull S, Dodds M, Shen R. Investigating the Influence of Covariates on Axicabtagene Ciloleucel (axi-cel) Kinetics in Patients with Non-Hodgkin's Lymphoma. Clin Pharmacokinet. 2024 Sep;63(9):1283-1299. doi: 10.1007/s40262-024-01413-z. Epub 2024 Sep 6.

  PMID: 39240498 BACKGROUND

• Filosto S, Vardhanabhuti S, Canales MA, Poire X, Lekakis LJ, de Vos S, Portell CA, Wang Z, To C, Schupp M, Poddar S, Trinh T, Warren CM, Aguilar EG, Budka J, Cheng P, Chou J, Bot A, Shen RR, Westin JR. Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7). Blood Cancer Discov. 2024 Jan 8;5(1):21-33. doi: 10.1158/2643-3230.BCD-23-0112.

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• Ghobadi A, Munoz J, Westin JR, Locke FL, Miklos DB, Rapoport AP, Perales MA, Reagan PM, McGuirk J, Jacobson CA, Kersten MJ, Avivi I, Peng A, Schupp M, To C, Oluwole OO. Outcomes of subsequent antilymphoma therapies after second-line axicabtagene ciloleucel or standard of care in ZUMA-7. Blood Adv. 2024 Jun 11;8(11):2982-2990. doi: 10.1182/bloodadvances.2023011532.

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Related Links

• Gilead Clinical Trials Website

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

axicabtagene ciloleucel; Cyclophosphamide; fludarabine

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Medical Information
• Organization: Kite, A Gilead Company

medinfo@kitepharma.com

844-454-5483 (1-844-454-KITE)

Study Officials

• Kite Study Director

  Kite, A Gilead Company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 21, 2017
• First Posted: January 5, 2018
• Study Start: January 25, 2018
• Primary Completion: March 18, 2021
• Study Completion: November 25, 2024
• Last Updated: December 1, 2025
• Results First Posted: March 7, 2024

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: 18 months after study completion
• Access Criteria: A secured external environment with username, password, and RSA code.

Locations

IL (1); DE (5); ES (5); SE (1); IT (2); NL (4); CH (2); BE (2); US (30); AU (2); CA (8); FR (4); GB (5)