Clinical trial NCT03391466: Study of Effectiveness of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Patients With Relapsed/Refractory Diffuse Large B Cell Lymphoma
Official title: A Phase 3, Randomized, Open-Label Study Evaluating the Efficacy of Axicabtagene Ciloleucel Versus Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma (ZUMA-7)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2018-01-05
Enrollment: 359
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two arms, SOC and experimental treatment
Primary purpose: TREATMENT

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 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Detailed description: This is a phase 3 randomized, open-label, multicenter study evaluating the efficacy of axicabtagene ciloleucel versus standard of care therapy in participants with relapsed/refractory DLBCL. Adult participants with relapsed/refractory DLBCL after first-line rituximab and anthracycline-based chemotherapy will be randomized in a 1:1 ratio to receive axicabtagene ciloleucel or standard of care second-line therapy.

Standard of care will consist of a protocol-defined, platinum-based salvage combination chemotherapy regimen followed by high-dose therapy and autologous stem cell transplant in those who respond to salvage chemotherapy. After completing the treatment period, all participants will be followed in the post-treatment follow-up period for up to 5 years. Thereafter, participants who received at least one dose of axicabtagene ciloleucel as protocol therapy will transition to a separate long term follow up (LTFU) study and complete the remainder of the 15-year follow-up assessments within KT-US-982-5968 (NCT05041309).

Eligibility criteria: Key Inclusion Criteria:

* Histologically proven large B-cell lymphoma 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 B-cell lymphoma (BCL) 2 and/or BCL6 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:

  * Anti-Cluster of Differentiation antigen (CD) 20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and
  * An anthracycline containing chemotherapy regimen.
* No known history or suspicion of central nervous system involvement by lymphoma.
* Eastern cooperative oncology group (ECOG) performance status of 0 or 1.
* Adequate bone marrow function as evidenced by:

  * Absolute neutrophil count (ANC) ≥ 1000/uL
  * Platelet ≥ 75,000/uL
  * Absolute lymphocyte count ≥ 100/uL
* Adequate renal, hepatic, cardiac, and pulmonary function as evidenced by:

  * Creatinine clearance (Cockcroft Gault) ≥ 60 mL/min.
  * Serum Alanine aminotransferase/Aspartate aminotransferase (ALT/AST) ≤ 2.5 Upper limit of normal (ULN).
  * Total bilirubin ≤ 1.5 mg/dl
  * 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.
* 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 hepatitis C virus (anti-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-CD19 or CAR-T therapy or history of prior randomization in ZUMA-7.

Note: Other protocol defined Inclusion/Exclusion criteria may apply

Primary outcomes:
measure: Event Free Survival (EFS) Per Blinded Central Assessment
timeFrame: From randomization date up to a median follow-up: 24.9 months
Secondary outcomes:
measure: Objective Response Rate (ORR) Per Blinded Central Assessment
timeFrame: From randomization date up to a median follow-up: 24.9 months
measure: Overall Survival (OS)
timeFrame: From randomization date up to a median follow-up: 47.2 months
measure: Duration of Response (DOR) Per Blinded Central Assessments
timeFrame: From the date of first confirmed objective response (CR or PR) to disease progression or death regardless of cause (Up to 37.8 months)
measure: Modified Event Free Survival (mEFS) Per Blinded Central Assessment
timeFrame: From randomization date up to a median follow-up: 24.9 months
measure: Event Free Survival Per Investigator Disease Assessments
timeFrame: From randomization date up to a median follow-up: 47.2 months
measure: Progression-Free Survival (PFS) Per Investigator Disease Assessments
timeFrame: From randomization date up to a median follow-up: 47.2 months
measure: Modified Event Free Survival (mEFS) Per Investigator Assessment
timeFrame: From randomization date up to a median follow-up: 47.2 months
measure: Change From Baseline in Global Health Status Scores
timeFrame: Baseline, Days 50, 100, and 150; Months 9, 12, 15, 18, 21 and 24
measure: Change From Baseline in EORTC QLQ-C30 Physical Functioning Score
timeFrame: Baseline, Days 50, 100, 150, Months 9, 12, 15, 18, 21 and 24
measure: Changes From Baseline in the European Quality of Life Five Dimensions Five Levels Scale (EQ-5D-5L) Index Score
timeFrame: Baseline, Days 50, 100, 150; Months 9, 12, 15, 18, 21 and 24
measure: Change From Baseline in EQ-5D-5L VAS Scale Score
timeFrame: Baseline, Days 50, 100, 150; Months 9, 12, 18, 21 and 24
measure: Number of Participants With Anti-Axicabtagene Ciloleucel Antibodies
timeFrame: From first dose of axicabtagene up to a median follow-up: 24 months
measure: Percentage of Participants Experiencing Treatment-emergent Adverse Events
timeFrame: Up to 5 years
measure: Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Santa Monica
country: United States
facility: UCLA
state: California
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Miami
country: United States
facility: University of Miami Hospital and Clinics/Sylvester Comprehensive Cancer Center
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinincs
state: Iowa
city: Kansas City
country: United States
facility: The University of Kansas Cancer Center
state: Kansas
city: Baltimore
country: United States
facility: University of Maryland, Greenbaum Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic, Patient Location
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Henry-Joyce Cancer Center
state: Tennessee
city: Houston
country: United States
facility: The University of Texas, MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Institute
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Center
state: Victoria
city: Graz
country: Austria
facility: Universitatsklinikum Graz, Division of Hematology
city: Innsbruck
country: Austria
facility: Medizinische Universitat Innsbruck, Innere Medizin V - Hamatologie und Onkologie
city: Brussels
country: Belgium
facility: Cliniques Universiaires Saint-Luc
city: Leuven
country: Belgium
facility: UZ Gasthuisberg
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Toronto
country: Canada
facility: Uninversity Health Network - Princess Margaret Cancer Center
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Center
state: Quebec
city: Halifax
country: Canada
facility: QEII Health Sciences Centre
city: Montréal
country: Canada
facility: Centre Integre Universitaire de Sante et Services Sociaux de l'Est-de-l'lle-de-Montreal / Hopital Maisonneuve-Rosemont
city: Ottawa
country: Canada
facility: The Ottawa Hospital - General Campus
city: Québec
country: Canada
facility: CHU de Quebec-Universite Laval, Hopital de L'Enfante-Jesus
city: Lille cedex
country: France
facility: CHRU de Lille - Hopital Claude Huriez
city: Paris
country: France
facility: Hopital Saint-Louis
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon-Sud - Service d'Hematologie clinique
city: Rennes
country: France
facility: Centre Hospitalier Universitaire de Rennes - Hopital Pontchaillou
city: Dresden
country: Germany
facility: Universitäts-klinikum Dresden
city: Göttingen
country: Germany
facility: Universitatsmedizin Gottingen
city: Hamburg
country: Germany
facility: Universitatsklinikum Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Würzburg
country: Germany
facility: Universitäts-klinikum Würzburg
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Bologna
country: Italy
facility: Instituto di Ematologia "L. e A. Seragnoli" - Dipartimento di Medicina Specialistica Diagnostica e Sperimentale
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele di Milano
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Uppsala
country: Sweden
facility: Uppsala Akademiska Sjukhus
city: Bellinzona
country: Switzerland
facility: IOSI, OSpedale Regionale Bellinzona e Valli
city: Zürich
country: Switzerland
facility: University Hospital Zurich
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Kite, A Gilead Company
name: Kite Study Director
role: STUDY_DIRECTOR
References:
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citation: 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.
citation: 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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citation: 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.
citation: 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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citation: Thiruvengadam SK, Hunter B, Varnavski A, Fakhri B, Kaplan L, Ai WZ, Pampaloni M, Huang CY, Martin T 3rd, Damon L, Andreadis CB. Ofatumumab, Etoposide, and Cytarabine Intensive Mobilization Regimen in Patients with High-risk Relapsed/Refractory Diffuse Large B-Cell Lymphoma Undergoing Autologous Stem Cell Transplantation. Clin Lymphoma Myeloma Leuk. 2021 Apr;21(4):246-256.e2. doi: 10.1016/j.clml.2020.11.005. Epub 2020 Nov 11.