Study to Compare Axicabtagene Ciloleucel With Standard of Care Therapy as First-line Treatment in Participants With High-risk Large B-cell Lymphoma (ZUMA-23)

• ClinicalTrials.gov Identifier: NCT05605899
• Recruitment Status: Recruiting
• First Posted: November 4, 2022
• Last Update Posted: April 25, 2024
• Sponsor: Kite, A Gilead Company
• Information provided by (Responsible Party): Gilead Sciences ( Kite, A Gilead Company )

Tracking Information

• First Submitted Date: October 31, 2022
• First Posted Date: November 4, 2022
• Last Update Posted Date: April 25, 2024
• Actual Study Start Date: February 10, 2023
• Estimated Primary Completion Date: March 2031 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 2, 2024)

Event-free Survival (EFS) by Blinded Central Assessment [ Time Frame: Up to 5 years ]

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.

Original Primary Outcome Measures (submitted: October 31, 2022)

Event-free Survival (EFS) by Central Assessment [ Time Frame: Up to 5 years ]

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.

Current Secondary Outcome Measures (submitted: April 2, 2024)

• Progression-free Survival (PFS) by Blinded Central Assessment [ Time Frame: Up to 5 years ]
  PFS is defined as the time from randomization to disease progression or death due to any cause.
• Overall Survival [ Time Frame: Up to 5 years ]
  OS is defined as the time from randomization to death due to any cause.
• PFS by Investigator Assessment [ Time Frame: Up to 5 years ]
  PFS is defined as the time from randomization to disease progression or death due to any cause.
• Complete Response (CR) Rate by Blinded Central Assessment [ Time Frame: Up to 5 years ]
  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.
• Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths [ Time Frame: First dose date up to 5 years plus 30 days ]
• Percentage of Participants Experiencing Clinically Significant Changes in Safety Laboratory Values [ Time Frame: 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 [ Time Frame: Baseline, Month 18 ]
  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.
• 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 [ Time Frame: Baseline, Month 18 ]
  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.
• Change From Baseline in the European Quality of Life Five Dimensions Five Levels Questionnaire (EQ-5D-5L) Score [ Time Frame: Baseline, Month 18 ]
  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.

Original Secondary Outcome Measures (submitted: October 31, 2022)

• Progression-free Survival (PFS) by Investigator Assessment [ Time Frame: Up to 5 years ]
  PFS is defined as the time from randomization to disease progression or death due to any cause.
• Overall Survival [ Time Frame: Up to 5 years ]
  OS is defined as the time from randomization to death due to any cause.
• PFS by Central Assessment [ Time Frame: Up to 5 years ]
  PFS is defined as the time from randomization to disease progression or death due to any cause.
• Complete Response (CR) Rate by Central Assessment [ Time Frame: Up to 5 years ]
  CR rate is defined as the proportion of participants who have achieved CR per Lungano classification after treatment completion and prior to subsequent new off protocol anti-lymphoma therapy.
• Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths [ Time Frame: First dose date up to 5 years plus 30 days ]
• Percentage of Participants Experiencing Clinically Significant Changes in Safety Laboratory Values [ Time Frame: 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 [ Time Frame: Baseline, Month 18 ]
  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.
• 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 [ Time Frame: Baseline, Month 18 ]
  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.
• Change From Baseline in the European Quality of Life Five Dimensions Five Levels Questionnaire (EQ-5D-5L) Score [ Time Frame: Baseline, Month 18 ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Compare Axicabtagene Ciloleucel With Standard of Care Therapy as First-line Treatment in Participants With High-risk Large B-cell Lymphoma
• Official Title: 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)
• Brief Summary: 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: Five years after randomization, 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: High-risk Large B-cell Lymphoma (LBCL)

Intervention

• Biological: Axicabtagene Ciloleucel
  A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells
  Other Names:

  • Yescarta®
  • Axi-cel
• Drug: Cyclophosphamide
  Administered intravenously
• Drug: Fludarabine
  Administered intravenously
• Drug: Etoposide
  Administered intravenously
• Drug: Rituximab
  Administered intravenously
• Drug: Doxorubicin
  Administered intravenously
• Drug: Vincristine
  Administered intravenously
• Drug: Prednisone
  Administered orally

Study Arms

• Experimental: Axicabtagene Ciloleucel
  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.
  Interventions:

  • Biological: Axicabtagene Ciloleucel
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
• Active Comparator: Standard of Care Therapy

  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
  Interventions:

  • Drug: Cyclophosphamide
  • Drug: Etoposide
  • Drug: Rituximab
  • Drug: Doxorubicin
  • Drug: Vincristine
  • Drug: Prednisone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 31, 2022): 300
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2031
• Estimated Primary Completion Date: March 2031 (Final data collection date for primary outcome measure)

Eligibility Criteria

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
  • History of Richter's transformation of chronic lymphocytic leukemia
• 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 or residual toxicities from prior therapies 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Medical Information; 844-454-5483(1-844-454-KITE); medinfo@kitepharma.com

• Listed Location Countries: Australia, Austria, Canada, France, Germany, Italy, Netherlands, Portugal, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT05605899
• Other Study ID Numbers: KT-US-484-0136; 2022-501489-24-00 ( Other Identifier: European Medicines Agency )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Gilead Sciences ( Kite, A Gilead Company )
• Original Responsible Party: Same as current
• Current Study Sponsor: Kite, A Gilead Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Kite Study Director; Kite, A Gilead Company

• PRS Account: Gilead Sciences
• Verification Date: April 2024