Study Evaluating the Safety and Efficacy of KTE-C19 in Adult Participants With Refractory Aggressive Non-Hodgkin Lymphoma (ZUMA-1)

A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma

This study will be separated into 3 distinct phases designated as the Phase 1 study, Phase 2 pivotal study (Cohort 1 and Cohort 2), and Phase 2 safety management study (Cohort 3 and Cohort 4, Cohort 5 and Cohort 6).

The primary objectives of this study are:

• Phase 1 Study: Evaluate the safety of axicabtagene ciloleucel regimens
• Phase 2 Pivotal Study; Evaluate the efficacy of axicabtagene ciloleucel
• Phase 2 Safety Management Study: Assess the impact of prophylactic regimens or earlier interventions on the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities

Subjects who received an infusion of KTE-C19 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: Relapsed Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B Cell Lymphoma (DLBCL); Transformed Follicular Lymphoma (TFL); Primary Mediastinal B-cell Lymphoma (PMBCL); High Grade B-cell Lymphoma (HGBCL)
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Axicabtagene Ciloleucel

• Study Type: Interventional
• Enrollment (Actual): 307
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret
• France
  • Paris, France, 75475
    • Hopital Saint Louis
  • Pessac, France, 44035
    • Hôpital Haut-Lévêque
  • Rennes, France, 35033
    • CHU de Rennes
• Germany
  • Dresden, Germany, 01307
    • Universitatsklinik Dresden
  • Essen, Germany, 45147
    • University Hospital of Essen
  • Würzburg, Germany, 97080
    • Universitaetsklinikum Wuerzburg
• Israel
  • Tel Aviv, Israel, 64239
    • Tel Aviv Souraski Medical Center
• Netherlands
  • Amsterdam, Netherlands
    • Academisch Medisch Centrum
  • Groningen, Netherlands, 9700 RB
    • University Medical Center Groningen
  • Rotterdam, Netherlands, 3015 CE
    • Erasmus MC
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
  • California
    • Duarte, California, United States, 91010-3012
      • City of Hope
    • La Jolla, California, United States, 92093-0820
      • University of California San Diego (UCSD)
    • Palo Alto, California, United States, 94305
      • Stanford University
    • Santa Monica, California, United States, 90404
      • University of California Los Angeles (UCLA)
  • Colorado
    • Denver, Colorado, United States, 80218
      • Sarah Cannon - Denver
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nebraska
    • Omaha, Nebraska, United States, 68198-7680
      • University of Nebraska
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic - Taussig Cancer Institute
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon - Tennesee
  • Texas
    • Houston, Texas, United States, 77030-4000
      • MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • Sarah Cannon-Methodist Healthcare System - San Antonio

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria

1. Histologically confirmed:

   • Diffuse Large B Cell Lymphoma (DLBCL)
   • Primary Mediastinal Large B Cell Lymphoma (PMBCL)
   • Transformation Follicular Lymphoma (TFL)
   • High grade B-cell lymphoma (HGBCL)

2. Chemotherapy-refractory disease, defined as one of more of the following:

   • No response to last line of therapy i. Progressive disease (PD) as best response to most recent therapy regimen ii. Stable disease (SD) as best response to most recent therapy with duration no longer than 6 month from last dose of therapy OR
   • Refractory post-autologous stem cell transplant (ASCT) i. Disease progression or relapsed less than or equal to 12 months of ASCT (must have biopsy proven recurrence in relapsed individuals) ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy

3. Individuals must have received adequate prior therapy including at a minimum:

   • anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20-negative and
   • an anthracycline containing chemotherapy regimen
   • for individual with transformed FL must have chemorefractory disease after transformation to DLBCL.
4. At least one measurable lesion per revised IWG Response Criteria
5. Eastern cooperative oncology group (ECOG) performance status of 0 or 1
6. Absolute neutrophil count (ANC) ≥ 1000/uL
7. Absolute lymphocyte count ≥ 100/uL
8. Platelet count ≥ 75,000/uL

9. Adequate renal, hepatic, pulmonary and cardiac function defined as:

   • Creatinine clearance (as estimated by Cockcroft Gault) > 60 mL/min
   • Serum alanine aminotransferase (ALT)/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 pleural effusion
   • Baseline oxygen saturation >92% on room air
10. All individuals or legally appointed representatives/caregivers, must personally sign and date the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved consent form before initiating any study specific procedures or activities.
11. Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL, and HGBCL after two systemic lines of therapy

Key Exclusion Criteria

1. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years
2. History of allogeneic stem cell transplantation
3. Prior CAR therapy or other genetically modified T cell therapy
4. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment
5. History of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection. Individuals with history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines
6. Individuals with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma, cerebrospinal fluid malignant cells or brain metastases
7. History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement

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; A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, axicabtagene ciloleucel.	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 administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.; Other Names: Yescarta®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1 Study: Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs)	DLT was defined as axicabtagene ciloleucel-related events with onset within first 30 days following infusion: Grade (GR) 4 neutropenia lasting > 21 days and GR 4 thrombocytopenia lasting > 35 days from day of cell transfer;; Any axicabtagene ciloleucel-related AE requiring intubation;; All other GR 3 toxicities lasting > 3 days and all GR 4 toxicities, with exception of following conditions which were not considered DLTs: aphasia/dysphasia or confusion/cognitive disturbance which resolved to GR ≤ 1 within 2 weeks and to baseline within 4 weeks; fever GR 3; myelosuppression defined as lymphopenia, decreased hemoglobin, neutropenia and thrombocytopenia unless neutropenia and thrombocytopenia met DLT definition described above; immediate hypersensitivity reactions occurring within 2 hours of cell infusion that were reversible to a ≤ GR 2 within 24 hours of cell administration with standard therapy; hypogammaglobulinemia GR 3 or 4.	First infusion date of axicabtagene ciloleucel up to 30 days
Phase 2 Pivotal Study (Cohorts 1 and 2): Overall Response Rate (ORR) as Assessed by Investigator Per Revised International Working Group (IWG) Response Criteria for Malignant Lymphoma	ORR was defined as the percentage of participants achieving either a complete response (CR) or a partial response (PR), as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; > 50% decrease in the greatest transverse diameter for single nodules. 95% confidence interval (CI) was calculated by Clopper-Pearson method.	First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months)
Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades	TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or continuous venovenous hemodialysis (CVVHD), and Grade 5: Death. Neurologic toxicities were graded by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.	First infusion date of axicabtagene ciloleucel to the data cutoff of 26 April 2018 (maximum: 35 months)
Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades	TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.	First infusion date of axicabtagene ciloleucel to the data cutoff of 06 May 2019 (maximum: 47.5 months)
Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades	TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.	First infusion date of axicabtagene ciloleucel to the data cutoff of 10 September 2020 (maximum: 64 months)
Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades	TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.	First infusion date of axicabtagene ciloleucel to the data cutoff of 16 June 2020 (maximum: 61 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma	Among participants who experience an objective response (OR), DOR was defined as the date of their first objective response (CR or PR which was subsequently confirmed) to disease progression per the revised IWG Response Criteria for Malignant Lymphoma or death regardless of cause. CR and PR as defined in outcome measure 2. Disease progression (PD) was defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. Kaplan-Meier (KM) estimates was used for analyses.	First OR to data cutoff date of 27 Jan 2017, 26 Apr 2018, 6 May 2019, 10 Sep 2010, and 16 Jun 2020 for Cohorts 1 and 2, 3, 4, 5, and 6 respectively (median duration: 5.3, 4.9, 11.1, 5.2, 11.4, and 5.8 months for Cohorts 1, 2, 3, 4, 5, and 6 respectively)
Phase 1 Study: ORR as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma	ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; > 50% decrease in the greatest transverse diameter for single nodules.	First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months)
Phase 2 Pivotal Study (Cohorts 1 and 2): ORR Per Independent Radiological Review Committee (IRRC)	ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; > 50% decrease in the greatest transverse diameter for single nodules. 95% CI was calculated by Clopper-Pearson method.	First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months)
Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator Per the Revised IWG Response Criteria for Malignant Lymphoma	ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; > 50% decrease in the greatest transverse diameter for single nodules. 95% CI was calculated by Clopper-Pearson method.	First infusion date of axicabtagene ciloleucel to the data cutoff date of 26 Apr 2018, 06 May 2019, 10 Sep 2020, and 16 Jun 2020 for Cohorts 3, 4, 5, and 6 respectively (maximum: 35, 47.5, 64, and 61 months for Cohorts 3, 4, 5, and 6 respectively)
Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma	PFS was defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per the revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death from any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. Disease progression was defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. KM estimates was used for analyses.	First infusion date to PD or death or data cutoff date 27 Jan 2017, 26 Apr 2018, 06 May 2019, 10 Sep 2020, and 16 Jun 2020 for Cohorts 1 and 2, 3, 4, 5, 6 respectively (maximum: 20, 35, 47.5, 64, and 61 months for Cohorts 1 and 2, 3, 4, 5, 6 respectively)
Phase 2: Overall Survival (OS)	OS was defined as the time from axicabtagene ciloleucel infusion to the date of death. Participants who did not die by the analysis data cutoff date were censored at their last contact date. KM estimates was used for analyses.	First infusion date to the death or data cutoff date of 27 Jan 2017, 26 Apr 2018, 6 May 2019, 10 Sep 2020, and 16 Jun 2020 for Cohorts 1 and 2, 3, 4, 5, 6 respectively (maximum: 20, 35, 47.5, 64, and 61 months for Cohorts 1 and 2, 3, 4, 5, 6 respectively)
Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC Per Cheson 2007	Among participants who experience an objective response, DOR was defined as the date of their first objective response (CR or PR which was subsequently confirmed) to PD per the revised IWG Response Criteria for Malignant Lymphoma or death regardless of cause. CR and PR as defined in outcome measure 2. PD was defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. Kaplan-Meier (KM) estimates was used for analyses.	First objective response to the data cutoff date of 27 January 2017 (maximum: 20 months)
Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007	The best overall response for each participant was based on the assessments of response (CR, PR, stable disease [SD], PD, and not done [ND]) made by the the IRRC using IWG 2007 criteria (Cheson et al, 2007). CR and PR as defined in outcome measure 2. PD defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Percentage of participants with best overall response of CR, PR, SD, PD, and ND was reported.	First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months)
Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC Per Cheson 2007	PFS was defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per the revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death from any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. PD defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. KM estimates was used for analyses.	First infusion date of axicabtagene ciloleucel to the date of disease progression or death from any cause or the data cutoff date of 27 January 2017 (maximum: 20 months)
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)	An adverse event was defined as any untoward medical occurrence in a clinical trial participants. The event did not necessarily have a relationship with study treatment. Adverse events included worsening of a pre-existing medical condition. Worsening indicated that the pre-existing medical condition had increased in severity, frequency, and/or duration or had an association with a worse outcome. A pre-existing condition that had not worsened during the study or involved an intervention such as elective cosmetic surgery or a medical procedure while on study, was not considered an adverse event. TEAE was defined as any AE with onset on or after the start of treatment.	First infusion date to data cutoff 27 Jan 2017 (Phase 1,Cohorts 1,2), 26 Apr 2018, 6 May 2019, 10 Sep 2020, 16 Jun 2020 for Cohorts 3,4,5,6 respectively (maximum: 20 months for Phase 1,Cohorts 1,2; 35, 47.5, 64, 61 months for Cohorts 3,4,5,6 respectively)
Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 4 and Grade 3 or Higher Resulting From Increased Parameter Value	Grading categories were determined by CTCAE version 4.03. Shifts to Grade 3 or higher has been reported for Phase 2 Cohort 3. For Phase 1 and all other cohorts of Phase 2, shifts to Grade 4 has been reported.	First infusion date to data cutoff 27 Jan 2017 (Phase 1,Cohorts 1,2), 26 Apr 2018, 6 May 2019, 10 Sep 2020, 16 Jun 2020 for Cohorts 3,4,5,6 respectively (maximum: 20 months for Phase 1,Cohorts 1,2; 35, 47.5, 64, 61 months for Cohorts 3,4,5,6 respectively)
Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 4 and Grade 3 or Higher Resulting From Decreased Parameter Value	Grading categories were determined by CTCAE version 4.03. Shifts to Grade 3 or higher has been reported for Phase 2 Cohort 3. For Phase 1 and all other cohorts of Phase 2, shifts to Grade 4 has been reported.	First infusion date to data cutoff 27 Jan 2017 (Phase 1,Cohorts 1,2), 26 Apr 2018, 6 May 2019, 10 Sep 2020, 16 Jun 2020 for Cohorts 3,4,5,6 respectively (maximum: 20 months for Phase 1,Cohorts 1,2; 35, 47.5, 64, 61 months for Cohorts 3,4,5,6 respectively)
Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies		First infusion date to data cutoff 27 Jan 2017 (Phase 1,Cohorts 1,2), 26 Apr 2018, 6 May 2019, 10 Sep 2020, 16 Jun 2020 for Cohorts 3,4,5,6 respectively (maximum: 20 months for Phase 1,Cohorts 1,2; 35, 47.5, 64, 61 months for Cohorts 3,4,5,6 respectively)
Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood	Peak was defined as the maximum number of CAR T cells measured post-infusion.	Enrollment up to Month 6
Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3)	Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: interferon-gamma induced protein 10 (IP-10), ferritin, granzyme B, intercellular adhesion molecule (ICAM-1), interferon-gamma (IFN-gamma), interleukin-1 receptor antagonist (IL-1RA), IL-2, interleukin-2 receptor alpha (IL-2 R alpha), IL-6, IL-7, IL-8, IL-10, IL-15, perforin, tumor necrosis factor alpha (TNF alpha), and vascular cell adhesion molecule- 1 (VCAM-1).	Enrollment up to Week 4
Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6)	Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: IP-10, granzyme B, IFN-gamma, IL-1 RA, IL-2, IL-6, IL-7, IL-8, IL-10, IL-15, TNF alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF).	Enrollment up to Week 4
Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6)	Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1.	Enrollment up to Week 4
Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum	Peak was defined as the maximum post-baseline level of the cytokine.	Enrollment up to Week 4
Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2)	Peak was defined as the maximum post-baseline level of the cytokine.	Enrollment up to Week 4
Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 2 Cohort 3)	Peak was defined as the maximum post-baseline level of the cytokine.	Enrollment up to Week 4
Percentage of Participants With Positive Replication Competent Retrovirus (RCR)	RCR was analyzed in blood samples by central laboratory. Because axicabtagene ciloleucel comprised retroviral vector transduced T cells, the presence of RCR in the blood of treated participants was reported.	Day 0 (pre-infusion) to data cutoff 27 Jan 2017 (Phase 1,Cohorts 1,2), 26 Apr 2018, 6 May 2019, 10 Sep 2020, 16 Jun 2020 for Cohorts 3,4,5,6 respectively (maximum:20 months for Phase 1,Cohorts 1,2; 35, 47.5, 64, 61 months for Cohorts 3,4,5,6 respectively)
Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score	EQ-5D is a self-reported questionnaire used for assessing the overall health status of a participant scoring 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension was divided into 5 levels of severity: "No problem", "Slight problems", "Moderate problems", "Severe problems", and "Extreme problems (unable to perform)". EQ-5D health states, defined by the EQ-5D descriptive system, are converted into a single summary index by applying a formula that attaches values (also called QOL weights or QOL utilities) to each of the levels in each dimension. EQ-5D Summary Index values range from -0.11 (worst health state) to 1.00 (perfect health state).	Baseline, Week 4, Month 3, and Month 6
Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score	EQ-5D is a self-reported questionnaire used for assessing the overall health status of a participant. The EQ-5D-VAS records the participant's self-rated health on a vertical visual analogue scale and is asked to make a global assessment of their current state of health with 0 indicating the worst health they can imagine and 100 indicating the best health they can imagine.	Baseline, Week 4, Month 3, and Month 6

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
• Westin JR, Kersten MJ, Salles G, Abramson JS, Schuster SJ, Locke FL, Andreadis C. Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed/refractory aggressive B-cell lymphomas: Observations from the JULIET, ZUMA-1, and TRANSCEND trials. Am J Hematol. 2021 Oct 1;96(10):1295-1312. doi: 10.1002/ajh.26301. Epub 2021 Aug 13.
• Maloney DG, Kuruvilla J, Liu FF, Kostic A, Kim Y, Bonner A, Zhang Y, Fox CP, Cartron G. Matching-adjusted indirect treatment comparison of liso-cel versus axi-cel in relapsed or refractory large B cell lymphoma. J Hematol Oncol. 2021 Sep 8;14(1):140. doi: 10.1186/s13045-021-01144-9.
• Topp MS, van Meerten T, Wermke M et al. Preliminary Results of Earlier Steroid Use with Axicabtagene Ciloleucel in Patients With Relapsed/Refractory Large B Cell Lymphoma. Poster presented at the American Society of Presented at: American Society of Clinical Oncology Annual Meeting. May 31-June 4, 2019; Chicago, Illinois; Abstract 7558.
• Topp, M, van Meerten T, Houot R, et al. (2019). Earlier Steroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Large B Cell Lymphoma. Blood (ASH Annual Meeting Abstracts) 134(Suppl 1): 243. Abstract 626.
• Abstract: Oluwole OO, et al. Prophylactic corticosteroid use with axicabtagene ciloleucel in patients with relapsed/refractory large B-cell lymphoma. Transplantation and Cellular Therapy 2021.
• Oluwole OO, Bouabdallah K, Munoz J, De Guibert S, Vose JM, Bartlett NL, Lin Y, Deol A, McSweeney PA, Goy AH, Kersten MJ, Jacobson CA, Farooq U, Minnema MC, Thieblemont C, Timmerman JM, Stiff P, Avivi I, Tzachanis D, Kim JJ, Bashir Z, McLeroy J, Zheng Y, Rossi JM, Johnson L, Goyal L, van Meerten T. Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma. Br J Haematol. 2021 Aug;194(4):690-700. doi: 10.1111/bjh.17527. Epub 2021 Jul 22.
• Santa Monica, Calif. New Four-Year Data Show Long-Term Survival in Patients With Large B-Cell Lymphoma Treated With Yescarta® in ZUMA-1 Trial. Data presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition. December 5, 2020; Abstract 1187
• Max S. Topp, Tom van Meerten, Martin Wermke, Pieternella J. Lugtenburg, Monique C. Minnema, Kevin W. Song, Catherine Thieblemont, Yizhou Jiang, Vicki Plaks, Anne Kerber, Marie José Kersten. Preliminary Results of Earlier Steroid Use With Axicabtagene Ciloleucel in Patients With Relapsed/ Refractory Large B Cell Lymphoma. Poster presented at ASCO 2019 Annual Meeting. June 3, 2019; Abstract 7558
• Sattva S. Neelapu, Caron A. Jacobson, Olalekan O. Oluwole, Javier Munoz, Abhinav Deol, David B. Miklos, Nancy L. Bartlett, Ira Braunschweig, Yizhou Jiang, Jenny J. Kim, Lianqing Zheng, John M. Rossi, Frederick L. Locke. Axicabtagene Ciloleucel (Axi-Cel) In Refractory Large B Cell Lymphoma: Outcomes in Patients ≥ or < 65 Years of Age in the Pivotal Phase 1/2 ZUMA-1 Study. Poster presented at EHA 2019. June 15, 2019; Abstract 1066
• Max S. Topp, Tom van Meerten, Martin Wermke, Pieternella J. Lugtenburg, Monique C. Minnema, Kevin W. Song, Catherine Thieblemont, Yizhou Jiang, Vicki Plaks, Anne Kerber, Marie José Kersten. Axicabtagene Ciloleucel (Axi-Cel) in Patients With Relapsed/Refractory Large B Cell Lymphoma: Preliminary Results of Earlier Steroid Use. Poster presented at EHA 2019. June 15, 2019; Abstract 1067
• Sattva S. Neelapu, John M. Rossi, Caron A. Jacobson, Frederick L. Locke, David B. Miklos, Patrick M. Reagan, Scott Rodig, Lazaros J. Lekakis, Ian W. Flinn, Lianqing Zheng, Francesca Milletti, Edmund Chang, Allen Xue, Vicki Plaks, Jenny J. Kim, Adrian Bot. CD19-Loss With Preservation of Other B Cell Lineage Features in Patients With Large B Cell Lymphoma Who Relapsed Post-Axi-Cel. Blood (ASH Annual Meeting Abstracts) 134(Suppl 1): 203. Abstract 704.
• Sattva S. Neelapu, Frederick L. Locke, Nancy L. Bartlett, Lazaros J. Lekakis, Patrick Reagan, David B. Miklos, Caron A. Jacobson, Ira Braunschweig, Olalekan Oluwole, Tanya Siddiqi, Yi Lin, Michael Crump, John Kuruvilla, Eric Van Den Neste, Umar Farooq, Lynn Navale, Venita DePuy, Jenny J. Kim, Christian Gisselbrecht. A Comparison of Two-Year Outcomes in ZUMA-1 (Axicabtagene Ciloleucel) and SCHOLAR-1 in Patients With Refractory Large B Cell Lymphoma. Blood (ASH Annual Meeting Abstracts) 134(Suppl 1): 4095. Abstract 626.
• Upadhyay R, Boiarsky JA, Pantsulaia G, Svensson-Arvelund J, Lin MJ, Wroblewska A, Bhalla S, Scholler N, Bot A, Rossi JM, Sadek N, Parekh S, Lagana A, Baccarini A, Merad M, Brown BD, Brody JD. A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy. Cancer Discov. 2021 Mar;11(3):599-613. doi: 10.1158/2159-8290.CD-20-0756. Epub 2020 Dec 17.
• Locke FL, Rossi JM, Neelapu SS, Jacobson CA, Miklos DB, Ghobadi A, Oluwole OO, Reagan PM, Lekakis LJ, Lin Y, Sherman M, Better M, Go WY, Wiezorek JS, Xue A, Bot A. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020 Oct 13;4(19):4898-4911. doi: 10.1182/bloodadvances.2020002394.
• Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, Deol A, Reagan PM, Stiff P, Flinn IW, Farooq U, Goy A, McSweeney PA, Munoz J, Siddiqi T, Chavez JC, Herrera AF, Bartlett NL, Wiezorek JS, Navale L, Xue A, Jiang Y, Bot A, Rossi JM, Kim JJ, Go WY, Neelapu SS. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019 Jan;20(1):31-42. doi: 10.1016/S1470-2045(18)30864-7. Epub 2018 Dec 2.
• Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Stiff PJ, Friedberg JW, Flinn IW, Goy A, Hill BT, Smith MR, Deol A, Farooq U, McSweeney P, Munoz J, Avivi I, Castro JE, Westin JR, Chavez JC, Ghobadi A, Komanduri KV, Levy R, Jacobsen ED, Witzig TE, Reagan P, Bot A, Rossi J, Navale L, Jiang Y, Aycock J, Elias M, Chang D, Wiezorek J, Go WY. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017 Dec 28;377(26):2531-2544. doi: 10.1056/NEJMoa1707447. Epub 2017 Dec 10.

Helpful Links

• Gilead Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2015
• Primary Completion (Actual): September 10, 2020
• Study Completion (Actual): July 27, 2023

Study Registration Dates

• First Submitted: January 22, 2015
• First Submitted That Met QC Criteria: January 27, 2015
• First Posted (Estimated): January 28, 2015

Study Record Updates

• Last Update Posted (Estimated): September 6, 2023
• Last Update Submitted That Met QC Criteria: August 23, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Fludarabine; Axicabtagene ciloleucel
• Other Study ID Numbers: KTE-C19-101; 2015-005007-86 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at http://www.gilead.com/research/disclosure-and transparency
• IPD Sharing Time Frame: 18 months after study completion
• IPD Sharing Access Criteria: A secured external environment with username, password, and RSA code.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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