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

• ClinicalTrials.gov Identifier: NCT03761056
• Recruitment Status: Completed
• First Posted: December 3, 2018
• Results First Posted: July 8, 2022
• Last Update Posted: November 2, 2023
• Sponsor: Kite, A Gilead Company
• Information provided by (Responsible Party): Gilead Sciences ( Kite, A Gilead Company )

Tracking Information

• First Submitted Date: November 29, 2018
• First Posted Date: December 3, 2018
• Results First Submitted Date: May 16, 2022
• Results First Posted Date: July 8, 2022
• Last Update Posted Date: November 2, 2023
• Actual Study Start Date: January 29, 2019
• Actual Primary Completion Date: May 17, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 16, 2022)

Complete Response (CR) Rate Per the Lugano Classification as Determined by Study Investigators [ Time Frame: First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (maximum duration: 26.2 months) ]

Complete Response Rate (CRR): percentage of participants with CR [complete metabolic response (CMR); complete radiological response (CRR)]. CMR: positron emission tomography (PET) 5-point scale (5-PS) scores of 1 (no uptake above background), 2 (uptake ≤ mediastinum), 3 (uptake > mediastinum but ≤ liver) with/without a residual mass); no new lesions; and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow (BM). CRR: target nodes/nodal masses regressed to ≤ 1.5 cm in longest transverse diameter of lesion (LDi); no extralymphatic sites of disease; absent non-measured lesion (NMLs); organ enlargement regress to normal; no new sites; and bone marrow normal by morphology.

Original Primary Outcome Measures (submitted: November 29, 2018)

Complete Response (CR) Rate [ Time Frame: Up to 2 years ]

Complete Response rate is defined as the incidence of a CR per the Lugano Classification as determined by study investigators.

Current Secondary Outcome Measures (submitted: May 16, 2022)

• Objective Response Rate (ORR) Per the Lugano Classification as Determined by Study Investigators [ Time Frame: First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (maximum duration: 26.2 months) ]
  ORR: percentage of participants with CR [CMR;CRR] or PR [partial metabolic response (PMR); partial radiologic response (PRR)].CMR: PET 5PS scores of 1 (no uptake above background, 2 (uptake ≤ mediastinum), 3 (uptake > mediastinum but ≤ liver) with/without a residual mass; no new lesions; no evidence of FDG-avid disease in BM. CRR:target nodes/nodal masses regressed to ≤ 1.5 cm in LDi;no extralymphatic sites of disease;absent NMLs;organ enlargement regress to normal;no new sites;bone marrow morphology normal. PMR:scores 4 (uptake moderately > liver),5 (uptake markedly > liver, new lesions) with reduced uptake compared with baseline and residual mass;no new lesions;responding disease at interim/residual disease at end of treatment (EOT).PRR: ≥ 50% decrease in sum of the product of perpendicular diameters (SPD) of up to 6 target measurable nodes and extra-nodal sites;absent/normal, regressed, but no increase of NMLs;spleen regressed by > 50% in length beyond normal;no new sites.
• Duration of Response (DOR) Per the Lugano Classification [ Time Frame: From the date of first confirmed objective response (CR or PR) to disease progression or death regardless of cause (up to approximately 26.2 months) ]
  DOR is defined only for participants who experience an objective response after axicabtagene ciloleucel infusion and is the time from the first objective response to disease progression or death from any cause. Objective response is defined in outcome measure (OM) 2.
• Event-Free Survival (EFS) [ Time Frame: First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) ]
  EFS was defined as time from axicabtagene ciloleucel infusion date to earliest date of disease progression (Lugano classification), commencement of subsequent new anti-lymphoma therapy including stem cell transplant, or death from any cause.
• Progression-Free Survival (PFS) [ Time Frame: First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) ]
  PFS is defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per Lugano classification or death from any cause.
• Overall Survival (OS) [ Time Frame: First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) ]
  OS is defined as the time from axicabtagene ciloleucel infusion to the date of death from any cause.
• Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Treatment-Emergent Serious Adverse Events (SAE) [ Time Frame: First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) ]
  An AE was any untoward medical occurrence in a participant in a clinical trial participant, which did not necessarily have a causal relationship with the treatment. Treatment-emergent adverse events were defined as any adverse event with onset on or after the axicabtagene ciloleucel infusion. Serious adverse event was defined as an event that resulted in the following: death; life-threatening situation; in-patient hospitalization or prolongation of existing hospitalization; persistent or significant disability or incapacity; congenital anomaly or birth defect; and medically important event or reaction.
• Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Value [ Time Frame: First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) ]
  Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
• Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Value [ Time Frame: First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) ]
  Grading categories were determined by CTCAE version 5.0.
• Relapse With Central Nervous Disease (CNS) Disease [ Time Frame: First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months) ]
  Relapse with CNS disease was defined as the time from the axicabtagene ciloleucel infusion date to the earliest date of CNS involvement with lymphoma as determined by typical symptoms, cerebrospinal fluid (CSF) evaluation, and/or diagnostic imaging.
• Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood [ Time Frame: From enrollment up to Month 24 ]
  Peak was defined as the maximum number of CAR T cells in blood measured after infusion.
• Peak Serum Level of Granzyme B, Interferon-gamma (IFNg), Interleukin (IL)-2, IL-5, IL-6, IL-8 [ Time Frame: From enrollment up to Week 4 ]
  Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4.
• Peak Serum Level of C-Reactive Protein (CRP) [ Time Frame: From enrollment up to Week 4 ]
  Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4.
• Peak Serum Level of Ferritin [ Time Frame: From enrollment up to Week 4 ]
  Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4.
• Time to Peak Serum Level of Granzyme B, Interferon-gamma (IFNg), Interleukin (IL)-2, IL-5, IL-6, IL-8, CRP, and Ferritin [ Time Frame: From enrollment up to Week 4 ]
  Time to peak is defined as the number of days from axicabtagene ciloleucel infusion to the date when the cytokine first reached the maximum post-baseline level.

Original Secondary Outcome Measures (submitted: November 29, 2018)

• Objective Response Rate (ORR) [ Time Frame: Up to 15 years ]
  ORR is defined as the incidence of either a CR or a partial response (PR) per the Lugano Classification as determined by study investigators.
• Duration of Response (DOR) [ Time Frame: Up to 15 years ]
  DOR is defined only for participants who experience an objective response after axicabtagene ciloleucel infusion and is the time from the first objective response to disease progression or death from any cause.

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

Descriptive Information

• Brief Title: Study to Evaluate the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma
• Official Title: A Phase 2 Multicenter Study Evaluating the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Subjects With High-Risk Large B-Cell Lymphoma (ZUMA-12)

Brief Summary

The primary objective of this study is to estimate the efficacy of axicabtagene ciloleucel in participants with high-risk large B-cell lymphoma.

After the end of KTE-C19-112 (ZUMA-12), participants who received an infusion of axicabtagene ciloleucel will complete the remainder of the 15-year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: B-cell Lymphoma

Intervention

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

Study Arms

Experimental: Axicabtagene Ciloleucel

Participants will receive cyclophosphamide 500 mg/m^2/day intravenously (IV) and fludarabine 30 mg/m^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-cluster of differentiation (CD)19 chimeric antigen receptor (CAR) transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10^8 anti-CD19 CAR T cells will be administered.

Interventions:

• Biological: Axicabtagene Ciloleucel
• Drug: Fludarabine
• Drug: Cyclophosphamide

Publications *

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

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 4, 2022): 42
• Original Estimated Enrollment (submitted: November 29, 2018): 40
• Actual Study Completion Date: October 12, 2023
• Actual Primary Completion Date: May 17, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Histologically confirmed large B-cell lymphoma
• High-grade large B-cell lymphoma
• Individuals must have a positive interim positron emission tomography (PET) per Cheson, 2014 (Deauville PET score of 4 or 5) after 2 cycles (PET2+) of chemoimmunotherapy
• No evidence, suspicion and/or history of central nervous system (CNS) involvement of lymphoma
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophil count ≥ 1000/μL
• Platelet count ≥ 75,000/μL
• Absolute lymphocyte count ≥ 100/μL

• Adequate renal, hepatic, pulmonary, and cardiac function defined as:

  • Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min
  • Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 upper limit of normal (ULN)
  • Total bilirubin ≤1.5 mg/dL, except in individuals with Gilbert's syndrome
• Cardiac ejection fraction ≥ 50% , no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings
• No clinically significant pleural effusion
• Baseline oxygen saturation > 92% on room air

Key Exclusion Criteria:

• History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg cervix, bladder, breast) unless disease free for at least 3 years
• History of Richter's transformation of chronic lymphocytic leukemia or primary mediastinal B-cell lymphoma
• History of autologous or allogeneic stem cell transplant
• Prior CD19-targeted therapy
• Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy
• Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management
• History of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection
• Presence of any indwelling line or drain dedicated central venous access catheters, such as a Port-a-Cath or Hickman catheter, are permitted
• Individuals with detectable cerebrospinal fluid malignant cells, brain metastases, or active CNS lymphoma
• History or presence of CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment
• History of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years
• History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, France, United States
• Removed Location Countries: Canada

Administrative Information

• NCT Number: NCT03761056
• Other Study ID Numbers: KTE-C19-112; 2019-002291-13 ( EudraCT Number )
• 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: October 2023