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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03761056
Registration number
NCT03761056
Ethics application status
Date submitted
29/11/2018
Date registered
3/12/2018
Date last updated
2/11/2023
Titles & IDs
Public title
Study to Evaluate the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma
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Scientific 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)
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Secondary ID [1]
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2019-002291-13
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Secondary ID [2]
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KTE-C19-112
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Universal Trial Number (UTN)
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Trial acronym
ZUMA-12
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
B-cell Lymphoma
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Condition category
Condition code
Cancer
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Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
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Cancer
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Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Other interventions - Axicabtagene Ciloleucel
Treatment: Drugs - Fludarabine
Treatment: Drugs - Cyclophosphamide
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.
Other interventions: Axicabtagene Ciloleucel
A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells
Treatment: Drugs: Fludarabine
Administered according to package insert
Treatment: Drugs: Cyclophosphamide
Administered according to package insert
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Intervention code [1]
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Other interventions
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Intervention code [2]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Complete Response (CR) Rate Per the Lugano Classification as Determined by Study Investigators
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Assessment method [1]
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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.
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Timepoint [1]
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First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (maximum duration: 26.2 months)
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Secondary outcome [1]
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Objective Response Rate (ORR) Per the Lugano Classification as Determined by Study Investigators
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Assessment method [1]
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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.
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Timepoint [1]
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First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (maximum duration: 26.2 months)
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Secondary outcome [2]
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Duration of Response (DOR) Per the Lugano Classification
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Assessment method [2]
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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.
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Timepoint [2]
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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)
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Secondary outcome [3]
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Event-Free Survival (EFS)
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Assessment method [3]
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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.
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Timepoint [3]
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First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
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Secondary outcome [4]
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Progression-Free Survival (PFS)
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Assessment method [4]
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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.
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Timepoint [4]
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First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
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Secondary outcome [5]
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Overall Survival (OS)
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Assessment method [5]
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OS is defined as the time from axicabtagene ciloleucel infusion to the date of death from any cause.
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Timepoint [5]
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First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
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Secondary outcome [6]
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Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Treatment-Emergent Serious Adverse Events (SAE)
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Assessment method [6]
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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.
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Timepoint [6]
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First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
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Secondary outcome [7]
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Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Value
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Assessment method [7]
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Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
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Timepoint [7]
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First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
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Secondary outcome [8]
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Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Value
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Assessment method [8]
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Grading categories were determined by CTCAE version 5.0.
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Timepoint [8]
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First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
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Secondary outcome [9]
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Relapse With Central Nervous Disease (CNS) Disease
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Assessment method [9]
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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.
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Timepoint [9]
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First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)
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Secondary outcome [10]
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Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood
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Assessment method [10]
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Peak was defined as the maximum number of CAR T cells in blood measured after infusion.
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Timepoint [10]
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From enrollment up to Month 24
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Secondary outcome [11]
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Peak Serum Level of Granzyme B, Interferon-gamma (IFNg), Interleukin (IL)-2, IL-5, IL-6, IL-8
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Assessment method [11]
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Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4.
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Timepoint [11]
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From enrollment up to Week 4
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Secondary outcome [12]
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Peak Serum Level of C-Reactive Protein (CRP)
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Assessment method [12]
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Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4.
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Timepoint [12]
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From enrollment up to Week 4
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Secondary outcome [13]
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Peak Serum Level of Ferritin
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Assessment method [13]
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Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4.
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Timepoint [13]
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From enrollment up to Week 4
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Secondary outcome [14]
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Time to Peak Serum Level of Granzyme B, Interferon-gamma (IFNg), Interleukin (IL)-2, IL-5, IL-6, IL-8, CRP, and Ferritin
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Assessment method [14]
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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.
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Timepoint [14]
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From enrollment up to Week 4
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Eligibility
Key inclusion criteria
Key
- 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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
29/01/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
12/10/2023
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Sample size
Target
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Accrual to date
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Final
42
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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Peter MacCallum Cancer Centre - Melbourne
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Recruitment postcode(s) [1]
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3000 - Melbourne
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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Arizona
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United States of America
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State/province [2]
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California
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United States of America
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Florida
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United States of America
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State/province [4]
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Tennessee
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Country [5]
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United States of America
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Texas
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Country [6]
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France
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State/province [6]
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Paris
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Kite, A Gilead Company
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03761056
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Trial related presentations / 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.
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Public notes
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Contacts
Principal investigator
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Kite Study Director
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Address
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Kite, A Gilead Company
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Fax
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Email
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Contact person for public queries
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03761056
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