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 )

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: B-cell Lymphoma
• Interventions: Biological: Axicabtagene Ciloleucel; Drug: Fludarabine; Drug: Cyclophosphamide
• Enrollment: 42

Participant Flow

Recruitment Details	Participants were enrolled at study sites in the United States, France, and Australia. The first participant screened was on 29 January 2019. Data submitted represent analysis performed on data collected by the Primary Completion Date. Non-chemotherapy bridging therapy was recommended to participants with high disease burden at screening or baseline (bulky disease or rapidly progressing disease).
Pre-assignment Details	54 participants were screened. Participants who achieve a partial response or complete response and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the same axicabtagene ciloleucel regimen as the original target dose.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description	Participants received 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 was administered.
Period Title: Overall Study
Started	42
Completed	0
Not Completed	42
Reason Not Completed
Still on Study	34
Death	6
Investigator Decision	1
Subject Withdrawal of Consent From Further Follow-up	1

Baseline Characteristics

Arm/Group Title		Axicabtagene Ciloleucel
Arm/Group Description		Participants received cyclophosphamide 500 mg/m^2/day 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-CD19 CAR 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 was administered.
Overall Number of Baseline Participants		40
Baseline Analysis Population Description		Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	40 participants
		60.2 (13.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants
	Female	13
	Male	27
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants
	Hispanic or Latino	2
	Not Hispanic or Latino	36
	Unknown or Not Reported	2
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Race	Number Analyzed	40 participants
	American Indian or Alaska Native	1
	Asian	1
	Black or African American	1
	White	33
	Other	1
	Not Reported	3
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	40 participants
United States		32
France		2
Australia		6

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The response evaluable analysis set included participants who were enrolled and treated with axicabtagene ciloleucel at a dose of at least 1 x 10^6 anti-CD19 CAR T cells/kg, and centrally confirmed disease type (double-/triple- hit lymphomas) or International Prognostic Index (IPI) score ≥ 3.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2/day 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	37
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	78; (62 to 90)

2. Secondary Outcome

Title	Objective Response Rate (ORR) Per the Lugano Classification as Determined by Study Investigators
Description	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.
Time Frame	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (maximum duration: 26.2 months)

Outcome Measure Data

Analysis Population Description

Participants in Response Evaluable Analysis Set were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2/day 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	37
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	89; (75 to 97)

3. Secondary Outcome

Title	Duration of Response (DOR) Per the Lugano Classification
Description	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.
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)

Outcome Measure Data

Analysis Population Description

Participants in Response Evaluable Analysis Set were analyzed. Participants not meeting the criteria by analysis data cutoff date were censored at their last evaluable disease assessment date prior to the data cutoff date or new anti-lymphoma therapy start (including stem cell transplant or retreatment of axicabtagene ciloleucel), whichever is earlier.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2/day 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	37
Median (Full Range); Unit of Measure: months
	NA [1]; (0.0 to 23.3)

[1]

Median was not estimable due to the insufficient number of participants with events.

4. Secondary Outcome

Title	Event-Free Survival (EFS)
Description	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.
Time Frame	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)

Outcome Measure Data

Analysis Population Description

Participants in Response Evaluable Analysis Set were analyzed. Participants not meeting the criteria by analysis data cutoff date were censored at their last evaluable disease assessment date prior to the data cutoff date.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2/day 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	37
Median (Full Range); Unit of Measure: months
	NA [1]; (1.0 to 24.2)

[1]

Not reached due to insufficient number of participants with events.

5. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	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.
Time Frame	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)

Outcome Measure Data

Analysis Population Description

Participants in Response Evaluable Analysis Set were analyzed. Participants not meeting the criteria by analysis data cutoff date were censored at their last evaluable disease assessment date prior to the data cut off date or new antilymphoma therapy start date (including stem cell transplant or retreatment of axicabtagene ciloleucel) whichever is earlier.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	37
Median (Full Range); Unit of Measure: months
	NA [1]; (1.0 to 24.2)

[1]

Not reached due to insufficient number of participants with events.

6. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time from axicabtagene ciloleucel infusion to the date of death from any cause.
Time Frame	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)

Outcome Measure Data

Analysis Population Description

Participants in Response Evaluable Analysis Set were analyzed. Participants who have not died by the analysis data cutoff date were censored at their last known alive date prior to the data cutoff date with the exception that the participants known to be alive or determined to have died after the data cutoff date were censored at the data cuttoff date.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2/day 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	37
Median (Full Range); Unit of Measure: months
	24.5; (3.6 to 24.5)

7. Secondary Outcome

Title	Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Treatment-Emergent Serious Adverse Events (SAE)
Description	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.
Time Frame	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)

Outcome Measure Data

Analysis Population Description

For Axicabtagene Ciloleucel arm: Safety Analysis Set included all participants treated with any does of axicabtagene ciloleucel.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2/day 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	40
Measure Type: Number; Unit of Measure: percentage of participants
TEAE	100
Treatment-Emergent SAE	45

8. Secondary Outcome

Title	Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Value
Description	Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time Frame	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)

Outcome Measure Data

Analysis Population Description

Participants in Safety Analysis Set were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2/day 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	40
Measure Type: Number; Unit of Measure: percentage of participants
Hemoglobin	3
Alanine Aminotransferase	8
Alkaline Aminotransferase	0
Aspartate Aminotransferase	5
Bilirubin	20
Calcium	5
Creatinine	5
Glucose	15
Magnesium	5
Sodium	0
Urate	18

9. Secondary Outcome

Title	Percentage of Participants Experiencing Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Value
Description	Grading categories were determined by CTCAE version 5.0.
Time Frame	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)

Outcome Measure Data

Analysis Population Description

Participants in Safety Analysis Set were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2/day 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	40
Measure Type: Number; Unit of Measure: percentage of participants
Hemoglobin	40
Leukocytes	93
Lymphocytes	75
Neutrophils	95
Platelets	25
Albumin	3
Calcium	10
Glucose	0
Magnesium	3
Potassium	5
Sodium	23

10. Secondary Outcome

Title	Relapse With Central Nervous Disease (CNS) Disease
Description	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.
Time Frame	First infusion date of axicabtagene ciloleucel to data cut off date of 17 May 2021 (Up to approximately 26.2 months)

Outcome Measure Data

Analysis Population Description

Participants in response evaluable analysis set with available data were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	40
Median (Full Range); Unit of Measure: months
	0; (0 to 0)

11. Secondary Outcome

Title	Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood
Description	Peak was defined as the maximum number of CAR T cells in blood measured after infusion.
Time Frame	From enrollment up to Month 24

Outcome Measure Data

Analysis Population Description

Participants in safety analysis set were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	40
Median (Inter-Quartile Range); Unit of Measure: cells/µL
	36.27; (20.51 to 133.96)

12. Secondary Outcome

Title	Peak Serum Level of Granzyme B, Interferon-gamma (IFNg), Interleukin (IL)-2, IL-5, IL-6, IL-8
Description	Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4.
Time Frame	From enrollment up to Week 4

Outcome Measure Data

Analysis Population Description

Participants in Safety Analysis Set were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2/day 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	40
Median (Inter-Quartile Range); Unit of Measure: pg/mL
Granzyme B	28.5; (11.8 to 75.6)
IFNg	409.4; (157.8 to 856.8)
IL-2	16.4; (9.7 to 32.9)
IL-5	6.3; (6.3 to 26.2)
IL-6	35.1; (13.2 to 181.1)
IL-8	63.0; (30.1 to 107.5)

13. Secondary Outcome

Title	Peak Serum Level of C-Reactive Protein (CRP)
Description	Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4.
Time Frame	From enrollment up to Week 4

Outcome Measure Data

Analysis Population Description

Participants in Safety Analysis Set were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2/day 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	40
Median (Inter-Quartile Range); Unit of Measure: mg/L
	208.4; (60.9 to 407.5)

14. Secondary Outcome

Title	Peak Serum Level of Ferritin
Description	Peak is defined as the maximum post-baseline level of cytokine from baseline to Week 4.
Time Frame	From enrollment up to Week 4

Outcome Measure Data

Analysis Population Description

Participants in Safety Analysis Set were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	40
Median (Inter-Quartile Range); Unit of Measure: ng/mL
	749.1; (473.9 to 1874.3)

15. Secondary Outcome

Title	Time to Peak Serum Level of Granzyme B, Interferon-gamma (IFNg), Interleukin (IL)-2, IL-5, IL-6, IL-8, CRP, and Ferritin
Description	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.
Time Frame	From enrollment up to Week 4

Outcome Measure Data

Analysis Population Description

Participants in Safety Analysis Set were analyzed.

Arm/Group Title	Axicabtagene Ciloleucel
Arm/Group Description:	Participants received cyclophosphamide 500 mg/m^2/day 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-CD19 CAR 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 was administered.
Overall Number of Participants Analyzed	40
Median (Inter-Quartile Range); Unit of Measure: days
Granzyme B	8; (8 to 8)
IFNg	4; (4 to 8)
IL-2	4; (4 to 4)
IL-5	1; (1 to 4)
IL-6	8; (4 to 8)
IL-8	8; (4 to 8)
CRP	4; (4 to 8)
Ferritin	8; (6 to 8)

Adverse Events

Time Frame	All-Cause Mortality: Enrollment up to maximum duration of 27 months; Adverse Events: First infusion date up to maximum duration of 26.2 months
Adverse Event Reporting Description	All-Cause Mortality: All Enrolled Analysis Set included all enrolled/leukapheresed participants. Adverse Events: For Axicabtagene Ciloleucel arm: Safety Analysis Set included all participants treated with any does of axicabtagene ciloleucel. For Retreatment arm: Safety Retreatment Analysis Set consisted of all participants who underwent retreatment with axicabtagene ciloleucel.
Arm/Group Title	Axicabtagene Ciloleucel	Retreatment Axicabtagene Ciloleucel
Arm/Group Description	Participants received 500 mg/m^2 cyclophosphamide IV and 30 mg/m^2/day fludarabine IV conditioning chemotherapy followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR 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 was administered.	This arm included participants who achieved partial response or complete response and subsequently experienced disease progression and received second course of conditioning chemotherapy therapy and axicabtagene ciloleucel. Participants received the same axicabtagene ciloleucel regimen as the original target dose.
All-Cause Mortality
	Axicabtagene Ciloleucel	Retreatment Axicabtagene Ciloleucel
	Affected / at Risk (%)	Affected / at Risk (%)
Total	6/42 (14.29%)	0/1 (0.00%)
Serious Adverse Events
	Axicabtagene Ciloleucel	Retreatment Axicabtagene Ciloleucel
	Affected / at Risk (%)	Affected / at Risk (%)
Total	18/40 (45.00%)	0/1 (0.00%)
Blood and lymphatic system disorders
Anaemia † 1	1/40 (2.50%)	0/1 (0.00%)
Neutropenia † 1	1/40 (2.50%)	0/1 (0.00%)
Cardiac disorders
Atrial fibrillation † 1	1/40 (2.50%)	0/1 (0.00%)
Sinus bradycardia † 1	1/40 (2.50%)	0/1 (0.00%)
Supraventricular tachycardia † 1	1/40 (2.50%)	0/1 (0.00%)
Endocrine disorders
Hypothyroidism † 1	1/40 (2.50%)	0/1 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	1/40 (2.50%)	0/1 (0.00%)
General disorders
Non-cardiac chest pain † 1	2/40 (5.00%)	0/1 (0.00%)
Pyrexia † 1	3/40 (7.50%)	0/1 (0.00%)
Infections and infestations
Covid-19 † 1	1/40 (2.50%)	0/1 (0.00%)
Covid-19 pneumonia † 1	1/40 (2.50%)	0/1 (0.00%)
Cytomegalovirus infection reactivation † 1	1/40 (2.50%)	0/1 (0.00%)
Periorbital infection † 1	1/40 (2.50%)	0/1 (0.00%)
Skin infection † 1	1/40 (2.50%)	0/1 (0.00%)
Urinary tract infection † 1	1/40 (2.50%)	0/1 (0.00%)
Investigations
Neutrophil count decreased † 1	1/40 (2.50%)	0/1 (0.00%)
Platelet count decreased † 1	1/40 (2.50%)	0/1 (0.00%)
Musculoskeletal and connective tissue disorders
Back pain † 1	2/40 (5.00%)	0/1 (0.00%)
Muscular weakness † 1	1/40 (2.50%)	0/1 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma † 1	1/40 (2.50%)	0/1 (0.00%)
Nervous system disorders
Dysarthria † 1	1/40 (2.50%)	0/1 (0.00%)
Encephalopathy † 1	5/40 (12.50%)	0/1 (0.00%)
Haemorrhage intracranial † 1	1/40 (2.50%)	0/1 (0.00%)
Memory impairment † 1	1/40 (2.50%)	0/1 (0.00%)
Neurotoxicity † 1	1/40 (2.50%)	0/1 (0.00%)
Psychiatric disorders
Agitation † 1	1/40 (2.50%)	0/1 (0.00%)
Confusional state † 1	4/40 (10.00%)	0/1 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema † 1	1/40 (2.50%)	0/1 (0.00%)
Vascular disorders
Hypertension † 1	1/40 (2.50%)	0/1 (0.00%)
Hypotension † 1	1/40 (2.50%)	0/1 (0.00%)
1 Term from vocabulary, MedDRA 23.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Axicabtagene Ciloleucel	Retreatment Axicabtagene Ciloleucel
	Affected / at Risk (%)	Affected / at Risk (%)
Total	40/40 (100.00%)	1/1 (100.00%)
Blood and lymphatic system disorders
Anaemia † 1	13/40 (32.50%)	0/1 (0.00%)
Neutropenia † 1	5/40 (12.50%)	0/1 (0.00%)
Cardiac disorders
Atrial fibrillation † 1	2/40 (5.00%)	0/1 (0.00%)
Sinus bradycardia † 1	3/40 (7.50%)	0/1 (0.00%)
Sinus tachycardia † 1	10/40 (25.00%)	0/1 (0.00%)
Tachycardia † 1	2/40 (5.00%)	0/1 (0.00%)
Ventricular arrhythmia † 1	3/40 (7.50%)	0/1 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	4/40 (10.00%)	0/1 (0.00%)
Constipation † 1	8/40 (20.00%)	1/1 (100.00%)
Diarrhoea † 1	20/40 (50.00%)	1/1 (100.00%)
Dry mouth † 1	3/40 (7.50%)	0/1 (0.00%)
Nausea † 1	21/40 (52.50%)	0/1 (0.00%)
Vomiting † 1	8/40 (20.00%)	0/1 (0.00%)
General disorders
Chills † 1	11/40 (27.50%)	0/1 (0.00%)
Fatigue † 1	20/40 (50.00%)	0/1 (0.00%)
Non-cardiac chest pain † 1	2/40 (5.00%)	0/1 (0.00%)
Oedema peripheral † 1	5/40 (12.50%)	0/1 (0.00%)
Pyrexia † 1	39/40 (97.50%)	0/1 (0.00%)
Immune system disorders
Hypogammaglobulinaemia † 1	4/40 (10.00%)	0/1 (0.00%)
Infections and infestations
Urinary tract infection † 1	3/40 (7.50%)	0/1 (0.00%)
Investigations
Alanine aminotransferase increased † 1	7/40 (17.50%)	0/1 (0.00%)
Aspartate aminotransferase increased † 1	5/40 (12.50%)	0/1 (0.00%)
Blood bilirubin increased † 1	3/40 (7.50%)	0/1 (0.00%)
Blood fibrinogen decreased † 1	3/40 (7.50%)	0/1 (0.00%)
Lymphocyte count decreased † 1	4/40 (10.00%)	0/1 (0.00%)
Neutrophil count decreased † 1	21/40 (52.50%)	1/1 (100.00%)
Platelet count decreased † 1	7/40 (17.50%)	0/1 (0.00%)
White blood cell count decreased † 1	18/40 (45.00%)	1/1 (100.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	8/40 (20.00%)	0/1 (0.00%)
Dehydration † 1	1/40 (2.50%)	1/1 (100.00%)
Hypoalbuminaemia † 1	3/40 (7.50%)	0/1 (0.00%)
Hypocalcaemia † 1	4/40 (10.00%)	0/1 (0.00%)
Hypokalaemia † 1	11/40 (27.50%)	0/1 (0.00%)
Hypomagnesaemia † 1	2/40 (5.00%)	0/1 (0.00%)
Hyponatraemia † 1	5/40 (12.50%)	0/1 (0.00%)
Hypophosphataemia † 1	7/40 (17.50%)	0/1 (0.00%)
Musculoskeletal and connective tissue disorders
Back pain † 1	4/40 (10.00%)	0/1 (0.00%)
Muscular weakness † 1	6/40 (15.00%)	0/1 (0.00%)
Nervous system disorders
Dizziness † 1	2/40 (5.00%)	0/1 (0.00%)
Dysgraphia † 1	3/40 (7.50%)	0/1 (0.00%)
Encephalopathy † 1	8/40 (20.00%)	0/1 (0.00%)
Headache † 1	28/40 (70.00%)	0/1 (0.00%)
Memory impairment † 1	2/40 (5.00%)	0/1 (0.00%)
Tremor † 1	10/40 (25.00%)	0/1 (0.00%)
Psychiatric disorders
Agitation † 1	4/40 (10.00%)	0/1 (0.00%)
Confusional state † 1	11/40 (27.50%)	0/1 (0.00%)
Insomnia † 1	6/40 (15.00%)	0/1 (0.00%)
Reproductive system and breast disorders
Pelvic pain † 1	2/40 (5.00%)	0/1 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	5/40 (12.50%)	0/1 (0.00%)
Dyspnoea † 1	3/40 (7.50%)	0/1 (0.00%)
Hypoxia † 1	11/40 (27.50%)	0/1 (0.00%)
Nasal congestion † 1	3/40 (7.50%)	0/1 (0.00%)
Pleural effusion † 1	3/40 (7.50%)	0/1 (0.00%)
Pulmonary oedema † 1	2/40 (5.00%)	0/1 (0.00%)
Skin and subcutaneous tissue disorders
Rash maculo-papular † 1	2/40 (5.00%)	0/1 (0.00%)
Vascular disorders
Hypertension † 1	2/40 (5.00%)	0/1 (0.00%)
Hypotension † 1	14/40 (35.00%)	0/1 (0.00%)
1 Term from vocabulary, MedDRA 23.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met:

• The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or
• The study has been completed at all study sites for at least 2 years

Results Point of Contact

• Name/Title: Medical Information
• Organization: Kite, A Gilead Company
• Phone: 844-454-5483 (1-844-454-KITE)
• EMail: medinfo@kitepharma.com

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.

• Responsible Party: Gilead Sciences ( Kite, A Gilead Company )
• ClinicalTrials.gov Identifier: NCT03761056
• Other Study ID Numbers: KTE-C19-112; 2019-002291-13 ( EudraCT Number )
• First Submitted: November 29, 2018
• First Posted: December 3, 2018
• Results First Submitted: May 16, 2022
• Results First Posted: July 8, 2022
• Last Update Posted: November 2, 2023