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)
Phase: PHASE2
Conditions: B-cell Lymphoma
Sponsor: Kite, A Gilead Company

  
CLINICAL STUDY PROTOCOL
Protocol 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)
Protocol Number:
KTE-C19-112
Indication:
First-line treatment of adult subjects with high-risk large 
B-cell lymphoma, including either high-grade B-cell 
lymphoma (HGBL) with MYC and BCL2 and/or BCL6 
translocations, or large B-cell lymphoma with a high 
intermediate/high risk International Prognostic Index (IPI) 
score of ≥ 3; all subjects must have positive positron 
emission tomography after 2 cycles (PET2+) of 
chemoimmunotherapy.
Kite Investigational Product:
Axicabtagene ciloleucel
Company Code:
KTE-C19
IND Number:
016278
EudraCT Number:
2019‐002291‐13
Clinical Trials.gov Identifier:
NCT03761056
Sponsor:
Kite Pharma, Inc.
2400 Broadway
Santa Monica, CA 90404
Contact Information:
The medical monitor name and contact information is 
provided on the Key Study Team Contact List.
Original Protocol Date:
26 June 2018
Amendment 1:
14 August 2019
Amendment 2:
25 March 2022
Amendment 3:
14 June 2022
CONFIDENTIALITY NOTICE
This document contains confidential information of Kite Pharma, Inc., a wholly owned 
subsidiary of Gilead Sciences Inc. This document must not be disclosed to anyone other than the 
study site research staff, collaborators, and members of the Institutional Review 
Board/Independent Ethics Committee, a scientific review board, or an equivalent. The 
information in this document cannot be used for any purpose other than the conduct of the 
clinical investigation without the prior written consent of Kite Pharma, Inc.

Axicabtagene Ciloleucel 
Kite Pharma, Inc. 
Clinical Protocol 
 
KTE-C19-112 (ZUMA-12) 
 
CONFIDENTIAL 
Page 2 
 
14 JUN 2022 
Sponsor and Investigator Signature Page 
KITE PHARMA, INC. 
2400 BROADWAY 
SANTA MONICA, CA 90404 
 
STUDY ACKNOWLEDGMENT 
 
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) 
Amendment 3.0, 14 June 2022 
This protocol has been approved by Kite Pharma, Inc. The following signature documents this 
approval. 
 
Kite Medical Monitor Name (Printed)
Date
 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I agree to comply with the International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use Harmonised Tripartite Guideline on Good Clinical Practice 
and applicable national or regional regulations and guidelines. I will provide all study personnel 
under my supervision copies of the protocol and access to all information provided by Kite 
Pharma, Inc. I will discuss this material with them to ensure that they are fully informed about 
the investigational product and study. 
I agree and will ensure that financial disclosure statements will be completed by: 
 Me (including, if applicable, my spouse, legal partner, and dependent children) 
 Sub investigators (including, if applicable, their spouse, legal partner, and dependent 
children) at the start of the study and for up to 1 year after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the conduct of the clinical investigation without prior written consent 
from Kite Pharma, Inc. 
Principal Investigator Name (Printed)
Signature
Date
Study Site Number
DocuSign Envelope ID: 7221257E-AECF-4BA3-89FD-152ACD70DA2F
15-Jun-2022
PPD
PPD

Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
Page 3
14 JUN 2022
PROTOCOL SYNOPSIS
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)
Indication:
The indication is for the first-line treatment of adult subjects with 
high-risk large B-cell lymphoma, including either high-grade B-cell 
lymphoma (HGBL) with MYC and BCL2 and/or BCL6 translocations 
(hereafter referred to as double-hit or triple-hit lymphomas), or large 
B-cell lymphoma with a high intermediate/ high risk International 
Prognostic Index [IPI] score of ≥ 3; all subjects must have positive 
positron emission tomography after 2 cycles (PET2+) of 
chemoimmunotherapy.
Study Design:
Approximately 40 subjects with high-risk large B-cell lymphoma 
(either double-/triple-hit lymphomas, or high-risk large B-cell 
lymphoma with IPI score ≥3) will be enrolled and treated with 
cyclophosphamide and fludarabine conditioning chemotherapy, 
followed by a target dose of 2 x 106 anti-CD19 chimeric antigen 
receptor (CAR) T cells/kg body weight.
Each subject with a positive interim positron emission 
tomography-computed tomography (PET-CT) per the Lugano 
Classification {Cheson 2014} (Deauville 5-point scale PET score of 
4 or 5) after 2 cycles (PET2+) of chemoimmunotherapy will proceed 
through the following study periods:

Screening

Enrollment/Leukapheresis


Conditioning chemotherapy period

Investigational product treatment period

Post-treatment assessment period

Long-term follow-up (LTFU) period
Following at least 36 months of assessments, subjects who received 
an infusion of axicabtagene ciloleucel will complete the remainder of 
the 15-year follow-up assessments in the separate LTFU study, 
KT-US-982-5968.
For study requirements assigned to each study period, refer to 
Section 7 for details.
A study schema is provided at the end of the protocol synopsis 
section.
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Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
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Study Objectives:
The primary objective of the study is to estimate the efficacy of 
axicabtagene ciloleucel, as measured by complete response (CR) rate, 
in subjects with high-risk large B-cell lymphoma. Secondary 
objectives will include assessing the safety of axicabtagene ciloleucel 
and additional efficacy endpoints.
Hypothesis:
No formal hypothesis will be tested in this study. The study is 
designed to estimate the CR rate in subjects with high-risk large 
B-cell lymphoma treated with axicabtagene ciloleucel as first-line 
therapy.
Primary Endpoints:
CR rate: CR rate is defined as the incidence of a CR per the Lugano 
Classification {Cheson 2014} as determined by study investigators. 
All evaluable subjects who do not meet the criteria for a CR by the 
analysis data cutoff date will be considered nonresponders.
Secondary 
Endpoints:

Objective response rate (ORR): ORR is defined as the incidence 
of either a CR or a partial response per the Lugano Classification 
{Cheson 2014} as determined by study investigators

Duration of response (DOR)

Event-free survival (EFS)

Progression-free survival (PFS)

Overall survival (OS)

Incidence of adverse events (AEs) and clinical significant 
changes in safety laboratory values

Relapse with central nervous system (CNS) disease
Additional Secondary Endpoints:

Pharmacokinetics (levels of anti-CD19 CAR T cells in blood)

Pharmacodynamics (levels of cytokines in serum)
Sample Size:
Approximately 40 enrolled and treated subjects
Study Eligibility:
Refer to Section 5 for a complete and detailed list of inclusion and 
exclusion criteria.

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19-l 12 (ZUMA-12) 
Kite Phruma, Inc. 
Treatment: Investigational Product: 
• 
Axicabtagene ciloleucel treatment consists of a single infusion of 
CAR transduced autologous T cells administered intravenously at 
a target dose of 2 x 106 anti-CD19 CART cells/kg. For subjects 
weighing 2::: 100 kg, a maximum flat dose of 2 x 108 anti-CD19 
CAR T cells will be administered. 
I 
I 
Procedures: At specific time points as outlined in the schedule of assessments, 
subjects will undergo the following assessments/procedures: 
collection of info1med consent, general medical histo1y including 
previous treatments for large B-cell lymphoma, physical exam 
including vital signs and Eastern Cooperative Oncology Group 
perfonnance status, neurologic examinations, blood draws for 
complete blood count, cheinistiy panels, cytokines, C-reactive 
protein, lymphocyte subsets, replication-competent retrovims and 
anti-CD 19 CAR T-cell analysis. 
CONFIDENTIAL 
Subjects will also undergo a baseline electrocardiogram, 
echocardiogram, PET-CT, and leukapheresis. Subjects may also need 
bone maiTow aspirate/biopsy, brain magnetic resonance image, and 
lumbar puncture. 
Routinely throughout the conduct of the study, subjects will be asked 
to repo1i concoinitant medications and AEs and will have their 
disease assessed. 
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Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
Page 6
14 JUN 2022
Data Safety 
Monitoring Board:
An independent Data Safety Monitoring Board (DSMB) will be 
chartered to meet and review the serious adverse events (SAEs) and 
suspected unexpected serious adverse reactions (SUSARs) on a semi-
annual basis after the first subject has been treated with axicabtagene 
ciloleucel up through the primary analysis. Kite Pharma, Inc., or 
delegate, will submit SAEs and SUSARs to the DSMB on a regular 
basis throughout the study up through the primary analysis. The 
DSMB will also meet to review safety data after 15 subjects have 
been enrolled and treated with axicabtagene ciloleucel and have had 
an opportunity to be followed for 3 months after axicabtagene 
ciloleucel infusion. The DSMB will make trial conduct 
recommendations on an ongoing basis based on an analysis of risk 
versus benefit. The DSMB may request additional safety data for 
review or recommend modifications to the study conduct if safety 
concerns are identified.
The DSMB may meet more often as needed. Refer to Section 9.10.
Statistical 
Considerations:
No formal hypothesis test will be performed. Analyses will be 
descriptive.
One planned interim analysis will be performed.

Interim Analysis 1 will be conducted after 15 subjects have been 
enrolled and treated with axicabtagene ciloleucel and have had an 
opportunity to be followed for 3 months after axicabtagene 
ciloleucel infusion. This analysis will be for efficacy and safety.
The primary endpoint for the study is CR rate per the Lugano 
Classification {Cheson 2014} as determined by study investigators.
The primary analysis will occur after all subjects treated with 
axicabtagene ciloleucel have an opportunity to be assessed for 
response 6 months after the Week 4 disease assessment.
The final analysis will occur when all subjects have had the 
opportunity to be followed for at least 36 months. Subjects treated 
with axicabtagene ciloleucel will be transitioned to the KT-US-982-
5968 study for the remainder of the 15-year LTFU period. 
Descriptive estimates of key efficacy and safety analyses may be 
updated to assess the overall treatment profile.

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19-l 12 (ZUMA-12) 
Kite Pha1ma, Inc. 
Figure 1. 
Study Schema 
Treatment Period: Axicabtagene Ciloleucel 
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Approximately 40 subjects who are either double hit/tdple hit or have IPI 2: 3 will be enrolled and treated. 
En.-ollment/Leukapheresis: Subjects who have a positive interim PET per the Lugano Classification {Cheson 2014} (Deauville PET score of 
4 or 5) after 2 cycles (PET2+) of an anti-CD20 monoclonal antibody and anthracycline-containing regimen per local standard of care 
b 
C 
d 
(eg, DA-EPOCH-R) if double hit/triple hit, or an anti-CD20 monoclonal antibody and anthracycline-containing regimen per local standard of 
care (eg, R-CHOP) iflarge B-cell lymphoma with IPI score c::: 3. 
Conditioning Chemotherapy: Subjects will receive a 3-day conditioning chemotherapy regimen consisting of fludarabine 30 mg/m2/day and 
cyclophosphamide 500 mg/m2/day (Day - 5 to Day -3) followed by 2 rest days (Day -2 and Day - 1). 
Long-term Follow-up Pe1iod: After the end of ZUMA-12, subjects who received an infusion of axicabtagene ciloleucel will complete the 
remainder of the 15-year follow-up assessments in a separate long-te1m follow-up study, KT-US-982-5968. 
CONFIDENTIAL 
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Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
Page 8
14 JUN 2022
TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL..................................................................................................................................1
PROTOCOL SYNOPSIS................................................................................................................................................3
TABLE OF CONTENTS................................................................................................................................................8
LIST OF TABLES........................................................................................................................................................10
LIST OF FIGURES ......................................................................................................................................................10
LIST OF ABBREVIATIONS.......................................................................................................................................11
1.
OBJECTIVES.......................................................................................................................................................13
1.1.
Primary Objective....................................................................................................................................13
1.2.
Secondary Objective(s) ...........................................................................................................................13
1.3.
.........................................................................................................................13
2.
DISEASE BACKGROUND ................................................................................................................................14
2.1.
Disease Background ................................................................................................................................14
2.2.
Standard First-line Therapy.....................................................................................................................16
2.3.
Axicabtagene Ciloleucel..........................................................................................................................16
2.4.
Prior Anti-CD19 CAR T-cell Study Designs and Results.......................................................................17
3.
STUDY DESIGN AND RATIONALE................................................................................................................18
3.1.
General Study Design..............................................................................................................................18
3.2.
Study Design Rationale ...........................................................................................................................19
3.2.1.
Rationale for Conditioning Chemotherapy ...........................................................................20
3.2.2.
Rationale for Axicabtagene Ciloleucel Dose ........................................................................20
3.3.
Participating Sites....................................................................................................................................21
3.4.
Number of Subjects .................................................................................................................................21
3.5.
Replacement of Subjects .........................................................................................................................21
3.6.
Study Duration.........................................................................................................................................21
3.6.1.
Study Duration for Individual Subjects.................................................................................21
3.6.2.
Completion of Study..............................................................................................................22
4.
SUBJECT IDENTIFICATION ASSIGNMENT .................................................................................................23
5.
SUBJECT ELIGIBILITY.....................................................................................................................................24
5.1.
Inclusion Criteria.....................................................................................................................................24
5.2.
Exclusion Criteria....................................................................................................................................25
6.
PROTOCOL TREATMENT................................................................................................................................28
6.1.
Study Treatment ......................................................................................................................................28
6.1.1.
Leukapheresis........................................................................................................................28
6.1.3.
Conditioning Chemotherapy .................................................................................................29
6.1.4.
Axicabtagene Ciloleucel........................................................................................................30
6.1.5.
Concomitant Therapy ............................................................................................................30
6.1.6.
Excluded Medications ...........................................................................................................31
6.1.7.
Subsequent Therapy ..............................................................................................................32
6.1.8.
Toxicity Management............................................................................................................32
7.
STUDY PROCEDURES......................................................................................................................................33
7.1.
Informed Consent ....................................................................................................................................33
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Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
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7.2.
Screening .................................................................................................................................................33
7.2.1.
Rescreening ...........................................................................................................................34
7.3.
Demographic Data...................................................................................................................................34
7.4.
Medical and Treatment History...............................................................................................................34
7.5.
Conditioning Chemotherapy and Axicabtagene Ciloleucel Infusion......................................................34
7.5.1.
Requirements for Initiating Conditioning Chemotherapy.....................................................35
7.5.2.
Requirements for Initiating Axicabtagene Ciloleucel Infusion.............................................36
7.5.3.
Requirements to Work-up Potential Infectious and/or Inflammatory States ........................37
7.5.4.
Conditioning Chemotherapy Administration (Day –5 Through Day –3 
Prior to Axicabtagene Ciloleucel Infusion)...........................................................................38
7.6.
Physical Exam, Vital Signs, and Performance Status .............................................................................38
7.7.
Cardiac Function .....................................................................................................................................39
7.8.
Neurological Examination.......................................................................................................................39
7.9.
Disease Assessment.................................................................................................................................39
7.9.1.
Imaging..................................................................................................................................39
7.9.2.
Determination of Bone Marrow Involvement .......................................................................40
7.10.
Cell Collection and Axicabtagene Ciloleucel Study Treatment Schedule and Administration ..............41
7.10.1.
Leukapheresis........................................................................................................................41
7.10.3.
Axicabtagene Ciloleucel Treatment Period...........................................................................42
7.11.
Laboratory ...............................................................................................................................................44
7.11.1.
Local Laboratory Analysis ....................................................................................................44
7.11.2.
Central Laboratory Analyses.................................................................................................45
7.12.
Post-treatment Assessment Period ..........................................................................................................47
7.13.
Long-term Follow-up Period...................................................................................................................48
7.14.
Summary of Scheduled Assessments ......................................................................................................48
8.
SUBJECT WITHDRAWAL ................................................................................................................................54
8.1.
Reasons for Removal from Treatment ....................................................................................................54
8.2.
Reasons for Removal from Study............................................................................................................55
9.
SAFETY REPORTING........................................................................................................................................56
9.1.
Adverse Events........................................................................................................................................56
9.2.
Reporting of Adverse Events...................................................................................................................56
9.2.1.
Reporting Abnormal Laboratory Findings ............................................................................57
9.3.
Definition of Serious Adverse Events .....................................................................................................58
9.4.
Reporting of Serious Adverse Events......................................................................................................58
9.5.
Reporting Deaths.....................................................................................................................................59
9.6.
Diagnosis Versus Signs and Symptoms ..................................................................................................59
9.7.
Pregnancy and Lactation .........................................................................................................................60
9.8.
Hospitalization and Prolonged Hospitalization.......................................................................................60
9.9.
Abnormal Vital Sign Values ...................................................................................................................61
9.10.
Data Safety Monitoring Board ................................................................................................................61
10.
STATISTICAL CONSIDERATIONS.................................................................................................................62
10.1.
Hypothesis ...............................................................................................................................................62
10.2.
Study Endpoints.......................................................................................................................................62
10.2.1.
Primary Endpoint...................................................................................................................62
10.2.2.
Secondary Endpoints.............................................................................................................62
10.2.3.
...........................................................................................................63
10.2.4.
Covariates and Subgroups .....................................................................................................63
10.3.
Sample Size Considerations ....................................................................................................................64
10.4.
Access to Individual Subject Treatment Assignments ............................................................................64
10.5.
Interim Analysis and Early Stopping Guidelines ....................................................................................64
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Clinical Protocol
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10.6.
Analysis Subsets......................................................................................................................................65
10.7.
Planned Method of Analysis ...................................................................................................................65
10.7.1.
CR Rate .................................................................................................................................65
10.7.2.
ORR.......................................................................................................................................65
10.7.3.
DOR.......................................................................................................................................66
10.7.4.
EFS ........................................................................................................................................66
10.7.5.
PFS ........................................................................................................................................66
10.7.6.
OS..........................................................................................................................................66
10.7.7.
Relapse with CNS Disease ....................................................................................................66
10.7.8.
Safety.....................................................................................................................................67
10.7.9.
Pharmacokinetic Analysis .....................................................................................................67
10.7.10.
Pharmacodynamics Analyses ................................................................................................67
10.7.11.
...........................................................................................67
11.
REGULATORY OBLIGATIONS.......................................................................................................................68
11.1.
Independent Review Board/Independent Ethics Committee...................................................................68
11.2.
Subject Confidentiality............................................................................................................................68
11.3.
Investigator Signatory Obligations..........................................................................................................69
12.
PROTOCOL AMENDMENTS AND TERMINATION .....................................................................................70
13.
STUDY DOCUMENTATION AND ARCHIVING............................................................................................71
14.
STUDY MONITORING AND DATA COLLECTION......................................................................................72
15.
PUBLICATION ...................................................................................................................................................73
16.
COMPENSATION...............................................................................................................................................74
17.
REFERENCES.....................................................................................................................................................75
18.
APPENDICES......................................................................................................................................................80
Appendix 1.
Lugano Classification {Cheson 2014} ....................................................................................81
Appendix 2.
International Prognostic Index in Aggressive Lymphomas.....................................................85
Appendix 3.
Country-Specific Regulatory Agency Requirements ..............................................................86
Appendix 4.
Birth Control Methods Which May Be Considered as Highly Effective................................87
LIST OF TABLES
Table 2.
Clinical Laboratory Parameters...............................................................................................44
Table 3.
Schedule of Assessments.........................................................................................................49
Table 4.
Long-term Follow-up Assessments.........................................................................................52
Table 5.
Lower and Upper Limits of 80%/95% CIs for CR Rates from 60% to 100% for a 
Sample of 40 Subjects .............................................................................................................64
LIST OF FIGURES
Figure 1.
Study Schema ............................................................................................................................7
Figure 2.
International Prognostic Index in Aggressive Lymphomas.....................................................15
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Axicabtagene Ciloleucel
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Clinical Protocol
KTE-C19-112 (ZUMA-12)
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LIST OF ABBREVIATIONS
Abbreviation 
Definition
5PS
5-point scale
ABC
activated B-cell
AE
adverse event
BP
blood pressure
CAR
chimeric antigen receptor 
CBC
complete blood count
CD
cluster of differentiation
CHOP
cyclophosphamide, doxorubicin, vincristine, prednisone 
CI
confidence interval
CNS
central nervous system
CR
complete response
CRF
case report form
CRP
C-reactive protein
CRS
cytokine release syndrome
CSF
cerebrospinal fluid
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria For Adverse Events 
DA-EPOCH-R
dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, 
rituximab
DH
double-hit
DLBCL
diffuse large B-cell lymphoma
DOR
duration of response 
DORR
duration of retreatment response
DSMB
Data Safety Monitoring Board
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EFS
event-free survival
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose 
GCB
germinal center B-cell
GCP
Good Clinical Practice
GELA
Groupe d’Etude des Lymphomes de l’Adulte
HIV
human immunodeficiency virus
HDMP
high-dose methylprednisolone
HEENT
head, eyes, ears, nose, and throat
HGBL
high-grade B-cell lymphoma
HR
heart rate

Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
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IB
Investigator’s Brochure  
ID
identification
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL
interleukin 
IPI
International Prognostic Index
IPM
investigational product manual
IRB
institutional review board
IRC
independent review committee
IV
intravenous
IWG
international working group
LDi
longest transverse diameter
LTFU
long-term follow-up
MCP
monocyte chemoattractant protein
NCI
National Cancer Institute
NHL
non-Hodgkin lymphoma
NOS
not otherwise specified
ORR
objective response rate 
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease
PET-CT
positron emission tomography–computed tomography
PFS
progression-free survival
PK
pharmacokinetic
PMBCL
primary mediastinal B-cell lymphoma 
PMD
progressive metabolic disease 
PR
partial response
PFS
progression-free survival
R-CHOP
rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone
R-ACVBP
rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone
RCR 
replication-competent retrovirus
SAE
serious adverse event
SCT
stem cell transplant
SDi
shortest transverse diameter
SOA
schedule of assessments
SUSAR
suspected unexpected serious adverse reactions
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19-l 12 (ZUMA-12) 
L 
OBJECTIVES 
1.1. 
Primary Objective 
Kite Phruma, Inc. 
• 
To estimate the efficacy of axicabtagene ciloleucel, as measured by complete response (CR) 
rate, in subjects with high-risk large B-cell lymphoma, as detennined by study investigators 
1.2. 
Secondary Objective(s) 
• 
To characterize the safety profile, and to further characterize efficacy with secondaiy 
endpoints; fmther secondaiy objectives will include phaim acokinetic/phaim acodynamic 
endpoints 
1.3. 
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Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
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2.
DISEASE BACKGROUND
2.1.
Disease Background
Non-Hodgkin lymphoma (NHL) comprises a heterogeneous group of cancers originating 
primarily in B lymphocytes, and to a lesser extent, in T lymphocytes and natural killer cells. 
NHL is the most prevalent hematological malignancy and is the seventh most common new 
cancer among men and women, accounting for 4% of all new cancer cases and 3% of 
cancer-related deaths {Howlader 2015}. Diffuse large B-cell lymphoma (DLBCL) is the most 
common subtype of B-cell NHL, accounting for approximately 30% to 40% of all cases across 
regions {Chaganti 2016, Morton 2006, Sehn 2015, Tilly 2012}. DLBCL can be further divided 
into subtypes based on factors including cytology, site of origin, and clinical background. 
Nevertheless, most cases are classified as DLBCL-not otherwise specified (NOS). The 2016 
revision of the World Health Organization (WHO) classification of lymphomas included 2 new 
subcategories of DLBCL-NOS by cell of origin: activated B-cell (ABC) and germinal center 
B-cell (GCB). Per the new classification system, DLBCL-NOS also includes those with MYC or 
BCL-2 protein overexpression, which has been suggested to confer worse outcome in patients 
treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) 
as first-line therapy {Swerdlow 2016}.
The 2016 revision of the WHO classification for lymphomas also included a new category, 
high-grade B-cell lymph oma (HGBL), which accounts for < 10% of DLBCL cases and is now 
considered distinct from DLBCL {Friedberg 2017, Swerdlow 2016}. HGBL includes 
2 subcategories, the first of which is characterized by gene rearrangements of MYC and BCL-2 
and/or BCL-6 (ie, double- or triple-hit lymphomas, depending on the number of rearrangements 
present). The second category lacks these rearrangements and is characterized by the presence of 
Ki67 protein (HGBL-NOS) {Broyde 2009, Swerdlow 2016}. Double- and triple-hit lymphomas 
typically do not respond to rituximab-based chemoimmunotherapy and are more likely to involve 
the central nervous system (CNS) {Friedberg 2017}. Only 40% and 41% of patients with MYC 
translocations and with double-hit lymphoma, respectively, were alive 2 years following 
first-line treatment {de Jonge 2016, Oki 2014}. Retrospective studies suggest a benefit of 
aggressive induction regimens, and consideration is even given for consolidation with high-dose 
therapy and transplant in select cases {Chen 2017, Friedberg 2017}.
The International Prognostic Index (IPI) is widely used for risk stratification of patients with 
aggressive B-cell lymphoma. In the original study of 2031 patients of all ages, the prognostic 
model, based on age, tumor stage, serum lactate dehydrogenase concentration, performance 
status, and number of extranodal disease sites, identified 4 risk groups of low, low-intermediate, 
high-intermediate, and high with predicted 5-year survival rates of 73%, 51%, 43%, and 26%, 
respectively {International Non-Hodgkin's Lymphoma Prognostic Factors Project 1993} 
(Figure 2). The IPI also remains a valid predictor of outcome in the rituximab era, independent of 
double-hit status and cell of origin (eg, GCB and ABC subtypes) {Staiger 2017, Ziepert 2010}.

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19-l 12 (ZUMA-12) 
Kite Phruma, Inc. 
Figure 2. 
International Prognostic Index in Aggressive Lymphomas 
(/J -
C 
:.:; 
«' 
a. -
0 
-::R. 
0 
0 
0 
2 
Overall Survival 
4 
L 
LI 
----HI 
H 
6 
8 
Death Rate per Year 
10 
2 
4 
6 
8 
10 
Year 
Prognostic factors: age > 60 years; pe1fo1mance status:;:: 2; lactate dehydrogenase > I x nonnal; extranodal sites> I; Stage III or 
IV 
Risk category (number of factors): Low (L: 0 or I) I Low-intermediate (LI; 2); High-intenuediate (HI; 3); High (H; 4 or 5) 
[Intemational NHL Prognostic Factors Project. N Engl J Med. 1993;329:987-94] 
A number of recent studies have assessed the role of early PET-CT using visual analysis by 
Deauville criteria {Banington 2014} to further predict patients with large B-cell lymphoma 
treated with rituximab-containing regimens who may be at higher risk. An international 
retrospective conf111nato1y study reported that early positive PET-CT after 2 induction cycles 
(PET2+) had prognostic value in DLBCL when there is no change in therapy: the 3-year PFS 
estimate was 59% in PET2+ patients versus 81 % in PET2-negative (PET2- ) patients (P = 0.003) 
{Itti 2013}. A meta-analysis of 11 studies revealed higher CR rates in the early ( after 2 to 
4 induction cycles) PET-negative group compared with the early PET-positive group (relative 
risk: 5.5, 95% confidence interval [CI]: 2.59 to 11.80) {Zhu 2015}. A prospective study in 
DLBCL patients assessed PET2 by central review, and found a 2-year EFS rate of 48% for 
PET2+ patients and 74% for PET2- patients (P = 0.004) {Mamot 2015}. Another prospective 
study in DLBCL patients revealed PET2 results to be prognostic for PFS based on cell of origin, 
with a 30-month PFS of 60% for PET2+ patients vs. 100% for PET2- patients with GCB 
DLBCL (P = 0.001) {de Oliveira Costa 2016}. Based on the results of these studies, patients 
with large B-cell lymphoma who are PET2+ based on Deauville criteria appear to have a worse 
prognosis compared with patients who are PET2- and represent a subgroup with a high unmet 
medical need. 
This study will emoll patients with high-risk large B-cell lymphoma, defined as either 
double-/triple-hit lymphoma or large B-cell lymphoma with high-intennediate and high risk 
(IPI 
3). All study subjects must also be PET2+. Given the poor outcomes observed with 
cmTently available therapies, this group has a high need for more effective treatment. 
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2.2.
Standard First-line Therapy
Since the 1970s, chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone 
(CHOP) had been standard-of-care first-line therapy for patients with DLBCL. More intensive 
combinations failed to show additional survival benefit. The current standard of care for first-line 
treatment is CHOP in combination with the anti-CD20 monoclonal antibody rituximab 
(R-CHOP, rituximab-based chemoimmunotherapy) {Flowers 2010}. In the seminal study by the 
Groupe d’Etude des Lymphomes de l’Adulte (GELA), first-line R-CHOP was superior to CHOP, 
with 10-year overall survival (OS) and progression-free survival (PFS) of 43.5% vs 27.6% and 
36.5% vs 20.1%, respectively {Coiffier 2010}. Thus, while more effective than chemotherapy 
alone, first-line R-CHOP still only results in long-term disease remission in < 40% of subjects. 
Recently a Phase 3 trial of first-line R-CHOP versus dose-adjusted etoposide, prednisone, 
vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) demonstrated no 
difference in event-free survival (EFS) or OS between the regimens {Wilson 2016}.
Patients with double- and triple-hit lymphomas have been shown to have a poor prognosis with 
R-CHOP chemoimmunotherapy, and there is no established standard of care {Green 2012, 
NCCN 2016}. In a large retrospective study of patients with double-hit lymphoma, there was no 
apparent benefit with the more aggressive induction regimen DA-EPOCH-R, compared with 
standard R-CHOP, with a median OS of 30 months and 34 months, respectively {Petrich 2014}. 
In the GELA randomized Phase 2 study, which evaluated the efficacy of rituximab, doxorubicin, 
cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) or R-CHOP-14 induction 
using IWG (International Working Group) 2007 criteria in young patients with high-risk 
DLBCL, the primary objective of achieving a higher than 50% CR rate after 4 cycles of 
induction regimen was not met in either randomization group {Casasnovas 2017}.
Unfortunately, there are no published prospective trials in the setting of double- or triple-hit 
lymphoma. These patients represent the greatest unmet clinical need in DLBCL according to a 
recent clinical trials planning meeting from the National Cancer Institute National Clinical Trials 
Network, and prospective randomized trials are currently being developed for double-hit 
lymphoma {Nowakowski 2016}.
2.3.
Axicabtagene Ciloleucel
On 18 October 2017, the Food and Drug Administration (FDA) granted regulatory approval to 
axicabtagene ciloleucel for the treatment of adult patients with relapsed or refractory large B-cell 
lymphoma after 2 or more lines of systemic therapy, including DLBCL-NOS, primary 
mediastinal large B-cell lymphoma (PMBCL), HGBL, and DLBCL arising from follicular 
lymphoma {YESCARTA 2019}.
Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T-cell immunotherapy. It consists 
of autologous T cells that are genetically modified to produce a CAR protein, allowing the 
T cells to identify and eliminate CD19-expressing normal and malignant cells. CD19 is expressed 
by most B-cell malignancies {Johnson 2009, Leonard 2001, Olejniczak 2006, Rodriguez 1994, 
Uckun 1988} as well as all normal B lymphocytes in peripheral blood and spleen, but not by 
granulocytes, monocytes, platelets, erythrocytes, and T lymphocytes {Uckun 1988}. Briefly, the 

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anti-CD19 CAR comprises the following domains: an anti-human CD19 single-chain variable 
region fragment derived from the murine monoclonal antibody FMC63; the partial extracellular 
domain and complete transmembrane and intracellular signaling domains of human CD28, a 
lymphocyte costimulatory receptor that plays an important role in optimizing T-cell survival and 
function; and the cytoplasmic portion, including the signaling domain, of human CD3ζ, a 
component of the T-cell receptor complex {Nicholson 1997}. Following CAR engagement with 
CD19+ target cells, the CD3ζ domain activates a downstream signaling cascade that leads to 
T-cell activation, proliferation, and acquisition of effector function.
Approval was based on ZUMA-1, a single-arm multicenter trial of 101 adult patients with 
aggressive B-cell NHL. Eligible patients had refractory disease to the most recent therapy or 
relapse within 1 year after autologous hematopoietic stem cell transplantation. Patients received 
a single infusion of axicabtagene ciloleucel following completion of conditioning chemotherapy. 
Efficacy was established on the basis of an objective response rate (ORR) of 72% with a CR rate 
of 51%, as determined by an independent review committee (IRC) per {Cheson 2007, 
YESCARTA 2019}. In addition, the median duration of response (DOR) by IRC assessment per 
{Cheson 2007} was 9.2 months. The DOR was longer in patients with a best overall response of 
CR, as compared to a best overall response of partial remission {YESCARTA 2019}.
The most common Grade 3 or higher adverse reactions (incidence of 10% or greater) include 
febrile neutropenia, fever, cytokine release syndrome (CRS), encephalopathy, infections-
pathogen unspecified, hypotension, hypoxia, and lung infections. Serious adverse reactions 
occurred in 52% of patients and the most common serious adverse reactions (> 2%) included 
encephalopathy, fever, lung infection, febrile neutropenia, cardiac arrhythmia, cardiac failure, 
urinary tract infection, renal insufficiency, aphasia, cardiac arrest, Clostridium difficile infection, 
delirium, hypotension, and hypoxia. Fatal cases of CRS and neurologic toxicity occurred. The 
FDA approved axicabtagene ciloleucel with a Risk Evaluation and Mitigation Strategy 
{YESCARTA 2019}.
The dose of axicabtagene ciloleucel is a single intravenous (IV) infusion with a target of 
2 x 106 CAR-positive viable T cells per kg body weight (maximum 2 x 108 CAR-positive viable 
T cells per kg body weight), preceded by fludarabine and cyclophosphamide conditioning 
chemotherapy. Axicabtagene ciloleucel is not indicated for the treatment of patients with primary 
CNS lymphoma. Additional details regarding the mechanism of action and clinical results of 
axicabtagene ciloleucel can be found in the Investigator’s Brochure (IB).
2.4.
Prior Anti-CD19 CAR T-cell Study Designs and Results
Refer to the current axicabtagene ciloleucel IB for the most current anti-CD19 CAR T-cell 
nonclinical and clinical information.

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3.
STUDY DESIGN AND RATIONALE
3.1.
General Study Design
Study KTE-C19-112 (ZUMA-12) is a Phase 2 multicenter, open-label study evaluating the 
efficacy and safety of axicabtagene ciloleucel as first-line therapy in adult subjects with high-risk 
large B-cell lymphoma, including either HGBL with MYC and BCL2 and/or BCL6 translocations 
(double-/triple-hit lymphomas) or large B-cell lymphomas with high-intermediate-/high-risk IPI 
scores (≥ 3). Approximately 40 subjects will be enrolled upon a positive interim PET per the 
Lugano Classification {Cheson 2014} (Deauville 5-point scale [5PS] PET score of 4 or 5) after 
2 cycles (PET2+) of standard-of-care chemoimmunotherapy.
Subjects will proceed through the following study periods:

Screening

Enrollment/Leukapheresis


Conditioning chemotherapy period

Investigational product treatment period

Post-treatment assessment period

Long-term follow-up (LTFU) period
At the end of ZUMA-12, subjects who received an infusion of axicabtagene ciloleucel will 
complete the remainder of the 15-year follow-up assessments in a separate LTFU study, 
KT-US-982-5968.
An independent Data Safety Monitoring Board (DSMB) will be chartered to meet and review the 
serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) on 
a semi-annual basis after the first subject has been treated with axicabtagene ciloleucel up 
through the primary analysis. Kite Pharma, Inc. (hereafter referred to as Kite or Kite Pharma), or 
delegate, will submit SAEs and SUSARs to the DSMB on a regular basis throughout the study 
up through the primary analysis. The DSMB will also meet to review safety data after 
15 subjects have been enrolled and treated with axicabtagene ciloleucel and have had an 
opportunity to be followed for 3 months after axicabtagene ciloleucel infusion. The DSMB will 
make trial conduct recommendations on an ongoing basis based on an analysis of risk versus 
benefit. The DSMB may request additional safety data for review or recommend modifications 
to the study conduct if safety concerns are identified. Refer to Section 9.10 for further details. 
For study requirements assigned to each study period, refer to the schedule of assessments 
(SOA) (Table 3) and Section 7 for details.
A study schema is described in Figure 1.
CCI

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19-l 12 (ZUMA-12) 
3.2. 
Study Design Rationale 
Kite Phruma, Inc. 
ZUMA-12 is an open-label, single-aim study evaluating the efficacy and safety of axicabtagene 
ciloleucel as first-line therapy in adult subjects with high-risk lai·ge B-cell lymphoma (ie, 
double-/triple-hit lymphomas or large B-cell lymphoma with IPI scores 2::. 3). 
Immunotherapy, which is based on the enhancement of an immune response against the tumor, is 
a promising approach to treating many cancer types. T cells play an important role in destrnying 
diseased cells throughout the body. Studies with immune checkpoint inhibitors and bi-specific 
T-cell engagers have demonstrated the potential of T cells to treat cancer. T cells need to possess 
the appropriate specificity for a tumor, be present in sufficient numbers, and overcome any local 
immunosuppressive factors to be effective. CAR-engineered T cells may address these issues 
and ai·e an approach for cancer therapy. 
Axicabtagene ciloleucel is an engineered autologous T-cell immunotherapy in which a patient's 
own T cells ai·e collected and subsequently genetically altered to recognize CD 19. CD 19 is 
expressed on the cell surface ofB-cell malignancies and nonnal B cells. In the pivotal ZUMA-I 
Phase 1/2 trial, the safety and efficacy of axicabtagene ciloleucel were evaluated in patients with 
refracto1y DLBCL, primaiy mediastinal B-cell lymphoma (PMBCL), and transfo1med folliculai· 
lymphoma. In ZUMA-I, the ORR was 72% with a CR rate of 51 %, as dete1mined by an IRC 
IWG 2007 criteria Cheson 2007 and met the rimai end oint YESCARTA 2019 . 
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Axicabtagene Ciloleucel 
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Axicabtagene ciloleucel may also have improved efficacy and tolerabili 
chemo-refracto1 disease or in atients with lower disease burden. 
Kite Phruma, Inc. 
Patients with double-/triple-hit lymphoma or high-inte1mediate-/high-risk IPI (IPI score ~ 3) 
have a high unmet medical need. Therefore, axicabtagene ciloleucel will be assessed as first-line 
treatment in these high-risk large B-cell lymphoma patients who are also PET positive after 
2 cycles (PET2+) of standard-of-care chemoimmunotherapy. 
3.2.1. 
Rationale for Conditioning Chemotherapy 
Increasing levels of conditioning chemotherapy coITelates with clinical responses to adoptive cell 
therapy {Dudley 2008}. Specifically, there appears to be a link between adequate 
lymphodepletion and adoptively transfe1Ted T-cell expansion and function in preclinical models, 
which demonstrate that the depth and duration of lymphodepletion coITelates with anti tumor 
activity of the adoptively transfe1Ted tumor-specific ens+ T cells { Gattinoni 2005}. 
Lymphodepletion may function by eradicating cytokine sinks for the transfe1Ted cells, 
eliminating T regulato1y cells, or enhancing antigen presenting cell activation {Klebanoff 2005}. 
The cyclophosphamide and fludarabine combination is a potent conditioning chemotherapy 
regimen. Cyclophosphamide (500 mg/m2/day) and fludarabine (30 mg/m2/day) are both given for 
3 consecutive days. This combination has been studied in subjects with B-cell malignancies and 
was tolerated by this population {Kochenderfer 2017, O'Brien 2001}. The low-dose conditioning 
chemotherapy regimens used in these studies could not directly induce durable remissions. 
Low-dose cyclophosphamide and fludarabine alone increases interleukin (IL )-15, IL-7 and 
monocyte chemoattractant protein (MCP)-1 sernm levels, which increased IL-15 sernm levels is 
associated with efficacy of anti-CD19 CART cells {Kochenderfer 2017}. This low-dose 
cyclophosphamide and fludarabine conditioning chemotherapy was also used in the pivotal 
ZUMA-I {Locke 2017, Neelapu 2017} 
3.2.2. 
Rationale for Axicabtagene Ciloleucel Dose 
The rationale for the axicabtagene ciloleucel dose in this study is based on the aggregate safety 
and efficacy data compiled from ZUMA-I as outlined in the IB. Based on the favorable 
benefit/risk ratio seen in ZUMA-I and FDA approval for the treatment of adult patients with 
relapsed or refracto1y large B-cell lymphoma after 2 or more lines of systemic therapy, 
axicabtagene ciloleucel will be administered at a target dose of 2 x 106 anti-CD19 
CART cells/kg but subjects may be dosed at a minimum of 1 x 106 anti-CD19 CART cells/kg. 
For subjects weighing~ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 
2 x 108 anti-CD19 CART cells will be administered. 
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A positive risk benefit ratio is further supported by the expectation that subjects in this study will 
have a lower disease burden at the time of axicabtagene ciloleucel administration as they are 
receiving the dose earlier in their disease course compared to subjects in ZUMA-1 {Locke 
2018}. In ZUMA-1, the observed response rates were consistent when comparing subsets with 
high versus lower tumor burden based on medians (ZUMA-1 clinical study report [CSR]; 
Section 11.1.1.3).
3.3.
Participating Sites
Approximately 10 centers located in North America and the European Union will participate in 
this study and other regions may be considered. During the conduct of the study, additional 
regions, countries, or sites may be added as necessary.
3.4.
Number of Subjects
Participants in this trial will be referred to as “subjects.” It is anticipated that approximately 
40 subjects will be enrolled and treated into this study.
3.5.
Replacement of Subjects
Subjects may continue to be enrolled until the specified number of subjects are dosed with 
axicabtagene ciloleucel. Subjects who have not received axicabtagene ciloleucel will be retained 
in the analyses of disposition and safety, where appropriate (see Section 10.6).
3.6.
Study Duration
3.6.1.
Study Duration for Individual Subjects
The duration of the study for individual subjects will be up to approximately 15 years. The 
duration of participation for individual subjects will vary depending on a subject’s screening 
requirements, response to treatment, survival, and timing of transition to the separate Kite LTFU 
study, KT-US-982-5968 (discussed in Section 7.13).
Following at least 36 months of assessments in the ZUMA-12 protocol, subjects who received an 
infusion of axicabtagene ciloleucel will complete the remainder of the 15-year follow-up 
assessments in the separate LTFU study, KT-US-982-5968. 
For a subject who completes participation in this study and also completes the LTFU period in 
the separate LTFU study, the entire duration of a subject’s participation in both studies will be up 
to approximately 15 years after the initial infusion of axicabtagene ciloleucel. The need for 
prolonged follow-up is based on the potential persistence of gene transfer vectors in treated 
subjects and need to understand and mitigate the potential risks of delayed onset adverse events 
(AEs) that could be the potential consequence of this emerging technology.

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3.6.2.
Completion of Study
Completion of the study is defined as the time at which the last subject completes at least 
36 months of assessments, is lost to follow-up, withdraws consent, or dies. Upon activation of 
the LTFU study, KT-US-982-5968 at the subject’s study site, the subject will be offered the 
opportunity to complete LTFU assessments under the KT-US-982-5968 protocol.

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4.
SUBJECT IDENTIFICATION ASSIGNMENT
Each subject who enters the screening period, which starts when the subject signs the informed 
consent form (ICF), will receive a unique subject identification (ID) number. This number will 
be used to identify the subject throughout the study and must be used on all study documentation 
related to the subject. The subject identification number will never be changed even if the subject 
is rescreened.

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5.
SUBJECT ELIGIBILITY
5.1.
Inclusion Criteria
101)
Large B-cell lymphoma with one or more of the following features:
a) HGBL with MYC and BCL2 and/or BCL6 translocations (double-hit or triple-hit) as 
determined by investigator by fluorescent in situ hybridization 
OR
b) Other histologically confirmed large B-cell lymphoma defined by WHO 2016 
{Swerdlow 2016} with an IPI score of ≥ 3 at initial diagnosis or anytime between 
initial diagnosis and enrollment, including the following lymphoma types:
i)
DLBCL-NOS, including GCB type and ABC type
ii) Intravascular large B-cell lymphoma
iii) T-cell/histiocyte-rich large B-cell lymphoma
iv) DLBCL associated with chronic inflammation
v) Epstein-Barr virus + DLBCL-NOS
vi) HGBL-NOS
102)
Subjects must have a positive interim PET per the Lugano Classification {Cheson 
2014}(Deauville PET score of 4 or 5) after 2 cycles (PET2+) of chemoimmunotherapy as 
follows:
a) 2 cycles of an anti-CD20 monoclonal antibody (unless investigator determines that 
tumor is CD20 negative) and anthracycline-containing regimen (eg, DA-EPOCH-R), 
with or without intrathecal chemotherapy, at the discretion of the investigator per 
local standard of care for double-hit or triple-hit lymphoma
OR
b) 2 cycles of an anti-CD20 monoclonal antibody (unless investigator determines that 
tumor is CD20 negative) and anthracycline-containing regimen (eg, R-CHOP) at the 
discretion of the investigator per local standard of care for large B-cell lymphoma 
with IPI score of ≥ 3
103)
At least 2 weeks must have elapsed since any prior systemic therapy at the time the 
subject is planned for leukapheresis

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104)
No evidence, suspicion, and/or history of CNS involvement of lymphoma
105)
Toxicities due to prior therapy must be stable and recovered to Grade 1 or less (except for 
clinically nonsignificant toxicities such as alopecia)
106)
Age 18 or older
107)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
108)
Adequate bone marrow, renal, hepatic, pulmonary, and cardiac function defined as:
a) Absolute neutrophil count ≥ 1000/μL
b) Platelet count ≥ 75,000/μL
c) Absolute lymphocyte count ≥ 100/μL
d) Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min
e) Serum alanine aminotransferase and aspartate aminotransferase ≤ 2.5 upper limit of 
normal (ULN)
f)
Total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert’s syndrome
g) Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion (except trace or 
physiological) as determined by an echocardiogram (ECHO), and no clinically 
significant electrocardiogram findings 
h) No clinically significant pleural effusion
i)
Baseline oxygen saturation > 92% on room air
109)
Females of childbearing potential must have a negative serum or urine pregnancy test 
(females who have undergone surgical sterilization or who have been postmenopausal for 
at least 2 years are not considered to be of childbearing potential).
5.2.
Exclusion Criteria
201)
History of malignancy other than nonmelanoma skin cancer or carcinoma in situ 
(eg, cervix, bladder, breast) unless disease free for at least 3 years
202)
History of Richter’s transformation of chronic lymphocytic leukemia or PMBCL
203)
History of autologous or allogeneic SCT
204)
Prior CD19-targeted therapy
205)
Prior CAR therapy or other genetically modified T-cell therapy

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206)
History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
207)
Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or 
requiring IV antimicrobials for management; simple urinary tract infection and 
uncomplicated bacterial pharyngitis are permitted if responding to active treatment and 
after consultation with the sponsor’s medical monitor
208)
History of human immunodeficiency virus (HIV) infection or acute or chronic active 
hepatitis B or C infection; subjects 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 guidelines or applicable country guidelines
209)
Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube, indwelling 
Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter); dedicated central 
venous access catheters, such as a Port-A-Cath® or Hickman® catheter, are permitted
210)
Subjects with detectable cerebrospinal fluid malignant cells, brain metastases, or active 
CNS lymphoma
211)
History or presence of CNS disorder, such as seizure disorder, cerebrovascular 
ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS 
involvement
212)
Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
213)
History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or 
other clinically significant cardiac disease within 12 months of enrollment
214)
Requirement for urgent therapy due to tumor mass effects (eg, blood vessel compression, 
bowel obstruction, or transmural gastric involvement)
215)
Primary immunodeficiency
216)
History of autoimmune disease (eg, Crohns, rheumatoid arthritis, systemic lupus) 
resulting in end organ injury or requiring systemic immunosuppression/systemic disease 
modifying agents within the last 2 years
217)
History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of 
enrollment
218)
Any medical condition likely to interfere with assessment of safety or efficacy of study 
treatment
219)
History of severe immediate hypersensitivity reaction to any of the agents used in this 
study
220)
Live vaccine ≤ 6 weeks prior to planned start of conditioning regimen

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221)
Women of childbearing potential who are pregnant or breastfeeding because of the 
potentially dangerous effects of the preparative chemotherapy on the fetus or infant. 
Females who have undergone surgical sterilization or who have been postmenopausal for 
at least 2 years are not considered to be of childbearing potential
222)
Subjects of either sex who are not willing to practice birth control from the time of 
consent through 6 months after the completion of conditioning chemotherapy or 
axicabtagene ciloleucel infusion, whichever is longer
223)
In the investigator’s judgment, the subject is unlikely to complete all protocol-required 
study visits or procedures, including follow-up visits, or comply with the study 
requirements for participation

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6_ 
6.1. 
6.1.1. 
PROTOCOL TREATMENT 
Study Treatment 
Leukapheresis 
Kite Phruma, Inc. 
Leukapheresis refers to the procedure for collecting peripheral blood mononuclear cells 
(PBMCs) that are used to manufacture axicabtagene ciloleucel. 
Subjects will undergo leukapheresis to obtain T cells for the manufacturing of axicabtagene 
ciloleucel. Leukapheresed cells obtained at paiiicipating centers will be shipped to the sponsor's 
manufacturing facility as described in the Investigational Product Manual (1PM). 
At least 2 weeks must have elapsed since any prior systemic therapy at the time the subject is 
planned for leukapheresis. 
-
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6.1.3.
Conditioning Chemotherapy
Conditioning chemotherapy refers to fludarabine and cyclophosphamide used for 
lymphodepletion prior to administration of axicabtagene ciloleucel.
Conditioning chemotherapy will be supplied by the investigative site unless otherwise noted.
Refer to the current product label for guidance on packaging, storage, preparation, administration, 
and toxicity management associated with the administration of chemotherapy agents.
6.1.3.1.
Fludarabine
Fludarabine phosphate is a synthetic purine nucleoside that differs from physiologic nucleosides 
in that the sugar moiety is arabinose instead of ribose or deoxyribose. Fludarabine is a purine 
antagonist antimetabolite.
Refer to the most recent version of the package insert for specific details surrounding the 
administration of fludarabine.
6.1.3.2.
Cyclophosphamide
Cyclophosphamide is a nitrogen mustard-derivative that acts as an alkylating agent following 
conversion to active metabolites in the liver and has potent immunosuppressive activity. The 
serum half-life after IV administration ranges from 3 to 12 hours; the drug and/or its metabolites 
can be detected in the serum for up to 72 hours after administration.
Refer to the most recent version of the package insert for specific details surrounding the 
administration of cyclophosphamide.
CCI

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19-l 12 (ZUMA-12) 
6.1.3.3. 
Mesna 
Kite Phruma, Inc. 
Mesna is a detoxifying agent used to inhibit the hemonhagic cystitis induced by chemotherapy. 
The active ingredient in mesna is a synthetic sulfhychy l compound designated as 
sodium-2-mercaptoethane sulfonate with a molecular fo1mula of C2H5NaO3S2. 
Mesna should be achninistered per institutional guidelines. Refer to the most recent version of the 
package insert for specific details smTounding the achninistration of mesna. 
6.1.4. 
Axicabtagene Ciloleucel 
Axicabtagene ciloleucel is the investigational product for this study. 
There have been no instances of accidental overdose of subjects in this program to date. In case 
of accidental overdose, treatment should be suppo1tive. Co1ticosteroid therapy may be 
considered if any dose is associated with severe toxicity. 
roblems related to the use of axicabta ene ciloleucel 
research staff should report the problem per the instructions in the IPM. 
Refer to the cmTent version of the IB for more details regarding axicabtagene ciloleucel. 
6.1.5. 
Concomitant Therapy 
Concomitant therapy refers to ti·eatment that subjects receive during the conduct of the study. 
During the course of the study, investigators may prescribe any concomitant therapies deemed 
necessaiy to provide adequate suppo1tive cai·e except those medications listed in Section 6.1.6. 
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All concomitant therapies, including medications, intubation, dialysis, oxygen, and blood 
products, will be recorded.
For subjects who receive axicabtagene ciloleucel treatment:

Concomitant therapies will be recorded from the date of the informed consent until 3 months 
after completing treatment with axicabtagene ciloleucel.

After this 3-month follow-up period, targeted concomitant therapies will be recorded for 
either 24 months after axicabtagene ciloleucel infusion or until disease progression, 
whichever occurs first. Targeted concomitant therapies include gammaglobulin, 
immunosuppressive drugs, anti-infective drugs, and vaccinations.
For subjects who are enrolled, but not dosed with axicabtagene ciloleucel, concomitant therapies 
will be recorded from the date of the informed consent until 30 days after the last study-specific 
procedure has occurred (eg, leukapheresis, conditioning chemotherapy) or until the initiation of 
new antilymphoma therapy, whichever occurs first.
For subjects who are not enrolled (eg, screen failure), only concomitant therapies related to any 
SAE[s] will be recorded.
Specific concomitant therapy collection requirements and instructions are included in the case 
report form (CRF) completion guidelines.
6.1.6.
Excluded Medications
Excluded medications refer to treatment that is not to be administered, unless otherwise 
specified, during the conduct of the study.
Corticosteroid therapy at a pharmacologic dose (≥ 5 mg/day of prednisone or equivalent doses of 
other corticosteroids) and other immunosuppressive drugs must be avoided for 7 days prior to 
leukapheresis and 5 days prior to axicabtagene ciloleucel administration.
Systemic corticosteroids may not be administered as premedication to subjects for whom 
CT scans with contrast are contraindicated (ie, subjects with contrast allergy or impaired renal 
clearance). Such subjects should undergo noncontrast CT scans instead.
Corticosteroids and other immunosuppressive drugs should also be avoided for 3 months after 
axicabtagene ciloleucel administration unless used to manage axicabtagene ciloleucel-related 
toxicities. Other medications that might interfere with the evaluation of axicabtagene ciloleucel, 
such as nonsteroidal anti-inflammatory agents, should also be avoided for the same period unless 
medically necessary.
Therapeutic doses of systemic anticoagulants, such as unfractionated heparin and low-molecular 
weight heparin, should be avoided when possible anytime subjects are at risk of bleeding due to 
thrombocytopenia.

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Treatments for lymphoma, such as chemotherapy, immunotherapy, targeted agents, radiation, 
and high-dose corticosteroids (other than those defined/allowed in this protocol) and other 
investigational agents, are prohibited, except as needed for treatment of disease progression after 
axicabtagene ciloleucel.
If permissibility of a specific medication/treatment is in question, contact the sponsor’s medical 
monitor.
6.1.7.
Subsequent Therapy
Subsequent therapy refers to treatment administered after axicabtagene ciloleucel that is 
necessary to treat a subject’s disease.
Subsequent therapy administered after axicabtagene ciloleucel that is necessary to treat a 
subject’s disease, such as non-study specified chemotherapy, immunotherapy, targeted agents, 
SCT, or radiation therapy, will be recorded for subjects until one of the following happens: the 
subject transitions to the LTFU study KT-US-982-5968, is considered lost to follow-up, 
withdraws consent, or dies.
For subjects who are enrolled, but do not receive axicabtagene ciloleucel infusion, any additional 
anti-lymphoma therapy will also be collected until the subject completes their participation in the 
current study, is considered lost to follow-up, withdraws consent, or dies, whichever occurs first.
6.1.8.
Toxicity Management
To date, the following risks have been identified with axicabtagene ciloleucel: CRS, neurologic 
events, infections, cytopenias, and hypogammaglobulinemia. Refer to Section 6 of the current IB 
for details regarding these events and management guidance.
As the safety experience with axicabtagene ciloleucel increases, the management guidance may 
be updated. Therefore, it is important to always refer to the most current version of the 
axicabtagene ciloleucel IB for guidance regarding managing axicabtagene ciloleucel-related 
toxicities. Additional information and management recommendations can also be found in the IB 
regarding important potential risks associated with axicabtagene ciloleucel, as well as possible 
complications associated with malignancy and cancer treatment.
Refer to the SOA (Table 3) for the timing of evaluations for CRS-related symptoms.

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7.
STUDY PROCEDURES
Research staff should refer to the SOA (Table 3) for an outline of the procedures required.
The visit schedule is calculated from axicabtagene ciloleucel infusion on Day 0.
The visit schedule for disease assessments is also calculated from axicabtagene ciloleucel 
infusion on Day 0, including CT scans, PET scans, bone marrow biopsy, physical exams needed 
to assess disease, and collection of subsequent antilymphoma therapy.
An overview of study assessments/procedures is outlined below. Refer to the CRF completion 
guidelines for data collection requirements and best practices for documentation of study procedures.
7.1.
Informed Consent
Before a subject participates in the clinical study, the investigator is responsible for obtaining 
written informed consent from the subject after adequately explaining the study design, anticipated 
benefits, and potential risks. Subjects should sign the most current institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)-approved ICF before any nonstandard-of-care 
study-specific activity or procedure is performed.
The consent process and the subject’s agreement or refusal to participate in the study must be 
documented in the subject’s medical records. If the subject agrees to participate, the ICF must be 
signed and dated by both the subject and the person who conducted the informed consent 
discussion. The original signed ICF will be retained in accordance with institution policy and 
IRB/IEC requirements, and a copy of the ICF will be provided to the subject.
All subjects who are enrolled into the study should be reconsented with any updated version of 
the IRB/IEC-approved ICF if the new version is relevant to their participation.
7.2.
Screening
Investigative sites will maintain a log of all screened subjects who were reviewed and evaluated 
for study participation. Information collected in the screening log should include limited 
information, such as the date of screening, date the subject was enrolled, or the reason for why 
the subject failed screening.
The screening period begins on the date the subject signs the IRB/IEC-approved ICF and 
continues through confirmation of eligibility into the study. Informed consent must be obtained 
before completion of any nonstandard-of-care study-specific procedures. Procedures that are part 
of standard of care are not considered study-specific and, therefore, may be performed prior to 
obtaining consent and used to confirm eligibility provided they occur within the time allowance 
outlined below and in the SOA.
After written informed consent has been obtained, Kite will assign a unique subject ID number to 
the subject.

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See Section 7.2.1 for the study procedures for subjects who rescreen into the study. Only subjects 
who meet the eligibility criteria listed in Section 5 will be enrolled into the study. If at any time 
prior to enrollment the subject fails to meet the eligibility criteria, the subject should be 
designated as a screen failure within the subject’s screening log, and the reasons for failing 
screening should also be recorded.
Refer to the SOA for a listing of study procedures to be completed during the screening period.
7.2.1.
Rescreening
Subjects who are unable to complete or meet the eligibility criteria during the 28-day screening 
period will be permitted to rescreen 1 time. Subjects will retain the same subject ID number 
assigned at the original screening. If rescreening occurs within 28 days of the signing of the 
original informed consent, it is only necessary to perform the procedure(s)/assessment(s) that did 
not originally meet the eligibility criteria; all other initial screening procedures/assessments do 
not need to be repeated. If rescreening occurs after more than 28 days, or leukapheresis is 
delayed more than 28 days from the signing of the original informed consent, subjects must be 
reconsented and repeat all screening procedures/assessments.
7.3.
Demographic Data
Demographic data will be collected as per country and local regulations and guidelines. Where 
applicable, demographic data will include sex, year of birth, race, ethnicity, and country of 
enrollment to study a possible association between these variables and subject safety and 
treatment effectiveness.
7.4.
Medical and Treatment History
Relevant medical history prior to the start of AE reporting will be collected. Relevant medical 
history is defined as data on the subject’s current medical condition that would be typically 
shared in a referral letter. In addition to the medical history, all history related to the subject’s 
disease, treatment, and response to treatment will be collected and must date back to the original 
diagnosis. All findings will be recorded on the CRFs.
For subjects who are being referred from another clinic or institution to the participating research 
center, copies from the subject’s chart should be obtained.
7.5.
Conditioning Chemotherapy and Axicabtagene Ciloleucel Infusion
Administration of CAR T cells to subjects with ongoing infection or inflammation, even if such 
processes are asymptomatic, increases the risk of high-grade and fatal toxicity. All efforts should 
be made to rule out such conditions prior to cell infusion. Signs, symptoms, or abnormal 
laboratory results attributed to the malignancy tumor fever and elevated C-reactive protein (CRP) 
are diagnoses of exclusion that require a documented workup to establish. Conditioning 
chemotherapy and axicabtagene ciloleucel infusion should be initiated only once it is reasonably 
assured that cell infusion can safely proceed.

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Refer to Section 7.5.3 for requirements for workup of potential infectious and/or inflammatory 
states.
7.5.1.
Requirements for Initiating Conditioning Chemotherapy
If any of the following criteria are met prior to the initiation of conditioning chemotherapy, then 
the workup listed in Section 7.5.3 must be performed to determine the potential cause if there is 
no identified source of infection.

Temperature > 38°C within 72 hours of conditioning chemotherapy

CRP > 100 mg/L anytime between enrollment to start of conditioning chemotherapy

White blood cell (WBC) count or WBC differential concerning for infectious process 
between enrollment to start of conditioning chemotherapy WBC > 20,000, rapidly increasing 
WBC, or differential with high percentage of segs/bands)
Additionally:

If any screening assessments or procedures are repeated between confirmation of eligibility 
and the start of conditioning chemotherapy and results are outside the eligibility criteria listed 
in Section 5, then the condition must resolve prior to proceeding with conditioning 
chemotherapy.

Complete history and physical exam including head, eyes, ears, nose, and throat (HEENT), 
and cardiac, vascular, respiratory, gastrointestinal, integumentary, and neurological systems 
must not reveal evidence of infection/inflammation.

The subject must not have received systemic antimicrobials for the treatment of a known or 
suspected infection within 48 hours before conditioning chemotherapy (prophylactic use of 
antimicrobials is allowed).

The treatment course of any antimicrobials given for known or suspected antecedent 
infection should be complete as per infectious disease consult (if applicable) 
recommendation before stopping or switching to prophylactic antimicrobials.

If a subject is confirmed to have an infectious process for which antimicrobials are not 
available (eg, viral pneumonia), the infection must be clinically resolved as determined by 
the investigator in consultation with the infectious disease service (if applicable).

Most recently collected blood, urine, or other body fluid cultures must show no growth for at 
least 48 hours, and any other infectious workup performed (bacterial, viral serologies, 
polymerase chain reaction (PCR), stool studies, imaging studies) must be negative. If clinical 
suspicion is for an infection for which cultures are unlikely to be positive within 48 hours 
(eg, fungal infection), adequate time must be allowed for cultures to become positive.
Once the above criteria are met, then the subject can proceed with conditioning chemotherapy.

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7.5.2.
Requirements for Initiating Axicabtagene Ciloleucel Infusion
If any of the following criteria are met prior to the initiation of axicabtagene ciloleucel infusion, 
then the workup listed in Section 7.5.3 must be performed to determine the potential cause if 
there is no identified source of infection.

Temperature > 38°C within 72 hours of axicabtagene ciloleucel infusion

CRP > 100 mg/L anytime between enrollment to start of axicabtagene ciloleucel infusion

WBC count or WBC differential concerning for infectious process between enrollment to 
start of axicabtagene ciloleucel infusion WBC > 20,000, rapidly increasing WBC, or 
differential with high percentage of segs/bands)
Additionally:

If any screening assessments or procedures are repeated between confirmation of eligibility 
and the start of axicabtagene ciloleucel infusion and results are outside the eligibility criteria 
listed in Section 5, then the condition must resolve prior to proceeding with axicabtagene 
ciloleucel infusion (except for peripheral blood cell counts that have been impacted by 
conditioning chemotherapy).

Complete history and physical exam including HEENT, and cardiac, vascular, respiratory, 
gastrointestinal, integumentary, and neurological systems must not reveal evidence of 
infection/inflammation.

The subject must not have received systemic antimicrobials for the treatment of a known or 
suspected infection within 48 hours before axicabtagene ciloleucel (prophylactic use of 
antimicrobials is allowed).

The treatment course of any antimicrobials given for known or suspected antecedent 
infection should be complete as per infectious disease consult (if applicable) 
recommendation before stopping or switching to prophylactic antimicrobials.

If a subject is confirmed to have an infectious process for which antimicrobials are not 
available (eg, viral pneumonia), the infection must be clinically resolved as determined by 
the investigator in consultation with the infectious disease service (if applicable).

Most recently collected blood, urine, or other body fluid cultures must show no growth for at 
least 48 hours, and any other infectious workup performed (bacterial, viral serologies, PCR, 
stool studies, imaging studies) must be negative. If clinical suspicion is for an infection for 
which cultures are unlikely to be positive within 48 hours (eg, fungal infection), adequate 
time must be allowed for cultures to become positive.
Once the above criteria are met, then the subject can proceed with administration of axicabtagene 
ciloleucel.
If the axicabtagene ciloleucel infusion is delayed > 2 weeks, protocol-specified conditioning 
chemotherapy must be repeated.

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7.5.3.
Requirements to Work-up Potential Infectious and/or Inflammatory States
In the absence of an identified source of infection (eg, line infection, pneumonia on chest x-ray), 
the minimum workup to be performed prior to administration of conditioning chemotherapy 
and/or axicabtagene ciloleucel consists of:

Call Kite medical monitor

Infectious disease service consult

CT imaging of the chest, abdomen, and pelvis with IV contrast. If there is a medical 
contraindication to contrast, then noncontrast CT is allowed.

The following must be performed (prior to the initiation of antimicrobials if clinically 
feasible):
Blood cultures (aerobic and anaerobic x 2 bottles each) and urinalysis and urine culture. 
Deep/induced sputum culture if clinically indicated
All indwelling lines, such as central venous catheters, should be examined for any signs 
of infection and additional cultures should be drawn from the line.
Nasopharyngeal-throat swab or equivalent assay for viral infection, such as influenza A/B 
(including H1N1), parainfluenza 1/2/3, adenovirus, respiratory syncytial virus, 
coronavirus, metapneumovirus
Collection of fungal cultures and markers as appropriate (galactomannan, Fungitell®)
Collection of appropriate serum viral studies (eg, cytomegalovirus)

If a CNS process is suspected, appropriate brain imaging and subsequent lumbar puncture 
with cytology, culture, Gram stain, and viral PCR should be performed.

Any additional sign or symptom-directed investigation should be performed as clinically 
indicated.
Prior to proceeding with conditioning chemotherapy or axicabtagene ciloleucel infusion, the 
above workup must not suggest the presence of an active infection and all requirements for 
conditioning chemotherapy and axicabtagene ciloleucel infusion must be satisfied.
If the above workup was triggered due to CRP > 100 mg/L, testing for CRP should be repeated, 
and if CRP continues to increase significantly, evaluation should be performed for any other 
potential infectious or inflammatory condition not previously evaluated.

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7.5.4.
Conditioning Chemotherapy Administration (Day –5 Through Day –3 Prior 
to Axicabtagene Ciloleucel Infusion)
Subjects will receive a conditioning chemotherapy regimen consisting of cyclophosphamide and 
fludarabine. The first dose of conditioning chemotherapy will be designated as Day –5. Subjects 
will initiate conditioning chemotherapy with cyclophosphamide and fludarabine beginning on 
Day –5 and through Day –3, with 2 rest days (Day –2 and Day –1) before receiving axicabtagene 
ciloleucel. The 3-day conditioning chemotherapy regimen will be administered in an outpatient 
setting.
The 3-day conditioning regimen of fludarabine and cyclophosphamide will be administered in 
accordance with the following daily dosing instructions:

IV hydration with a balanced crystalloid according to institutional guidelines prior to 
administration of cyclophosphamide on the day of infusion

Cyclophosphamide 500 mg/m2 IV over approximately 60 minutes or per institutional 
guidelines

Fludarabine 30 mg/m2 IV over approximately 30 minutes or per institutional guidelines

Additional IV hydration with a balanced crystalloid according to institutional guidelines to be 
administered upon completion of the cyclophosphamide infusion

Mesna to be administered per institutional guidelines
Subjects should be instructed to drink plenty of liquids during chemotherapy and throughout the 
24-hour period following chemotherapy (approximately 2 L/24 hours). In general, subjects 
should be kept well hydrated but closely monitored to prevent fluid overload. 
Refer to the SOA Table 3 for a listing of study procedures to be completed during the 
axicabtagene ciloleucel conditioning chemotherapy period.
7.6.
Physical Exam, Vital Signs, and Performance Status
Physical exams will be performed during screening and at times noted in the SOA. All physical 
exam changes noted in subsequent exams when compared to the baseline exam will be reported 
as AEs.
Vital signs, including blood pressure (BP), heart rate, respiratory rate, oxygen saturation, and 
temperature, will be monitored and recorded at screening and at times outlined in the SOA. In 
addition to the time points outlined in the SOA, it is recommended that vital signs are monitored 
during and after study treatment (see Section 6) and as clinically indicated.
Performance status as measured by the ECOG scale will be performed to quantify the subject’s 
general well-being and ability to perform activities of daily life.

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7.7.
Cardiac Function
Each subject’s cardiac function, as measured by left ventricular ejection fraction, will be 
assessed during the screening period to confirm study eligibility. No evidence of pericardial 
effusion will also be confirmed, per study eligibility criteria. Both the left ventricular ejection 
fraction and pericardial effusion will be assessed prior to study entrance by an ECHO. An ECHO 
that was performed after the subject’s last chemoimmunotherapy treatment may also be used to 
confirm eligibility, provided that it occurred ≤ 28 days prior to signing the consent.
To establish a baseline, a 12-lead electrocardiogram will also be performed during the screening 
period.
7.8.
Neurological Examination
A neurological examination will be performed, and any of the following abnormalities will be 
recorded: level of consciousness, orientation, vision, cranial nerves and brain stem functions, 
pyramidal and extra pyramidal motor system, reflexes, muscle tone and trophic findings, 
coordination, sensory system, and neuropsychological findings (eg, speech, cognition, and 
emotion).
A neurological examination should be done prior to axicabtagene ciloleucel infusion on 
treatment Day 0, then on Day 1, Day 3, Day 5, and Day 7 during the observation period, which 
must last a minimum of 7 days.
For new onset of neurologic symptoms suspected to be related to axicabtagene ciloleucel 
treatment, refer to Section 6.1.8. Subjects will be specifically asked about changes in 
neurological status since the previous neurological examination, as noted in the SOA 
(see Table 3).
7.9.
Disease Assessment
Subjects will be evaluated for disease response by the site investigator at times indicated in the 
SOA. Disease assessments will be evaluated per the Lugano Classification {Cheson 2014} 
(see Appendix 1). Flow cytometric, molecular, or cytogenetic studies will not be used to 
determine response.
7.9.1.
Imaging
7.9.1.1.
Pre-treatment Disease Assessment
A fluorodeoxyglucose (FDG)-PET from skull base to mid-thighs and a diagnostic quality 
contrast-enhanced (unless contraindicated) CT from skull base through lesser trochanters 
(PET-CT), along with the appropriate imaging of all other sites of disease must be performed 
within 28 days prior to enrollment/leukapheresis.

Axicabtagene Ciloleucel 
Clinical Protocol 
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If a PET-CT cannot be perfonned as standard of care following 2 cycles of 
chemoimmunotherapy, a subject may have the PET-CT perfonned on study after infonned 
consent is obtained. 
7.9.1.2. 
Post-ti·eatment Response Assessment 
Post-ti·eatment PET-CT response assessments will begin at Day 28 and continue at time points 
outlined in the SOA (Table 3). If there was evidence of baseline bone maITow involvement and 
no PET-CT is available or if there are unexplained cytopenias or suspicion of bone maITow 
involvement, then a bone maiTow aspirate and biopsy will be perfo1med in subjects who are 
being assessed for CR. To confnm a CR, the bone man ow aspirate and biopsy must show no 
evidence of disease by m01phology, or, if indetenninate by mo1phology, must be negative by 
immunohistochemistiy. 
PET-CTs will continue through Month 24 or until disease progression, whichever comes first. If 
the subject's disease has not progressed by Month 24, disease assessments can then be perfo1med 
at standai·d-of-cai·e intervals. Subjects with symptoms suggestive of disease progression should 
be evaluated for progression at the time symptoms occur even if this requires an unscheduled 
visit. If the subject has sta1ted subsequent antilymphoma therapy, then imaging assessments will 
no longer be required per protocol. PET-CT can be perfonned at any time disease progression is 
suspected. FDG-PET assessment takes precedence over CT assessment for time points when 
both are available. If only CT is available for a paiticulai· time point, then the CT assessment 
should include a comparison with and may be affected by the PET-CT assessment at the prior 
time point. Please refer to the imaging manual for finther details. 
Bone maiTow aspirate/biopsy should also be considered to evaluate hemophagocytic 
lymphohistiocytosis as indicated. Refer to the IB for additional infonnation. 
7.9.1.3. 
Response Evaluation to Reti·eatment 
For the pmpose of dete1mining response to reti·eatment with axicabtagene ciloleucel, the last 
scan prior to reu-eatment will be considered the baseline. 
7.9.2. 
Determination of Bone Marrow Involvement 
A subject's bone maiTow involvement should be confnmed by PET-CT or bone maITow biopsy 
and aspirate prior to enrollment. Confinnation of man ow involvement from dete1mination at 
initial diagnosis or between diagnosis and screening is acceptable. 
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7.10. 
Cell Collection and Axicabtagene Ciloleucel Study Treatment Schedule and 
Administration 
7.10.1. 
Leukapheresis 
Subjects must remain eligible per the eligibility criteria outlined in Section 5 prior to the sta1t of 
leukapheresis. 
If any screening assessments or procedures are repeated between confinnation of eligibility and 
the strut of leukapheresis and results m·e outside the eligibility criteria listed in Section 5, conta.ct 
the sponsor's medical monitor prior to proceeding with leukapheresis. 
Before leukapheresis commences, the following criteria must be met: 
• 
No evidence or suspicion of an infection 
• 
Co1ticosteroid therapy at a phmmacologic dose (~ 5 mg/day of prednisone or equivalent 
doses of other c01ticosteroids) and other immunosuppressive diugs must be avoided for 
7 days prior to leukapheresis 
The leukapheresis visit should occur within approximately 5 days of eligibility confnmation. 
After a subject commences leukapheresis, the subject will be considered emolled into the study. 
If criteria m·e not met, leukapheresis must be delayed until the event resolves. If leukapheresis is 
delayed more than 5 days after eligibility confnmation, baseline complete blood count (CBC) 
with differential and chemistry panel must be repeated. If results are outside the eligibility 
criteria listed in Section 5, contact the medical monitor prior to proceeding with leukapheresis. 
After the above criteria m·e met, mononuclem· cells will be obtained by leukapheresis 
(12 to 15 L) with a goal to tm·get approximately 5 to 10 x 109 mononuclem· cells. The 
leukapheresed cells m·e then packaged for expedited shipment to the manufacturing facility as 
described in the IPM. 
Refer to the SOA Table 3 for a listing of study procedures to be completed on the leukapheresis 
collection day and as outlined in the SOA. 
-
CONFIDENTIAL 
Page 41 
14 JUN 2022 

Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
Page 42
14 JUN 2022
7.10.3.
Axicabtagene Ciloleucel Treatment Period
7.10.3.1.
Axicabtagene Ciloleucel Premedication Dosing
The following pre-axicabtagene ciloleucel infusion medications should be administered 
approximately 1 hour prior to infusion:

Acetaminophen 500 to 1000 mg taken orally or equivalent

Diphenhydramine 12.5 to 25 mg administered either orally or via IV or equivalent
7.10.3.2.
Axicabtagene Ciloleucel Administration Day 0
All subjects will receive axicabtagene ciloleucel infusion at a healthcare facility, followed by 
daily monitoring at a healthcare facility for ≥ 7 days to monitor for signs and symptoms of CRS 
and neurologic events. Alternatively, subjects may be hospitalized to receive their axicabtagene 
ciloleucel infusion and be observed for CRS and neurologic events in the hospital setting, if 
deemed appropriate by the investigator. Post-infusion monitoring of subjects must be for a 
minimum of 7 days unless otherwise required by country regulatory agencies (refer to 
Appendix 3).
If subjects are hospitalized, subjects should not be discharged from the hospital until all 
axicabtagene ciloleucel-related non-hematological toxicities resolve to Grade 1 or lower, or 
return to baseline. Subjects may be discharged with noncritical and clinically stable or improving 
toxicities (eg, renal insufficiency) even if higher than Grade 1, if deemed appropriate by the 
investigator. Subjects should remain in a hospital for ongoing axicabtagene ciloleucel-related 
fever, hypotension, hypoxia, or ongoing neurologic events higher than Grade 1, or if deemed 
necessary by the investigator.
Subjects should be instructed to remain within proximity of the clinical study site for at least 
4 weeks following axicabtagene ciloleucel infusion. Subjects should be advised to refrain from 
driving and engaging in hazardous occupations or activities, such as or operating heavy or 
potentially dangerous machinery, for at least 8 weeks following axicabtagene ciloleucel infusion. 
Subjects and their family members/caregivers should be educated on potential CRS and 
neurologic symptoms, such as fever, dyspnea, confusion, aphasia, dysphasia, somnolence, 
encephalopathy, ataxia, or tremor. Subjects or their family members/caregivers should be 
instructed to immediately contact the treating investigator or seek immediate medical attention if 
any of these symptoms develop.
Refer to the SOA for a listing of study procedures to be completed during the axicabtagene 
ciloleucel treatment period.
Central venous access, such as a port or a peripherally inserted central catheter, is required for 
the administration of axicabtagene ciloleucel. Catheter care, per institutional guidelines, should 
be followed. Materials and instructions for the thawing, timing, and administering of 
axicabtagene ciloleucel are outlined in the IPM. Vital signs should be measured during and after 
axicabtagene ciloleucel treatment (see Section 7.6).
Research sites should follow institutional guidelines for the infusion of cell products.

Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
Page 43
14 JUN 2022
7.10.3.3.
Axicabtagene Ciloleucel Retreatment
Subjects who achieve a partial response (PR) or CR and subsequently experience disease 
progression may have an option to receive a second course of conditioning chemotherapy and 
axicabtagene ciloleucel. If subject is eligible, retreatment must occur within 24 months after the 
initial axicabtagene ciloleucel infusion.
The following criteria must be met prior to being considered for a repeat course of therapy:

Subject had a PR or CR at any time after axicabtagene ciloleucel therapy and then 
subsequently progressed with CD19 tumor expression confirmed centrally by biopsy after 
disease progression and prior to retreatment

Subject continues to meet the original study eligibility criteria with the exception of prior 
axicabtagene ciloleucel use in this study; screening assessments and procedures should be 
repeated if clinically indicated (eg, ECHO)

Subject has not received subsequent therapy (see Section 6.1.7) for the treatment of 
lymphoma

Subject did not experience a life-threatening toxicity related to axicabtagene ciloleucel 
during the original course of treatment 

Toxicities related to conditioning chemotherapy (fludarabine and cyclophosphamide), with 
the exception of alopecia, have resolved to Grade 1 or lower, or returned to baseline prior to 
retreatment
Sites are required to collect a biopsy confirming disease progression and CD19 expression and to 
submit the biopsied tissue to the central laboratory before initiating retreatment.
The decision to retreat should be made in consultation with the sponsor’s medical monitor. In 
addition, before performing any study-related procedures or treatment, it is necessary to 
1) discuss the risks and benefits of retreatment with the subject, and 2) confirm with the subject 
how the second dose will be manufactured. The second dose could be manufactured at the same 
time that the first axicabtagene ciloleucel dose is made with existing cryopreserved PBMCs. 
Alternatively, the subject may need to undergo a second leukapheresis and should be informed of 
this possibility. These conversations should also be recorded in the subject’s source document.
A maximum of 1 retreatment course may occur per subject. Subjects who are retreated will 
follow the same treatment schedule and procedural requirements per the initial treatment.
Allowance for retreatment is based on clinical experience in ZUMA-1, where a total of 
10 subjects were retreated with axicabtagene ciloleucel (1 subject in Phase 1 and 9 subjects in 
Phase 2), and in ZUMA-7, where 9 subjects received retreatment with axicabtagene ciloleucel 
and were included in the retreatment analysis set. 
Overall, in ZUMA-1, six of 10 retreated subjects had a PR or CR to the retreatment. The subject 
retreated in Phase 1 achieved a PR at Month 1 after retreatment. Among the 9 subjects retreated 

Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
Page 44
14 JUN 2022
in Phase 2, five subjects responded (2 CR and 3 PR) at Month 1. Analysis of duration of 
retreatment response (DORR) among the retreated subjects in Phase 2 showed a median DORR 
of 3.5 months.
In ZUMA-7, nine subjects were retreated with axicabtagene ciloleucel. After retreatment, 
5 subjects had a response per central assessment, with all 5 subjects achieving a CR. Using the 
investigator assessment of response, 6 subjects had a response and 4 subjects had a CR.
After a subject is deemed eligible for retreatment and the means by which the second dose of 
axicabtagene ciloleucel has been confirmed (which will include determining whether a second 
leukapheresis is required), the subject will follow the study procedure requirements of the current 
IRB-approved protocol.
Re-treated subjects will be eligible for rollover to the LTFU study after completion of at least 
36 months of assessments from the initial IP treatment.
7.11.
Laboratory
7.11.1.
Local Laboratory Analysis
Assessments listed in Table 2 will be performed at the local laboratory at the time points 
indicated in the SOA.
Table 2.
Clinical Laboratory Parameters
Serum Chemistries
Hematology
Other
Albumin
Alanine aminotransferase
Alkaline phosphatase
Aspartate aminotransferase
Bicarbonate total
Bilirubin total
BUN or ureaa 
Calcium total
Chloride
Creatinine
Glucose
Lactate dehydrogenase
Magnesium total
Potassium
Sodium
Uric acidb 
CBC with differentialc
C-reactive protein
Ferritin
Pregnancy test
Viral testingd
Abbreviations: BUN, blood urea nitrogen; CBC, complete blood count; EU, European Union.
a
If BUN test cannot be analyzed by the local laboratory, urea should be analyzed. 
b
Per institutional guidelines. 

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19-l 12 (ZUMA-12) 
Kite Phruma, Inc. 
c 
At the following phannacokinetic time points, CBC with differential will be analyzed centrally: prior to leukapheresis, 
Day 7, Weeks 2 and 4, and Months 3, 6, 9, 12, and 24. 
d 
For EU sites only, serologic tests (eg, human innnunodeficiency vims, hepatitis B, hepatitis C, syphilis) may be can-ied out 
per institution guidelines and EU regulations 
7.11.2. 
Central Laboratory Analyses 
Assessment of CBC with differential will be submitted for central analysis at the following 
phannacokinetic (PK) time points: prior to leukapheresis, Day 7, Weeks 2 and 4, and Months 3, 
6, 9, 12, and 24. 
Clinical biospecimens (eg, tumor, maiTow, blood, cerebral spinal fluid [CSF], or other tissues) 
will be sent from clinical study centers to the centrnl laborato1y for sample processing, 
accessioning, and distribution to specialty laboratories. 
• 
Biospecimens are obtained at the times indicated in the SOA and instructions regai·ding 
sainple submission to centr·al laboratories ai·e provided in the Centr·al Laborato1y Manual. 
• 
Biospecimens to be collected by study sites: 
-
Archival tumor tissue (biopsy or slides) or fresh tumor sainple if archive tissue is not 
available 
-
Bone maiTow biopsy and aspirate, at baseline and/or post-tr·eatment as needed, for 
confinnation of diagnosis and genetic analyses related specifically to lai·ge B-cell 
lymphoma 
-
Blood for phannacokinetics (levels of anti-CD19 CART cells), replication-competent 
retrovims (RCR), and minimal residual disease (MRD) testing 
-
Semm for phannacodynainics (levels of sennn cytokines) 
-
CSF, if applicable, for phannacokinetics and phannacodynainics 
Multiple specialty laboratories may be employed for specific analyses. Refer to the Central 
Laborato1y Manual for instructions regarding submitting such samples to the appropriate 
laborato1y. 
CONFIDENTIAL 
Page45 
14 JUN 2022 

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19-l 12 (ZUMA-12) 
7.11.2.1. 
Central Confinnation of Diagnosis 
Kite Phruma, Inc. 
Local diagnosis of large B-cell lymphoma for detennination of study eligibility will be made by 
the investigator at each site. Diagnosis will be confnmed retrospectively by a centrnlized 
specialty laborato1y (see Central Laborato1y Manual) using tumor tissue in the fo1m of an 
archival fonnalin-fixed paraffin-embedded block, unstained pre-cut slides, or fresh tumor tissue 
from an on-study baseline (prior to conditioning chemotherapy) biopsy, along with a pathology 
repo1i. 
This confnmation of diagnosis will include the following: 
• 
Assessment of expression of other indication specific markers by immunohistochemistry or 
fluorescence in situ hybridization as needed for central confnmation of disease histology 
• 
Mo1phological evaluation by hematoxylin and eosin staining 
• 
Anatomical location of the biopsy 
• 
Central review of local pathology report 
If the central laborato1y pathologist's diagnosis is discordant with local laborato1y diagnosis, an 
additional pathologist will review the case for adjudication. If the inte1pretation remains 
discordant with the local laborato1y diagnosis, the sponsor will be consulted to detennine if the 
con ect tissue block or slides was received. If the con ect sample was received, the original slides 
used for local diagnosis will be requested for central review. If results are still discordant, the 
central laborato1y's pathologist and the sponsor's medical monitor will review the 
documentation and images. The central diagnosis will be used in cases where adjudication fails 
to reach a concordant result with the local diagnosis. Additional details will be specified in the 
cha1ier for the central specialty laborato1y. 
7.11.2.2. 
I 
I 
I 
Com lete details concerning these analyses will be provided in separate documents-
CONFIDENTIAL 
Page46 
14 JUN 2022 

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19-l 12 (ZUMA-12) 
7.11.2.3. 
Phaimacokinetics and Phannacodynamics 
7.11.2.4. 
Product Characteristics 
Kite Phruma, Inc. 
Sainples of leukapheresis material or final product will be retained and tested by the sponsor or 
specialty laborato1y for the pmpose of understanding the mechanism of action and safety profile 
of axicabtagene ciloleucel. 
7.11.2.5. 
Replication-competent Retrovirns Testing 
Axicabtagene ciloleucel comprises T cells transduced with a y-retroviral vector; hence, there is a 
theoretical risk for RCR developing in exposed subjects. Additional info1mation is provided in 
the IB. The timing of blood draws for detennination of the presence of RCR is specified in the 
SOA or may be done as clinically indicated. 
RCR testing will occur at leukapheresis and at Months 3, 6, and 12. If a subject tests positive for 
RCR at any time point within the first yeai·, samples will continue to be collected and tested 
yearly for up 15 years or as clinically indicated. 
7.12. 
Post-treatment Assessment Period 
After completing study treatment, all subjects will return to the clinic for post-treatment 
follow-up visits. 
If a subject does not respond to treatment at any time during the post-treatment assessment 
period, then the subject will continue to undergo the post-treatment follow-up procedures per the 
SOA, and then be followed for survival and disease outcomes in the LTFU portion of the study 
staiiing with the Month 6 visit (Table 4). 
CONFIDENTIAL 
Page 47 
14 JUN 2022 

Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
Page 48
14 JUN 2022
Refer to the SOA (Table 3) for a listing of study procedures and disease assessments to be 
completed during the post-treatment follow-up period.
7.13.
Long-term Follow-up Period
All enrolled subjects will be followed in the LTFU for safety analysis and survival and disease 
status for up to 15 years, if applicable. Subjects will begin the LTFU period beginning at the 
Month 6 visit. After completion of at least 36 months of assessments in the current protocol, 
subjects will transition to the LTFU study, KT-US-982-5968, after providing signed informed 
consent. Subjects who did not respond to treatment may receive off-protocol therapy but will 
continue to be followed for disease assessments (if progression was not documented), subsequent 
antilymphoma therapy, and survival.
Subjects may also be contacted by telephone to confirm survival status and subsequent 
antilymphoma therapy use. If the subject fails to return to the clinic for a scheduled 
protocol-specific visit, sites will need to make 2 attempts, using both the telephone and either 
mail or email to contact the subject. Sites must document both attempts to contact the subject. If 
a subject does not respond within 1 month after the second contact, then the subject will be 
considered lost to follow-up, and no additional contact will be required.
Refer to the SOA (Table 4) for a listing of study procedures and disease assessments to be 
completed during the LTFU period.
Subjects who are enrolled but did not receive the investigational product will be followed only 
until the end of this study and will undergo the following assessments at the time points outlined 
in the SOA:

Subsequent therapy for the treatment of NHL

Survival status 

Disease assessment per protocol
All subjects who received an infusion of axicabtagene ciloleucel will transition to the LTFU 
study KT-US-982-5968, where they will be monitored for occurrence of late-onset targeted 
AEs/SAEs suspected to be possibly related to axicabtagene ciloleucel as defined in Protocol 
KT-US-982-5968 and presence of RCR for up to 15 years from the time of axicabtagene 
ciloleucel infusion (also refer to Section 7.14).
In the LTFU study, KT-US-982-5968, subjects will continue assessments at timepoints 
contiguous with the LTFU timepoints in this study.
7.14.
Summary of Scheduled Assessments
The SOA and the LTFU assessments are provided in Table 3 and Table 4, respectively.

Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
Page 49
14 JUN 2022
Table 3.
Schedule of Assessments
Procedure
Screening
Enrollment/ 
Leukapheresis
Conditioning Chemotherapy
Axicabtagene 
Ciloleucel 
Administration
Post-treatment Follow-up
(each visit calculated from Day 0)
Visit
Within 
28 days of 
enrollment
Within approx.  
5 days of 
eligibility 
confirmation
D-5
D-4
D-3
D-2
D-1
D0
D1 to 7a
Week 2
(± 3 
days)
Week 4
(± 3 
days)
Month 2
(± 1 
week)
Month 3
(± 1 
week)
Medical history 
X
Physical examinationb
X
X
X
X
X
X
X
X
X
Neurological examinationc
X
X
QOD
X
X
Weight (plus height at 
screening)
X
X
Vital signs (BP, HR,RR, O2 
saturation, temperature)
Xd
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
Electrocardiogram
X
X
ECHOe
X
PET-CT disease assessmentf
Xd
X
X
Archival /Fresh tumor sampleg
X
D7-14
Pregnancy test (serum or urine)
X
Xh
Xh
X
Blood draw for chemistry panel
X
X
X
X
X
X
X
X
X
X
Blood draw for CBC with 
differentiali
X
X
X
X
X
X
X
X
X
X
Blood draw for serology (EU 
sites)j
X
X
Blood draw for LDH
X
Blood draw for MRD
X
X

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19- l 12 (ZUMA-12) 
I 
Procedure 
Visit 
Lumbar puncture'< 
-
Blood draw for CRP/ferritin 
Blood draw for RCR analysisn 
Blood draw for cytokines0 
Leukapheresis 
Fludarabine/Cyclophosphamide 
Axicabtagene ciloleucel 
intravenous infusion 
Adverse events/Concomitant 
therapy!' 
Screening 
Within 
28 days of 
enrollment 
X 
X 
Kite Pha1ma, Inc. 
Axicabtagene 
Em·ollment/ 
Ciloleucel 
Post-tr·eatment Follow-up 
Leukapheresis 
Conditioning Chemotherapy 
Administr·ation 
(each visit calculated from Day 0) 
Within approx. 
Week2 
Week4 
Month 2 
5 days of 
eligibility 
(± 3 
(± 3 
(± 1 
confirmation 
D-5 
D-4 
D-3 
D-2 
D-1 
DO 
Dl to 7• 
days) 
days) 
week) 
--------------------------------------------
--------------------------------------------
X 
X 
X 
Dl , D3, 
D7 
X 
X 
--------------------------------------------
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Month 3 
(± 1 
week) 
X 
X 
Abbreviations: BP, blood presstu·e; CAR, chimeric antigen receptor; CBC, complete blood count; CNS, central nervous system; CRP, C-reactive protein; CRS, cytokine release 
syndrome; D, day; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; EU, European Union; HR, heart rate; LDH, lactate dehydrogenase; MRD, minimal 
residual disease; MRI, magnetic resonance imaging; PET-CT, positron emission tomography-computed tomography; PK, phannacokinetics; QOD, eve1y other day; RCR, 
replication-competent retrovims; RR, respirato1y rate. 
a 
Axicabtagene ciloleucel administration period, refer to Appendix 3 for requirements by countiy regulatory agencies. 
b 
Subjects with new onset symptoms related to CRS should undergo physical examination at least daily until symptoms resolve to baseline. Subjects with symptoms of CNS 
malignancy, such as new onset severe headaches, neck stiffness, seizures, encephalopathy, cranial nerve deficits, or any focal netu·ologic findings on physical exam, will have 
a brain MRI and lumbar puncture for examination of cerebral spinal fluid. A physical exam is required prior to the start of conditioning chemotherapy and prior to 
axicabtagene ciloleucel infusion. 
CONFIDENTIAL 
Page 50 
14 JUN 2022 

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19- l 12 (ZUMA-12) 
Kite Pha1ma, Inc. 
C 
d 
e 
f 
g 
h 
k 
1 I 
Nem·ologic assessment: A neurological assessment should be done prior to axicabtagene ciloleucel infusion on treatment Day 0, on treatment Day 1, Day 3, Day 5, and Day 7 
dtuing the minimum 7-day observation period. For new onset of neurologic symptoms or if neurologic symptoms persist, neurologic examination will be performed at least 
daily until symptoms resolve to baseline. 
In addition to the time points outlined in the SOA, it is recommended that vital signs are monitored during and after study treatment (see Section 6) and as clinically indicated. 
ECHO will be performed following the subject's last chemotherapy treatment and within 28 days prior to signing the consent may be used for confinnation of eligibility. 
PET-CT w-ill be performed within 28 days prior to enrollment. If bone marrow involvement was not evaluated within 28 days of enrolhuent, a PET-CT or a bone marrow 
biopsy will be performed to establish a baseline. PET-CT shall be pe1fo1med at any time disease progression is suspected. If there is evidence of baseline bone ma1l'Ow 
involvement, or if there are unexplained cytopenias, or suspicion of bone marrow involvement. a bone ma1l'Ow as irate and bio 
will be e1fon11ed in sub· ects who are 
being assessed for CR in order to confirm complete response. 
-
~-embedded tumor block or 30 unstained slides will be re uired. If an archived ttuuor sam le is not available a fresh ttuuor sam le is re uired 
iii
. t 
tat of chemotherapy to continue on study. 
Archived and fresh tumor samples (if app 1c 
e w1 
e su rmtte to a centra a orato1y a er e 1gi 1 1ty as een con lffile an pnor to sta1t o con 1tiomng 
a . Slides that have been reviousl stained with antibodies or other reagents are not acceptable. Screen failed subjects' archived samples should not be submitted. 
regnancy test serum or m,ne : 
o y: test to e comp ete w1 Ill days prior to both leukapheresis and conditioning chemotherapy for females of childbea1ing potential. 
At the following time points, CBC with differential will be analyzed centi·ally: prior to leukapheresis, Day 7, Weeks 2 and 4, and Month 3. 
For EU sites, serologic test (eg, HIV, hepatitis B, hepatitis C, syphilis) will be carried out per institutional guidelines and EU regulations. This may be done within 30 days 
prior to leukapheresis or on the day of leukapheresis. 
Subjects w-ith symptoms of CNS malignancy ( eg, new onset severe headaches, neck stiffness, or focal neurological fill dings) will have lumbar puncture pe1fon11ed at 
screening to assess cerebral spinal fluid for possible CNS involvement. Subjects with new onset Grade 2 or higher neurologic symptoms after axicabtagene ciloleucel infusion 
will have lumbar puncture pe1fo1med to assess cerebral spinal fluid when feasible. Measuring the opening pressure should be done, if possible, with recording of the results in 
the sub· ect site chart. 
n 
B oo 
·aws or RCR w1 
e co ecte pnor to et ap eres1s an at Mont 1s 3, 6, an 12 en collect yearly for up to 15 years. Yearly samples will only be collected/analyzed 
if positive at Month 3, 6, or 12. Blood and senun samples may also be used for fiuiher RCR evaluation as clinically indicated. 
o 
Blood draws for cytokines will be collected prior to leukapheresis, on Day 0 prior to administi·ation of axicabtagene ciloleucel, on Days 1, 3, 7, and Weeks 2 and 4. If a 
subject who was admitted to the hospital within the 7-day observation period is discharged and then subsequently re-admitted to the hospital with any axicabtagene ciloleucel-
related adverse events, blood samples for cytokines will be collected on the day of hospital re-admission and then weekly tlu·ough and including the day of discharge. Blood 
samples for cytokines will also be collected at the time of disease progression prior to starting any subsequent antilymphoma therapy. If the subject experiences a Grade 3 or 
higher axicabtagene ciloleucel-related toxicity, such as a Grade 3 CRS or neurologic event, 1 additional blood draw for cytokines will be taken at the time of the Grade 3 or 
higher axicabtagene ciloleucel-related toxicity and upon resolution of the event. 
p 
Adverse events will be recorded from the date of enrollment tmtil 3 months after completing treatment with axicabtagene ciloleucel. Concomitant therapies will be recorded 
from the date of info1med consent tmtil 3 months after completing treatment with axicabtagene ciloleucel. 
CONFIDENTIAL 
Page 51 
14 JUN 2022 

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19-l 12 (ZUMA-12) 
Table 4. 
Long-term Follow-up Assessments 
Procedure 
Visit 
Month 
Month 
Month 
Month 
Month 
frequency 
6 
9 
12 
15 
18 
Physical 
examination 
(with 
X 
X 
X 
X 
X 
neurological 
examination? 
PET-CT 
disease 
X 
X 
X 
X 
X 
assessment" 
Survival status 
X 
X 
X 
X 
X 
Blood draw for 
CBC with 
X 
X 
X 
X 
X 
differentiald 
CONFIDENTIAL 
Kite Pha1ma, Inc. 
Long-term Follow-up Period 
Each visit calculated from Day 0 
(all visits have± 28 day window) 
Month 72 
and 
Month 
Month 
Month 
Month 
Month 
Month 
Month 
Annually 
24 
30 
36 3 
42 
48 
54 
60 
Thereafter 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 52 
14 JUN 2022 

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19-l 12 (ZUMA-12) 
Kite Pha1ma, Inc. 
Long-term Follow-up Period 
Each visit calculated from Day 0 
Procedure 
(all visits have ± 28 day window) 
Month 72 
and 
Visit 
Month 
Month 
Month 
Month 
Month 
Month 
Month 
Month 
Month 
Month 
Month 
Month 
Annually 
frequency 
6 
9 
12 
15 
18 
24 
30 
36• 
42 
48 
54 
60 
Thereafter 
Targeted 
X 
X 
X 
X 
X 
X 
AEs/SAEsg 
Targeted 
concomitant 
X 
X 
X 
X 
X 
X 
medicationsh 
Subsequent 
therapy for 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NHLi 
Abbreviations: AE, adverse event; CAR, chimenc antigen receptor; CBC, complete blood count; CT, computed tomography; NHL, non-Hodgkin lymphoma; PET-CT, positron enuss1on 
tomography-computed tomography; MRD, minimal residual disease; RCR, replication-competent retrovirus; SAE, serious adverse event. 
a 
After completion of at least 36 months of assessments in ZUMA-12, subjects who received an infusion of axicabtagene ciloleucel will transition to the L TFU study KT-US-982-5968 
after providing signed informed consent, to complete the remainder of the 15-year LTFU period. 
b 
Physical exams will continue through Month 24. 
c 
PET-CT/disease assessments will continue through Month 24 or until disease progression, whichever comes first. If subject's disease has not progressed by Month 24, disease 
assessments will continue to be performed per standard of care. 
g 
h 
Blood draw for CBC with differentials will continue throu 
Month 24 or until disease 
o ession, whichever comes first. 
aws or RCR ana ys1s w 
continue 
u 
Mon 
yzed if positive at Month 3, 6, or 12. Blood and serum saniples may also be 
used for further RCR evaluation as clinically indicated. 
After 3 months, only targeted AEs/SAEs will be reported. Targeted AEs/SAEs are defined as infections; neurological, hematological, and autoinlmune disorders; and secondary 
malignancies that occur up to 15 years after axicabtagene ciloleucel infusion or until disease progression (whichever occurs first). 
Targeted concomitant medications will be collected for 24 months or until disease progression (whichever occurs first). 
Subsequent therapy refers to therapy administered after axicabtagene ciloleucel infusion for a subject's disease, such as non-study-specified chemotherapy, inlmunotherapy, target 
agents, as well as stem cell transplant and radiation therapy, which must be collected until the subject completes the LTFU period, is considered lost to follow-up, withdraws consent, or 
dies. Subjects may be contacted by telephone to collect information about subsequent therapy for NHL and to assess survival status. 
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8.
SUBJECT WITHDRAWAL
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the physician or at the institution.
Subjects can decline to continue to receive study-required treatment and/or other 
protocol-required procedures at any time during the study while continuing to participate in the 
study. This is referred to as partial withdrawal of consent.
If partial withdrawal of consent occurs, the investigator must discuss with the subject the 
appropriate process for discontinuation from the investigational product, study treatment, or 
other protocol-required therapies and must also discuss options for continued participation, 
completion of procedures, and the associated data collection as outlined in the SOA. The level of 
follow-up and method of communication should also be discussed between the research staff and 
the subject and documented in the source documents.
Withdrawal of full consent from a study means that the subject does not wish to receive further 
protocol-required therapy, undergo procedures, and continue participating in study follow-up. 
Subject data collected up until withdrawal of consent will be retained and included in the 
analysis of the study. Publicly available data (death records) can be included after withdrawal of 
consent if local regulations permit. The investigator is to discuss with the subject appropriate 
procedures for withdrawal from the study.
As part of the study, sites may be asked to conduct searches of public records, such as those 
establishing survival status, if available, to obtain survival data for any subject for whom the 
survival status is not known. Sites may be asked to also retrieve autopsy reports to confirm status 
of disease at the time of death.
The investigator and/or sponsor can also decide to withdraw a subject from the investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a whole at 
any time prior to study completion.
8.1.
Reasons for Removal from Treatment
Reasons for removal from protocol-required investigational products or procedures include any 
of the following:

AEs

Subject request

Product not available

Lost to follow-up

Death

Decision by sponsor

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8.2.
Reasons for Removal from Study
Reasons for removal of a subject from the study are as follows:

Subject withdrawal of consent from further follow-up

Investigator decision

Lost to follow-up

Death

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9.
SAFETY REPORTING
9.1.
Adverse Events
An AE is defined as any untoward medical occurrence in a clinical trial subject. The event does 
not necessarily have a relationship with study treatment. The investigator is responsible for 
ensuring that any AEs observed by the investigator or reported by the subject are recorded in the 
subject’s medical record. The definition of AEs includes worsening of a pre-existing medical 
condition. Worsening indicates that the pre-existing medical condition has increased in severity, 
frequency, and/or duration or has an association with a worse outcome. When recording such 
events, provide descriptions that the pre-existing condition has changed (eg, more frequent 
headaches for a subject with pre-existing headaches or BP has increased in a subject with 
pre-existing hypertension).
A pre-existing condition that has not worsened during the study or involves an intervention, such 
as elective cosmetic surgery or a medical procedure while on study, is not considered an AE.
Interventions for pretreatment conditions (such as elective cosmetic surgery) or medical procedures 
that were planned before study participation are not considered AEs. Hospitalization for study-
treatment infusions or precautionary measures per institutional policy are not considered AEs.
The term “disease progression,” as assessed by measurement of malignant lesions on radiographs 
or other methods, should not be reported as AEs. Death due to disease progression in the absence 
of signs and symptoms should be reported under the primary tumor type (eg, B-cell lymphoma).
When an AE or SAE is due to the disease under investigation, it is necessary to report the signs 
and symptoms. Worsening of signs and symptoms of the malignancy under study should also be 
reported as AEs in the appropriate section of the CRF.
The investigator’s clinical judgment is used to determine whether a subject is to be removed 
from treatment due to an AE. If a subject requests to withdraw from protocol-required therapies 
or the study because of an AE, then the subject should undergo the procedures outlined in the 
Month 3 visit of the SOA.
9.2.
Reporting of Adverse Events
The investigator is responsible for reporting all AEs observed by the investigator or reported by 
the subject that occur after enrollment (ie, commencement of leukapheresis) through 3 months 
after treatment with axicabtagene ciloleucel infusion.
After 3 months, targeted AEs (eg, infections, neurological, hematological, and autoimmune 
disorders, and secondary malignancies) will be monitored and reported for 15 years after 
treatment with axicabtagene ciloleucel or until disease progression, whichever occurs first.
For subjects who are enrolled, but do not receive axicabtagene ciloleucel, the AE reporting 
period ends 30 days after the last study-specific procedure (eg, leukapheresis, conditioning 
chemotherapy).

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The investigator must provide the information listed below regarding the AEs being reported:

AE diagnosis or syndrome (if not known, signs or symptoms)

Dates of onset and resolution

Severity

Assessment of relatedness to axicabtagene ciloleucel, conditioning chemotherapy, or study 
procedures

Action taken
The AE grading scale used will be the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. A copy of the grading scale can be 
downloaded from the Cancer Therapy Evaluation Program home page (http://ctep.cancer.gov). 
CRS events will be reported using the grading scale outlined in the IB.
In reviewing AEs, investigators must assess whether the AE is possibly related to 
1) axicabtagene ciloleucel, 2) conditioning chemotherapy, 3) any protocol-required study 
procedure or treatment, 4) disease progression, 5) concurrent disease, 6) concomitant medication, 
or 7) other. The relationship is indicated by a Yes or No response and entered into the CRF. A 
Yes response should indicate that there is evidence to suggest a causal relationship between the 
study treatment or procedure and the AE. Additional relevant data with respect to describing the 
AE will be collected in the CRFs.
The investigator is expected to follow reported AEs until stabilization or resolution. If a subject 
begins a new antilymphoma therapy, the AE reporting period for non-SAEs ends at the time the 
new treatment is started.
9.2.1.
Reporting Abnormal Laboratory Findings
The investigator is responsible for reviewing laboratory test results and determining whether an 
abnormal value in an individual study subject represents a clinically significant change from the 
subject’s baseline values. In general, abnormal laboratory findings without clinical significance 
(based on the investigator’s judgment) are not to be recorded as AEs. However, abnormal 
laboratory findings that result in new or worsening clinical sequelae, or that require therapy or 
adjustment in current therapy, are considered AEs. Where applicable, clinical sequelae (not the 
laboratory abnormality) are to be recorded as the AE.
An abnormal laboratory test result must be reported as an AE if it is a change from baseline and 
meets any of the following criteria:

Is associated with clinical symptoms

Results in a medical intervention (eg, potassium supplementation for hypokalemia or iron 
replacement therapy for anemia) or a change in concomitant therapy

Is clinically significant in the investigator’s judgment

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9.3.
Definition of Serious Adverse Events
An SAE is defined as an AE that meets at least 1 of the following serious criteria:

Fatal

Life-threatening (places the subject at immediate risk of death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Congenital anomaly/birth defect

Other medically important event
An AE would meet the criterion of “requires hospitalization” if the event necessitated an 
admission to a healthcare facility (eg, overnight stay).
Events that require an escalation of care when the subject is already hospitalized should be 
recorded as an SAE. Examples of such events include movement from routine care in the 
hospital to the intensive care unit or if that event resulted in a prolongation of the existing 
planned hospitalization.
If an investigator considers an event to be clinically important, but it does not meet any of the 
serious criteria, the event could be classified as an SAE with the criterion of “other medically 
important serious event.”
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
according to NCI CTCAE criteria; the event itself may be of relatively minor medical 
significance and, therefore, may not meet the seriousness criteria. Severity and seriousness need 
to be independently assessed for each AE recorded on the electronic CRF (eCRF).
9.4.
Reporting of Serious Adverse Events 
The investigator is responsible for reporting all SAEs observed by the investigator or reported by 
the subject that occur after signing of the informed consent through 3 months after the 
axicabtagene ciloleucel infusion or until the initiation of another antilymphoma therapy, 
whichever occurs first. After 3 months, only targeted SAEs will be reported. Targeted SAEs are 
defined as and include infections; neurological, hematological, and autoimmune disorders; and 
secondary malignancies that occur up to 15 years after axicabtagene ciloleucel infusion or until 
disease progression, whichever occurs first.
SAEs, which the investigator assesses as related to axicabtagene ciloleucel, should be reported 
regardless of the time period.

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For subjects who screen fail or are enrolled but do not receive axicabtagene ciloleucel, the 
reporting period for SAEs ends 30 days after the last study-specific procedure (eg, screening 
procedure, leukapheresis, conditioning chemotherapy).
All SAEs must be submitted to Kite via the electronic SAE system within 24 hours of the 
investigator’s knowledge of the event. If the electronic SAE system is unavailable (eg, system 
outage), then the SAE must be submitted using the SAE Report Form and emailed to the SAE 
Reporting mailbox: safety_fc@gilead.com.
Following completion of ZUMA-12, any relevant information on ongoing SAEs must be 
submitted to Kite Pharma within 24 hours of the investigator’s knowledge of the event using the 
paper SAE Report Form and sent via e-mail to the SAE Reporting mailbox: 
safety_fc@gilead.com.
Subsequently, all SAEs will be reported to the health authorities per local reporting guidelines.
Disease progression of the malignancy is not considered an AE. However, signs and symptoms 
of disease progression may be recorded on the CRF as AEs or SAEs and indicated as being due 
to disease progression. If the malignancy has a fatal outcome before the end of the SAE reporting 
period, then the event leading to the death must be recorded as an SAE with the outcome being 
fatal.
Death must be reported if it occurs during the SAE reporting period, irrespective of any 
intervening treatment.
Any death occurring after the first dose of chemotherapy, for the purpose of pre-conditioning, 
and within 3 months of axicabtagene ciloleucel infusion, regardless of attribution to treatment, 
requires expedited reporting within 24 hours. Any death occurring after the SAE reporting period 
requires expedited reporting within 24 hours only if it is considered related to treatment.
9.5.
Reporting Deaths
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of underlying lymphoma should be recorded as SAEs with the 
preferred term “B-cell lymphoma” and must be reported immediately to the sponsor. Death is an 
outcome and not a distinct event. The event or condition that caused or contributed to the fatal 
outcome should be recorded on the AE form. However, every effort should be made to capture 
the established cause of death, which may become available later on (eg, after autopsy). Refer to 
the CRF completion guidelines for detailed instructions.
9.6.
Diagnosis Versus Signs and Symptoms
For AEs, a diagnosis (if known) rather than individual signs and symptoms should be recorded 
on the AE form. The exception is for CRS where both the diagnosis and the signs and symptoms 
will be captured on the AE form. For signs and symptoms of the underlying cancer, the signs and 
symptoms should be captured. However, on the AE form, the investigator should state that these 
signs and symptoms are due to the underlying disease.

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9.7.
Pregnancy and Lactation
There is no relevant clinical experience with axicabtagene ciloleucel in pregnant or lactating 
women, and animal reproductive studies have not been performed. Women of childbearing 
potential must have a negative pregnancy test prior to enrollment because of the potentially 
dangerous effects of the preparative chemotherapy on the fetus. Women of childbearing potential 
should be monitored according to local and country-specific regulations. This experimental 
therapy should not be administered to pregnant women or women who are breastfeeding.
Female subjects and female partners of male subjects are recommended to use highly effective 
contraception (method must achieve an annual failure rate of < 1%) for at least 6 months after 
conditioning chemotherapy dosing or the administration of axicabtagene ciloleucel, whichever is 
longer. Male subjects are recommended to not father a child for at least 6 months after the 
conditioning chemotherapy dosing or the administration of axicabtagene ciloleucel, whichever is 
longer. Refer to Appendix 4 for a complete list of highly effective contraception methods.
If a pregnancy occurs in either a female subject enrolled into the study or a female partner of a 
male subject within 6 months of completing conditioning chemotherapy or the administration of 
axicabtagene ciloleucel, whichever is longer, the pregnancy must be reported to the sponsor. 
Information regarding the pregnancy and/or the outcome may be requested by the sponsor.
The pregnancy should be reported to the sponsor within 24 hours of the investigator’s knowledge 
of the pregnancy event by using the pregnancy report form and emailing it to: 
safety_fc@gilead.com.
The pregnancy outcome should be reported to the sponsor using the pregnancy outcome report 
form and emailing it to: safety_fc@gilead.com.
Lactation cases occurring in female patients taking protocol-required therapies (PRT) and up to 
6 months after PRT should be reported to safety_fc@gilead.com within 24 hours of awareness 
using the lactation reporting form.
9.8.
Hospitalization and Prolonged Hospitalization
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE as described in Section 9.4.
The following hospitalization scenarios are not considered to be SAEs:

Hospitalization for palliative care or hospice care

Planned hospitalization required by the protocol (eg, for monitoring of the subject or to 
perform an efficacy measurement for the study)

Planned hospitalization for a pre-existing condition

Hospitalization due to progression of the underlying cancer

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9.9.
Abnormal Vital Sign Values
Not all vital sign abnormalities qualify as an AE. A vital sign result must be reported as an AE if 
it is a change from baseline and meets any of the following criteria:

Accompanied by clinical symptoms

Results in a medical intervention or a change in concomitant therapy

Clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding if an isolated vital sign abnormality should be 
classified as an AE. However, if a clinically significant vital sign abnormality is a sign of a 
disease or syndrome (eg, high BP), only the diagnosis (ie, hypertension) should be recorded on 
the CRF.
9.10.
Data Safety Monitoring Board 
An independent DSMB will be chartered to meet and review the SAEs and SUSARs on a semi-
annual basis after the first subject has been treated with axicabtagene ciloleucel up through the 
primary analysis. Kite Pharma, or delegate, will submit SAEs and SUSARs to the DSMB on a 
regular basis throughout the study up through the primary analysis. The DSMB will also meet to 
review safety data after 15 subjects have been enrolled and treated with axicabtagene ciloleucel 
and have had an opportunity to be followed for 3 months after axicabtagene ciloleucel infusion. 
The DSMB will make trial conduct recommendations on an ongoing basis based on an analysis 
of risk vs benefit. The DSMB may request additional safety data for review or recommend 
modifications to the study conduct if safety concerns are identified. The DSMB may meet more 
often as needed.
The sponsor may request additional reviews by the DSMB. Data submitted to the DSMB may be 
monitored or unmonitored to facilitate timely DSMB review. At the time of expedited reporting 
of SUSARs to the FDA, Kite Pharma (or designee) will concurrently submit these reports to the 
DSMB chair.

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10.
STATISTICAL CONSIDERATIONS
10.1.
Hypothesis
No formal hypothesis will be tested. This study is designed to estimate the CR rate in subjects 
with high-risk large B-cell lymphoma. The CR rate targeted in this study is 60%.
10.2.
Study Endpoints
10.2.1.
Primary Endpoint
CR rate is defined as the incidence of a CR per the Lugano Classification {Cheson 2014} as 
determined by study investigators. All evaluable subjects who do not meet the criteria for a CR 
by the analysis data cutoff date will be considered non-responders.
The final analysis will be performed on subjects in this study after at least 36 months of follow-
up. Subjects will be transitioned to the KT-US-982-5968 study for the remainder of the 15-year 
LTFU period. Descriptive estimates of key efficacy and safety analyses may be updated to assess 
the overall treatment profile.
10.2.2.
Secondary Endpoints
ORR is defined as the incidence of either a CR or a PR per the Lugano Classification {Cheson 
2014} as determined by the study investigators. All evaluable subjects who do not meet the 
criteria for an objective response by the analysis cutoff date will be considered non-responders.
DOR is defined only for subjects who experience an objective response after axicabtagene 
ciloleucel infusion and is the time from the first objective response to disease progression per the 
Lugano Classification {Cheson 2014} or death from any cause. Subjects not meeting the criteria 
for disease progression or death from any cause by the analysis data cutoff date will be censored 
at their last evaluable disease assessment date. Subjects who receive any subsequent new 
antilymphoma therapy, including SCT in the absence of documented disease progression or 
death, will be censored at the last evaluable disease assessment prior to the subsequent new 
antilymphoma therapy.
EFS is defined as the time from the axicabtagene ciloleucel infusion date to the earliest date of 
disease progression per the Lugano Classification {Cheson 2014}, commencement of subsequent 
new antilymphoma therapy including SCT, or death from any cause. Subjects alive, in response, 
and with no new antilymphoma therapy including SCT will be censored at the last evaluable 
disease assessment.
PFS is defined as the time from the axicabtagene ciloleucel infusion date to the date of disease 
progression per the Lugano Classification {Cheson 2014} or death from any cause. Subjects not 
meeting the criteria for disease progression or death from any cause by the analysis data cutoff 
date will be censored at the last evaluable disease assessment. Subjects who receive any 
subsequent new antilymphoma therapy including SCT in the absence of documented disease 
progression or death will be censored at the last evaluable disease assessment prior to the 
subsequent new antilymphoma therapy.

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OS is defined as the time from axicabtagene ciloleucel infusion to the date of death from any 
cause. Subjects who are alive will be censored at their last date known to be alive or the data 
cutoff date, whichever is earlier. Subjects who die after the data cutoff date will be censored at 
the data cutoff date.
Relapse with CNS disease is defined as the time from the axicabtagene ciloleucel infusion date 
to the earliest date of CNS involvement with lymphoma, as determined by typical symptoms, 
CSF evaluation, and/or diagnostic imaging.
Incidence of AEs (including Grade 3 or higher, serious, fatal, and AEs of interest) and clinically 
significant changes in safety laboratory values. Additional secondary endpoints include PK and 
pharmacodynamic endpoints, such as the evaluation of anti-CD19 CAR T-cell levels in the blood 
and cytokine levels in the serum in relationship with clinical outcome.
10.2.3.
10.2.4.
Covariates and Subgroups
The following covariates at screening/baseline may be used in efficacy and safety analyses:

Age (< 65, ≥ 65 years)

Gender

Race

Ethnicity

ECOG status 

IPI score

Diagnosis category (double-hit lymphomas versus triple-hit lymphomas versus 
non-double-/triple-hit with IPI score ≥ 3)

Levels of cytokines

Levels of CAR T cells

CR achieved on the study
Additional associative analyses of covariates with subject outcomes will be specified in the 
statistical analysis plan.
CCI
CCI

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10.3.
Sample Size Considerations
In the GELA randomized Phase 2 study evaluating the efficacy of R-ACVBP or R-CHOP-14 
induction, using IWF 2007 criteria in young patients with high-risk DLBCL, the primary 
objective of achieving a higher than 50% CR rate after 4 cycles of induction regimen was not 
met in both randomization groups (47% in R-ACVBP and 39% in R-CHOP-14) {Casasnovas 
2017}. Accordingly, it is postulated that a CR rate of 60% would represent a clinically 
meaningful improvement over standard chemoimmunotherapy in a high-risk large B-cell 
lymphoma patient population. Although there is no formal hypothesis testing, the sample size 
has been determined in part with descriptive analysis described below.
The trial uses a single-arm design to estimate the CR rate in subjects with high-risk large B-cell 
lymphoma treated with axicabtagene ciloleucel. A CR rate of 60% with axicabtagene ciloleucel 
treatment is targeted. With a total sample size of 40 subjects, an observed CR rate of 60% will 
yield an 80% CI for the response rate with a maximum half-width of less than or equal to 11%, 
corresponding to a lower limit of at least 48.6%. This target CR rate, and the lower limit of the 
80% CI for the CR rate, is meaningful because it would represent a significant improvement in 
the response rate for the subjects with high-risk large B-cell lymphoma and would likely offer an 
improvement over existing therapies in patients with high-risk large B-cell lymphoma.
Table 5 provides the estimated CR rate and the lower and upper limits of 80%/95% CI based on 
the Clopper-Pearson method for a range of possible CR rates for a sample of 40 subjects. 
Table 5.
Lower and Upper Limits of 80%/95% CIs for CR Rates from 60% to 
100% for a Sample of 40 Subjects
Number (%) of CRs
24 (60)
28 (70)
32 (80)
36 (90)
40 (100)
Lower and upper limits 
of 80% CI (%, %)
48.6, 70.6
58.8, 79.5
69.6, 88.0
81.0, 95.6
94.4, 100
Lower and upper limits 
of 95% CI (%, %)
43.3, 75.1
53.5, 83.4
64.4, 90.9
76.3, 97.2
91.2, 100
Abbreviations: CI, confidence interval; CR, complete response.
10.4.
Access to Individual Subject Treatment Assignments
This is a single-arm, open-label study, and subjects and investigators will be aware of treatment 
received. Data-handling procedures for the study will be devised to reduce potential sources of 
bias and maintain the validity and credibility of the study. These procedures will be outlined in 
the study statistical plan, DSMB charter, and trial integrity document.
10.5.
Interim Analysis and Early Stopping Guidelines
The DSMB will meet and review SAEs and SUSARs on a semi-annual basis after the first 
subject has been dosed. The DSMB may request additional safety data.

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One planned interim analysis will be performed. Interim Analysis 1 will be conducted after 
15 subjects have been enrolled and treated with axicabtagene ciloleucel and have had an 
opportunity to be followed for 3 months after axicabtagene ciloleucel infusion. This analysis will 
be for efficacy and safety and will be descriptive.
10.6.
Analysis Subsets
In this study, subjects are to be dosed at a target of 2 x 106 (1.0 x 106 to 2.4 x 106) anti-CD19 
CAR T cells/kg. A minimum dose of 1 x 106 anti-CD19 CAR T cells/kg may be administered. 
For subjects weighing ≥ 100 kg, a maximum flat dose of 2 x 108 anti-CD19 CAR T cells will be 
administered. Subjects are considered to have received the target dose if they receive at least 
1 x 106 anti-CD19 CAR T cells/kg.
The safety analysis set is defined as all subjects treated with any dose of axicabtagene ciloleucel. 
This analysis set will be used for all safety data analyses.
The full analysis set will consist of all enrolled/leukapheresed subjects and will be used for the 
summary of subject disposition and the listing of deaths.
The response evaluable analysis set will consist of the subjects who are enrolled and treated with 
axicabtagene ciloleucel at a dose of at least 1 x 106 anti-CD19 CAR T cells/kg and have a 
centrally confirmed disease type (double-/triple-hit lymphomas) or large B-cell lymphoma with 
an IPI score ≥ 3. This analysis set will be used for all efficacy data analyses including CR rate, 
ORR, endpoints based on response (DOR, EFS, and PFS), relapse with CNS, and OS.
10.7.
Planned Method of Analysis
The primary analysis will occur after all treated subjects have an opportunity to be assessed for 
response 6 months after the Week 4 disease assessment. The CSR will be written based on the 
data collected and analyzed from this primary analysis. The final analysis will occur after all 
subjects complete at least 36 months of follow-up.
The primary analysis of CR rate will be based on the investigator’s review of disease 
assessments in the response evaluable analysis set.
10.7.1.
CR Rate
The subject incidence of CR will be calculated. The 2-sided 80%/90%/95% CIs will be provided 
about the CR rate, calculated with the Clopper-Pearson method.
10.7.2.
ORR
The subject incidence of objective response will be calculated. The 2-sided 80%/90%/95% CIs 
will be provided about the ORR, calculated with the Clopper-Pearson method.
The incidence of subjects with CR, PR, stable disease, PD, not done, and not evaluable, as best 
overall response to treatment, and exact 2-sided 80%/90%/95% CIs about the incidence will be 
generated.

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10.7.3.
DOR
Kaplan-Meier plots, estimates, and 2-sided 80%/90%/95% CIs will be generated for DOR among 
the subjects who achieve an objective response. Kaplan-Meier estimates of the proportion of 
subjects alive and PFS at 3-month intervals will be provided. The number of subjects censored or 
having events and the reasons for censoring or type of events (PD or death) will be summarized.
A sensitivity analysis of DOR will be conducted in which disease assessments obtained after 
SCT (for subjects who undergo SCT while in an axicabtagene ciloleucel-induced response) will 
be used in the derivation of DOR.
DOR may be evaluated in subgroups defined by the covariates described in Section 10.2.4.
10.7.4.
EFS
Kaplan-Meier plots, estimates, and 2-sided 80%/90%/95% CIs will be generated for EFS. 
Kaplan-Meier estimates of the proportion of subjects alive and event-free at 3-month intervals 
will be provided. The number of subjects censored or having events, and the reasons for 
censoring or type of events (PD, subsequent new antilymphoma therapy, or death) will be 
summarized.
EFS may be evaluated in subgroups defined by the covariates described in Section 10.2.4.
10.7.5.
PFS
Kaplan-Meier plots, estimates, and 2-sided 80%/90%/95% CIs will be generated for PFS. 
Kaplan-Meier estimates of the proportion of subjects alive and progression-free at 3-month 
intervals will be provided. The number of subjects censored or having events, and the reasons for 
censoring or type of events (PD or death) will be summarized. 
PFS may be evaluated in subgroups defined by the covariates described in Section 10.2.4.
10.7.6.
OS
Kaplan-Meier plots, estimates, and 2-sided 80%/90%/95% CIs will be generated for OS. 
Estimates of the proportion of subjects alive at 3-month intervals will be provided through 
2 years after the final subject has been enrolled and then annually through the completion of the 
study. The number of subjects censored or having events, and the reasons for censoring or type 
of events (death) will be summarized. 
OS may be evaluated in subgroups defined by the covariates described in Section 10.2.4.
10.7.7.
Relapse with CNS Disease
The number of subjects with CNS relapse and time to relapse with CNS disease among the 
subjects who experience CNS relapse will be summarized.
Relapse with CNS disease may be evaluated in subgroups defined by the covariates described in 
Section 10.2.4.

Axicabtagene Ciloleucel 
Clinical Protocol 
KTE-C19-l 12 (ZUMA-12) 
10.7.8. 
Safety 
Kite Phruma, Inc. 
Subject incidence rates of AEs, including all, serious, fatal, CTCAE Grade 3 or higher, 
treatment-related AEs, and AEs of interest repo1ted throughout the conduct of the study, will be 
tabulated by system organ class and prefened tenns or prefened te1ms only, coded with the 
Medical Dictiona1y for Regulato1y Activities. Changes in laborato1y values and vital signs will 
be summarized with descriptive statistics. 
The incidence of concomitant medications will be summarized. 
Tables and/or nairntives of deaths through the LTFU and treatment-related SAEs will be 
provided. 
The incidence, prevalence, duration, and reversibility of identified risks, RCR, and secondaiy 
malignancies will be summai·ized. 
10.7.9. 
Pharmacokinetic Analysis 
The levels of anti-CD19 CART cells measured in peripheral blood at Day 7 after axicabtagene 
ciloleucel infusion will be summarized with descriptive statistics. 
10.7.10. 
Pharmacodynamics Analyses 
The levels of cytokines in sernm will be summai·ized with descriptive statistics. 
10.7.11. 
will be 
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11.
REGULATORY OBLIGATIONS
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki

Applicable International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines

Applicable local laws and regulations
11.1.
Independent Review Board/Independent Ethics Committee
A copy of the protocol, ICF, and any additional subject or trial information, such as subject 
recruitment materials, must be submitted to each site’s respective IRB/IEC for approval. After 
approval is obtained from the IRB/IEC, all documents must be provided to the key sponsor 
contact before subject recruitment can begin.
The investigator must also receive IRB/IEC approval for all protocol and ICF changes or 
amendments. Investigators must ensure that ongoing/continuous IRB/IEC approval (ie, annual 
approval) is provided throughout the conduct of the study. Copies of IRB/IEC approval are to be 
forwarded to the key sponsor contact for archiving.
During the course of the study, investigators will submit site-specific and study SAEs (provided 
to the site by the key sponsor contact) along with any protocol deviations to their IRB/IEC in 
accordance with their respective IRB/IEC policies. 
11.2.
Subject Confidentiality
Subject confidentiality must be maintained within all material that is submitted to the key 
sponsor contact. The following rules are to be applied.

Subjects will be identified by a unique ID number

Year of birth/age at time of enrollment will be reported according with local laws and 
regulations
For the reporting of SAEs, subjects will be identified by their respective subject ID number, 
initials, and year of birth (as per their local reporting requirements for both initials and year of 
birth).

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Per country-specific regulations and ICH/GCP guidelines, investigators and institutions are 
required to permit authorization to the sponsor, contract research organization, IRB/IEC, and 
regulatory agencies to subject’s original source documents for verification of study data. The 
investigator is responsible for informing potential subjects that such individuals will have access 
to their medical records, which includes personal information.
11.3.
Investigator Signatory Obligations
Each CSR will be signed by the coordinating investigator. The coordinating investigator will be 
identified by Kite under the following criteria:

Is a recognized expert in the disease setting

Provided significant contributions to the design or analysis of study data

Participated in the study and enrolled a high number of eligible subjects

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12.
PROTOCOL AMENDMENTS AND TERMINATION
If the protocol is amended, the investigator’s agreement with the amendment and the IRB/IEC 
approval of the amendment must be obtained. Documentation acknowledging approval from 
both parties are to be submitted to the key sponsor contact.
Both Kite Pharma and the investigator reserve the right to terminate the investigator’s 
participation in the study as per the terms of the agreement in the study contract. The investigator 
is to provide written communication to the IRB/IEC regarding either the trial completion or early 
termination and provide the contract research organization with a copy of the correspondence.
Kite Pharma reserves the unilateral right, at its sole discretion, to determine whether to 
manufacture axicabtagene ciloleucel and provide it to sites and subjects after the completion of 
the study.

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13.
STUDY DOCUMENTATION AND ARCHIVING
The investigator will maintain a list of qualified staff to whom study responsibilities have been 
delegated. The individuals authorized to fulfil these responsibilities should be outlined and 
included in the Delegation of Authority Form.
Source documents are original documents, data, and records for which the study data are 
collected and verified. Examples of such source documents may include, but are not limited to, 
hospital records and patient charts; laboratory, pharmacy, and radiology records; subject diaries; 
microfiches; correspondence; and death registries. CRF entries may be considered as source data 
if the site of the original data collection is not available. However, the use of the CRFs as source 
documentation is not recommended as a routine practice.
The investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system of all subject records that are readily retrieved to be monitored and or audited at 
any time by the key sponsor contact, health authorities, and IRB/IECs. The filing system will 
include at a minimum:

Subject content including ICFs and subject ID lists

Protocols and protocol amendments, IB, copies of pre-study documentation, and all IRB/IEC 
and sponsor communication

Proof of receipt, experimental treatment flow records, and experimental product-related 
correspondence
Original source documents supporting entries into CRFs must be maintained at the site and 
readily available upon request. No study documents should be discarded without prior written 
agreement between Kite and the investigator. If storage is no longer available to archive source 
documents, or if source documents must be moved to an alternative location, the research staff 
should notify the key sponsor contact prior to shipping the documents.

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14.
STUDY MONITORING AND DATA COLLECTION
The key sponsor contact, monitors, auditors, or regulatory inspectors are responsible for 
contacting, and visiting the investigator for the purpose of inspecting the facilities and verifying 
source documents and records must also assure that subject confidentially is respected.
The monitor is responsible for source document verification of CRF data at regular intervals 
during the study. Protocol adherence and accuracy and consistency of study conduct and data 
collection with respect to local regulations will be confirmed. Monitors will have access to 
subject records as identified in Section 13.
By signing the investigator’s agreement, the investigator agrees to cooperate with the monitor to 
address and resolve issues identified during monitoring visits.
In accordance with ICH/GCP and the audit plan, a site may be chosen for a site audit. A site 
audit would include, but is not limited to, an inspection of the facility(ies), review of subject- and 
study-related records, and compliance with protocol requirements as well as ICH/GCP and 
applicable regulatory policies.
All data will be collected in an electronic CRF system. All entries must be completed in English 
and concomitant therapies should be identified by tradenames. For further details surrounding 
the completion of CRFs, please refer to the CRF completion guidelines.

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15.
PUBLICATION
Authorship of publications from data generated in study KTE-C19-112 (ZUMA-12) will be 
determined based on the uniform requirements for manuscripts submitted to biomedical journals 
(as outlined in the International Committee of Medical Journal Editors December 2013), which 
states that authorship should be based on:

Substantial contributions to the conception or design of the work, acquisition of data, 
analysis, or interpretation of data for the work; and

Drafting the article or revising it critically for important intellectual content; and

Final approval of the version to be published; and

Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated or resolved
When a large, multicenter group has conducted the work, the group should identify the 
individuals who accept direct responsibility for the manuscript. This individual should fully meet 
the criteria for authorship defined above.
Funding, collection of data, or general supervision of the research alone or in combination does 
not qualify an individual for authorship.
Any publication, in any form, that is derived from this study must be submitted to Kite for 
review and approval. The study contract among the institution, principal investigator, and Kite or 
its delegate will outline the requirements for publication review.

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16.
COMPENSATION
Kite will provide compensation for study-related illness or injury pursuant to the information 
outlined in the injury section of the ICF.

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17.
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de Jonge AV, Roosma TJ, Houtenbos I, Vasmel WL, van de Hem K, de Boer JP, et al. Diffuse 
large B-cell lymphoma with MYC gene rearrangements: Current perspective on 
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de Oliveira Costa R, Hallack Neto A, Siqueira S, Lage LA, de Paula HM, Coutinho AM, et al. 
Interim Fluorine-18 Fluorodeoxyglucose PET-Computed Tomography and Cell of 
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in Diffuse Large B-Cell Lymphoma Patients in the Rituximab Era. Nucl Med 
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18.
APPENDICES
Appendix 1.
Lugano Classification {Cheson 2014}
Appendix 2.
International Prognostic Index in Aggressive Lymphomas
Appendix 3.
Country-Specific Regulatory Agency Requirements
Appendix 4.
Birth Control Methods Which May Be Considered as Highly Effective

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Appendix 1.
Lugano Classification {Cheson 2014}
Please refer to {Cheson 2014} for details of assessment.
Deauville 5-Point Scale (5PS) {Barrington 2014}
Score
Description 
1 
No uptake above background 
2 
Uptake ≤ mediastinum 
3 
Uptake > mediastinum but ≤ liver 
4 
Uptake moderately higher than liver 
5 
Uptake markedly higher than liver and/or new lesions
X 
New areas of uptake unlikely to be related to lymphoma  
Complete Remission:
Complete Metabolic Response for Positron Emission Tomography–Computed Tomography-
Based Response
The designation of complete metabolic response requires all of the following:

A 5PS (5-point scale) score of 1, 2 or 3, with or without a residual mass 
In Waldeyer’s ring or extranodal sites with high physiologic uptake or with activation 
within spleen or marrow, uptake may be greater than normal in the mediastinum and/or 
liver. In this circumstance, complete metabolic response may be inferred if uptake at sites 
of initial involvement is no greater than surrounding normal tissue even if the tissue has 
high physiologic uptake.

No new sites of disease should be observed 

No evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow
Complete Radiologic Response for Computed Tomography-Based Response 
The designation of complete radiologic response requires all of the following:

Target nodes/nodal masses must regress to ≤ 1.5 cm in longest transverse diameter (LDi) of a 
lesion

No extralymphatic sites of disease

Absent nonmeasured lesion

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
Organ enlargement regress to normal

No new sites of disease should be observed

Bone marrow normal by morphology; if indeterminate, immunohistochemistry negative
Partial Remission: 
Partial Metabolic Response for Positron Emission Tomography–Computed Tomography-Based 
Response
The designation of partial metabolic response requires all of the following:

A 5PS score of 4 or 5, with reduced uptake compared to baseline (screening), and residual 
mass(es) of any size 
Note:
At interim, these findings suggest responding disease 
At end of treatment, these findings suggest residual disease 

No new sites of disease should be observed 

Residual uptake is higher than uptake in normal bone marrow but reduced compared with 
baseline (diffuse uptake is compatible with reactive changes from chemotherapy allowed)
If there are persistent focal changes in the marrow in the context of a nodal response, 
consideration should be given to further evaluation with magnetic resonance image or biopsy or 
an interval scan.
Partial Radiologic Response for Computed Tomography-Based Response 
The designation of partial radiologic response requires all of the following:

≥ 50% decrease in sum of the product of the perpendicular diameters of up to 6 target 
measurable nodes and extranodal sites 
When a lesion is too small to measure on a computed tomography scan, assign 5 mm x 
5 mm as the default value
When no longer visible, 0 x 0 mm
For a node > 5 mm x 5 mm, but smaller than normal, use actual measurement for 
calculation 

Absent/normal, regressed, but no increase of nonmeasured lesions

Spleen must have regressed by > 50% in length beyond normal 

No new sites of disease should be observed

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Stable Disease:
No Metabolic Response for Positron Emission Tomography–Computed Tomography-Based 
Response 
The designation of no metabolic response requires all of the following:

A 5PS score of 4 or 5, with no significant change in FDG uptake compared to baseline 
(screening) at an interim time point or end of treatment 

No new sites of disease should be observed 

No change from baseline in bone marrow
Stable Radiologic Disease for Computed Tomography-Based Response
The designation of stable radiologic disease requires all of the following:

< 50% decrease from baseline in the sum of the product of the perpendicular diameters of up 
to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease are 
met

No increase consistent with progression in nonmeasured lesion and organ enlargement 

No new sites of disease should be observed 
Progressive Disease:
Progressive Metabolic Disease for Positron Emission Tomography–Computed 
Tomography-Based Response 
The designation of progressive metabolic disease requires at least 1 of the following:

A 5PS score 4 or 5 with an increase in intensity of uptake from baseline and/or

New FDG-avid foci consistent with lymphoma at interim or end of treatment assessment 

New FDG-avid foci consistent with lymphoma rather than another etiology (eg, infection, 
inflammation). If uncertain regarding etiology of new lesions, biopsy or interval scan may be 
considered

New or recurrent FDG-avid foci in bone marrow 

Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
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14 JUN 2022
Progressive Radiologic Disease for Computed Tomography-Based Response 
The designation of progressive radiologic disease requires at least one of the following:

An individual node/lesion must be abnormal with:
LDi > 1.5 cm and 
Increase by ≥ 50% from cross product of LDi and perpendicular diameter nadir and
An increase in LDi or SDi, shortest axis perpendicular to the LDi, (SDi) from nadir 
■
0.5 cm for lesions ≤ 2 cm
■
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the splenic length must increase by > 50% of the extent of 
its prior increase beyond baseline (eg, a 15-cm spleen must increase to > 16 cm). If no 
prior splenomegaly, spleen must increase by at least 2 cm from baseline 
New or recurrent splenomegaly

New or clear progression of pre-existing nonmeasured lesions

New lesion
Regrowth of previously resolved lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to lymphoma
Assessable disease of any size unequivocally attributable to lymphoma

New or recurrent bone marrow involvement

Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
Page 85
14 JUN 2022
Appendix 2.
International Prognostic Index in Aggressive Lymphomas
The International Prognostic Index (IPI) score is calculated by adding the number of prognostic 
factors:

Age > 60 years

Performance status ≥ 2

Lactate dehydrogenase > 1 x normal

Extranodal sites > 1

Stage III or IV
The IPI risk level is determined based on the IPI score: 
Risk Level
IPI Score
Low (L)
0 or 1
Low-intermediate (LI)
2
High-intermediate (HI)
3
High (H)
4 or 5

Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
Page 86
14 JUN 2022
Appendix 3.
Country-Specific Regulatory Agency Requirements 
France
The post-infusion monitoring of subjects, described in Section 7.10.3.2 of this protocol, will be 
extended by monitoring on Day 8, Day 9, and Day 10, according to procedures outlined in 
Table 3, column “Axicabtagene Ciloleucel Administration Period, D1 to 7.” The subject may 
stay hospitalized or return to the clinic daily for this extended monitoring at the discretion of the 
investigator.
The daily monitoring will include vital signs (see Section 7.6), blood draw for chemistry panel 
with C-reactive protein, blood draw for complete blood count with differential, and neurological 
examination (see Section 7.8). Any observed toxicity will be managed according to Section 6.1.8 
of this protocol.

Axicabtagene Ciloleucel
Kite Pharma, Inc.
Clinical Protocol
KTE-C19-112 (ZUMA-12)
CONFIDENTIAL
Page 87
14 JUN 2022
Appendix 4.
Birth Control Methods Which May Be Considered as Highly Effective
For the purpose of this guidance, methods that can achieve a failure rate of < 1% per year when 
used consistently and correctly are considered as highly effective birth control methods. Such 
methods include:

Combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation1:
Oral
Intravaginal
Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation2:
Oral 
Injectable
Implantable2

Intrauterine device2

Intrauterine hormone-releasing system2

Bilateral tubal occlusion2

Vasectomized partner2,3

Sexual abstinence4
1 Hormonal contraception may be susceptible to interaction with the investigational product, which may reduce the 
efficacy of the contraception method.
2 Contraception methods that in the context of this guidance are considered to have low user dependency.
3 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the woman of childbearing potential trial subject and that the vasectomized partner has received medical assessment 
of the surgical success.
4 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the subject.