Clinical trial NCT02348216
Conditions: Refractory Diffuse Large B Cell Lymphoma (DLBCL) Relapsed Diffuse Large B-Cell Lymphoma Transformed Follicular Lymphoma (TFL) Primary Mediastinal B-cell Lymphoma (PMBCL) High Grade B-cell Lymphoma (HGBCL)
Sponsor: Kite, A Gilead Company
Start date: 2015-04-21; Completion date: 2023-07-27
Enrollment: 307 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

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

The primary objectives of this study are:

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

Subjects who received an infusion of KTE-C19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968.

Detailed description:

Arms: arm 1: Participants with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) will receive conditioning chemotherapy (fludarabine 30 mg/m\^2 intravenously \[IV\] over 30 minutes and cyclophosphamide 500 mg/m\^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel chimeric antigen receptor (CAR) transduced autologous T cells administered IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of body weight (BW) on Day 0. arm 2: Participants with refractory DLBCL will receive conditioning chemotherapy (fludarabine 30 mg/m\^2 IV over 30 minutes and cyclophosphamide 500 mg/m\^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0. arm 3: Participants with refractory PMBCL or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m\^2 IV over 30 minutes and cyclophosphamide 500 mg/m\^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0. arm 4: Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m\^2 IV over 30 minutes and cyclophosphamide 500 mg/m\^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV twice daily (BID) starting on Day 0) and tocilizumab (8 mg/kg IV over 1 hour (not to exceed 800 mg)) on Day 2). arm 5: Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m\^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m\^2 weekly for 3 weeks or bendamustine 90 mg/m\^2 on Days 1 and 2 and rituximab 375mg/m\^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m\^2 IV and cyclophosphamide 500mg/m\^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants will receive tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity). arm 6: Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m\^2 D1,doxorubicin 50mg/m\^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m\^2 D1,vincristine 1.4 mg/m\^2 D1 or R-ICE:rituximab 375mg/ m\^2 D1,ifosfamide 5g/m\^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m\^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m\^2 D1,gemcitabine 1000mg/m\^2 D2,oxaliplatin 100mg/m\^2 D2 or R-GDP:rituximab 375mg/m\^2 D1 or D8,gemcitabine 1g/m\^2 D1 \& D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m\^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m\^2 IV and cyclophosphamide 500mg/m\^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day. arm 7: Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m\^2 HDMP for 3 days with rituximab at 375mg/m\^2 weekly for 3 weeks or bendamustine 90 mg/m\^2 on Days 1 and 2 and rituximab 375mg/m\^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m\^2 IV and cyclophosphamide 500mg/m\^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).
Interventions: intervention 1: Axicabtagene Ciloleucel intervention 2: Fludarabine intervention 3: Cyclophosphamide intervention 4: Levetiracetam intervention 5: Tocilizumab intervention 6: Dexamethasone intervention 7: High-dose methylprednisolone intervention 8: Bendamustine intervention 9: Rituximab intervention 10: Doxorubicin intervention 11: Prednisone intervention 12: Vincristine intervention 13: Ifosfamide intervention 14: Carboplatin intervention 15: Etoposide intervention 16: Gemcitabine intervention 17: Oxaliplatin intervention 18: Cisplatin intervention 19: Methylprednisolone
Intervention descriptions: intervention 1: A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg. intervention 2: Administered according to package insert intervention 3: Administered according to package insert intervention 4: Administered according to package insert intervention 5: Administered according to package insert intervention 6: Administered according to package insert intervention 7: Administered according to package insert intervention 8: Administered according to package insert intervention 9: Administered according to package insert intervention 10: Administered according to package insert intervention 11: Administered according to package insert intervention 12: Administered according to package insert intervention 13: Administered according to package insert intervention 14: Administered according to package insert intervention 15: Administered according to package insert intervention 16: Administered according to package insert intervention 17: Administered according to package insert intervention 18: Administered according to package insert intervention 19: Administered according to package insert

Protocol documents:
Prot_002.pdf: 
CLINICAL STUDY PROTOCOL
Protocol Title:
A Phase 1/2 Multicenter Study Evaluating the Safety and 
Efficacy of KTE-C19 in Subjects with Refractory 
Aggressive Non-Hodgkin Lymphoma (ZUMA-1)
Protocol Number:
KTE-C19-101 (ZUMA-1)
Indication:
Relapsed/Refractory Large B-Cell Lymphoma
Kite Investigational Product 
KTE-C19
Kite IND Number:
016278 
EudraCT Number:
2015-005007-86
Clinical Trials.gov 
Identifier:
NCT02348216
Sponsor:
Kite Pharma, Inc.
2400 Broadway
Santa Monica, CA 90404
United States of America
Contact Information:
The medical monitor name and contact information is 
provided on the Key Study Team Contact List
Protocol Version/Date:
Original:
26 November 2014 
Amendment 10.0:
14 June 2022
CONFIDENTIALITY STATEMENT
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. 


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SPONSOR AND INVESTIGATOR SIGNATURE PAGE 
KITE PHARMA, INC. 
2400 BROADWAY 
SANTA MONICA, CA 90404 
STUDY ACKNOWLEDGMENT 
A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of KTE C19 in Subjects with 
Refractory Aggressive Non-Hodgkin Lymphoma (ZUMA-1) 
Amendment 10.0, 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 (ICH) 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: 
x
Me (including, if applicable, my spouse, legal partner, and dependent children) 
x
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: 55B3EF44-0288-4B06-A966-F8CB9E125FF5
June 22, 2022 | 11:21:42 AM PDT
PPD
PPD


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PROTOCOL SYNOPSIS
Title
A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of 
KTE-C19 in Subjects with Refractory Aggressive Non-Hodgkin 
Lymphoma (ZUMA-1).
Indication
The indication is for the treatment of adult subjects with relapsed or 
refractory diffuse large B-cell lymphoma (DLBCL), primary 
mediastinal B-cell lymphoma (PMBCL), transformed follicular 
lymphoma (TFL), and high grade B-cell lymphoma (HGBCL) after 
two or more lines of systemic therapy.
Study Design
Study KTE-C19-101 is a Phase 1/2 multicenter, open-label study 
evaluating the safety and efficacy of axicabtagene ciloleucel in subjects 
with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). 
The trial will be separated into 3 distinct phases designated as the 
Phase 1 study, Phase 2 pivotal study (Cohort 1 and Cohort 2), and 
Phase 2 safety management study (Cohort 3, Cohort 4, Cohort 5, and 
Cohort 6).
Phase 1 Study
During Phase 1 study, approximately 6 to 24 subjects with DLBCL, 
PMBCL, or TFL will be enrolled to evaluate the safety of axicabtagene 
ciloleucel regimens. A safety review team (SRT), internal to the study 
sponsor, will review the safety data and make recommendations on 
further study conduct of Phase 1 and progression to Phase 2 pivotal 
study as depicted in Figure 3 and outlined in Section 9.10.
Phase 2 Pivotal Study
In the Phase 2 pivotal study, approximately 92 subjects will enroll into 
2 separate cohorts designated as Cohort 1 and Cohort 2:

Cohort 1 will enroll approximately 72 adult subjects with refractory 
DLBCL.

Cohort 2 will enroll approximately 20 adult subjects with refractory 
PMBCL and TFL. TFL is defined as subjects who received prior 
therapy for follicular lymphoma.
Phase 2 Safety Management Study
In the Phase 2 safety management study (SMS), approximately 
170 subjects will enroll into 4 separate cohorts designated as Cohort 3, 
Cohort 4, Cohort 5, and Cohort 6.

Cohort 3 will enroll approximately 40 adult subjects with relapsed 
or refractory transplant ineligible DLBCL, PMBCL, or TFL.


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
Cohort 4 will enroll and dose approximately 40 adult subjects with 
relapsed or refractory DLBCL, PMBCL, TFL or HGBCL after 2 or 
more lines of systemic therapy.

Cohort 5 will enroll and dose approximately 50 adult subjects with 
relapsed or refractory DLBCL, PMBCL, TFL or HGBCL after 2 or 
more lines of systemic therapy.

Cohort 6 will enroll and dose approximately 40 adult subjects with 
relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 
2 or more lines of systemic therapy.
NOTE: Cohort 6 is not open for enrollment in Germany
Independent of the phase of the study each subject will follow the same 
study treatment schedule and procedural requirements. Each subject 
will proceed through the following study periods:

Screening

Enrollment/Leukapheresis period

Bridging therapy (if applicable; safety management study only) or 
debulking therapy (if applicable, safety management study, Cohort 
5 only)

Conditioning chemotherapy period

Investigational product (IP) treatment period

Post-treatment assessment period

Long-term follow-up period
For study requirements assigned to each study period, refer to 
Section 7 for details.
At the end of KTE-C19-101, subjects who received an infusion of 
axicabtagene ciloleucel will complete the remainder of the 15-year 
follow-up assessments in a separate long-term Follow-up (LTFU) 
study, KT-US-982-5968.
Study Objectives
Phase 1 Study
The primary objective of Phase 1 is to evaluate the safety of 
axicabtagene ciloleucel regimens.
Phase 2 Pivotal Study
The primary objective of the Phase 2 pivotal study is to evaluate the 
efficacy of axicabtagene ciloleucel, as measured by objective response 
rate (ORR) in subjects with DLBCL, PMBCL, and TFL. Secondary 
objectives will include assessing the safety and tolerability of 
axicabtagene ciloleucel and additional efficacy endpoints.








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
Cohort 6: approximately 40 subjects
NOTE: Cohort 6 is not open for enrollment in Germany.


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Study Eligibility
Please refer to Section 5 for a complete and detailed list of inclusion 
and exclusion criteria for both phases of the study.
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 CAR T cells/kg. For subjects 
weighing greater than 100 kg, a maximum flat dose of 
2 x 108 anti-CD19 CAR T cells will be administered. Under 
circumstances where subjects initially respond and subsequently 
relapse, subjects may be eligible for a second course of 
conditioning chemotherapy and axicabtagene ciloleucel. Refer to 
Section 6 for treatment and Section  7.13.10 for retreatment details.
Bridging Therapy (Phase 2 Safety Management Study)

At the discretion of the investigator, bridging therapy may be 
considered for subjects particularly with high disease burden at 
screening or baseline assessment (eg, bulky disease or rapidly 
progressing disease).

For subjects receiving bridging therapy, refer to Section 6 for 
bridging therapy details.
Debulking Therapy (Phase 2 Safety Management Study, Cohort 5)

Debulking therapy should be applied to all subjects enrolled in 
Cohort 5 with the aim of reducing lymphoma burden. Debulking 
therapy is to be administered after leukapheresis and prior to 
administration of conditioning chemotherapy or axicabtagene 
ciloleucel.

Refer to Section 6.2.2 for debulking therapy details
Conditioning Chemotherapy

Axicabtagene ciloleucel is administered after a conditioning 
chemotherapy regimen consisting of fludarabine 30 mg/m2/day and 
cyclophosphamide 500 mg/m2/day, administered x 3 days. Refer to 
Section 6 for chemotherapy treatment details.
Additional axicabtagene ciloleucel regimens may be explored in 
Phase 1 per Section 9.10.
Phase 2 Safety Management Study

Subjects assigned to Cohort 3 will receive the same conditioning 
chemotherapy and axicabtagene ciloleucel regimen as described 
above and will also receive prophylactic tocilizumab and 
levetiracetam for toxicity management as outlined in Section 6.3.4 
and Section 6.4.


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
Subjects assigned to Cohort 4 will receive the same conditioning 
chemotherapy and axicabtagene ciloleucel regimen as described 
above, but toxicity management will intervene at lower grades of 
CRS and neurologic toxicities as outlined in Section 6.4.1.

Subjects assigned to Cohort 5 will receive the same conditioning 
chemotherapy and axicabtagene ciloleucel regimen as other safety 
management cohorts; toxicity management will be completed as 
outlined in Section 6.4.2.

Subjects assigned to Cohort 6 will receive the same conditioning 
chemotherapy and axicabtagene ciloleucel regimen as described 
above 
; toxicity management 
will intervene at lower grades of CRS and neurologic toxicities as 
outlined in Section 6.4.1.
NOTE: Cohort 6 is not open for enrollment in Germany.
Procedures
At specific time points as outlined in the schedule of assessments, 
subjects will undergo the following assessments/procedures: collection 
of informed consent, general medical history including previous 
treatments for NHL, physical exam including vital signs and 
performance status, neurologic assessments, blood draws for complete 
blood count (CBC), chemistry panels, cytokines, C-reactive protein, 
lymphocyte subsets, anti-axicabtagene ciloleucel antibodies, 
replication-competent retrovirus (RCR) and anti-CD19 CAR T cell 
analysis. Women of childbearing potential will undergo a urine or 
serum pregnancy test.
Subjects will also undergo a baseline electrocardiogram (ECG), 
echocardiogram (ECHO), brain magnetic resonance image (MRI), a 
positron emission tomography–computed tomography (PET-CT), 
possible bone marrow aspirate/biopsy and leukapheresis.
Subjects assigned to Cohort 3, Cohort 4, Cohort 5, and Cohort 6 will 
complete the EQ-5D questionnaire at baseline and after axicabtagene 
ciloleucel (see Section 7.4 and schedule of assessments [SOA]) 
infusion and will have lumbar punctures performed for the collection 
of cerebrospinal fluid (CSF) (see Section 7.9 and SOA) before and 
after axicabtagene ciloleucel infusion.
Routinely throughout the conduct of the study, subjects will be asked 
to report concomitant medications and adverse events and will have 
their disease assessed.
NOTE: Cohort 6 is not open for enrollment in Germany.
CCI






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The secondary objectives of Cohort 3, Cohort 4, Cohort 5, and Cohort 
6 include assessment of efficacy endpoints (ORR, DOR, PFS, OS) and 
levels of anti-CD19 CAR T cells and cytokines in the blood.
Analyses of the safety and efficacy endpoints of this portion of the 
study will be entirely descriptive, with no formal statistical testing 
being performed.
NOTE: Cohort 6 is not open for enrollment in Germany.


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STUDY GLOSSARY
Abbreviation or Term
Definition/Explanation
AE
Adverse event
ALL
Acute lymphoblastic leukemia
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ASCT
Autologous stem cell transplant
AST
Aspartate aminotransferase
AUC
Area under the curve
BBB
Blood brain barrier
BUN
Blood urea nitrogen
CAR
Chimeric antigen receptor
CBC
Complete blood count
CLL
Chronic lymphocytic leukemia
CMV
Cytomegalovirus
CNS
Central nervous system
CPF
Cell processing facility
CR
Complete response
CRF
Case report form
CRP
C-reactive protein
CRS
Cytokine release syndrome
CSF
Cerebrospinal fluid
CTCAE
Common Terminology Criteria for Adverse Events
DLBCL
Diffuse large B-cell lymphoma
DLT
Dose-limiting toxicity
DOR
Duration of response
DSMB
Data Safety Monitoring Board
eACT™
Engineered autologous cell therapy
EBV
Epstein-Barr virus
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EQ-5D
European Quality of Life-5 Dimensions
FAS
Full analysis set
FL
Follicular lymphoma
GCP
Good Clinical Practice
GOT
Glutamic-oxaloacetic transaminase
GPT
Glutamic-pyruvic transaminase
HGBCL
High grade B-cell lymphoma
HIV
Human immunodeficiency virus


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Abbreviation or Term
Definition/Explanation
HLH
Hemophagocytic lymphohistiocytosis
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICU
Intensive care unit
ID
Identification
IP
Investigational product
IRB/IEC
Institutional Review Board/Independent Ethics Committee
IRRC
Independent Radiological Review Committee
IV
Intravenous
IWG
International Working Group
LDH
Lactate dehydrogenase
LTFU
Long-term follow-up
LVEF
Left ventricular ejection fraction
mITT
Modified intent-to-treat
MMSE
Mini-Mental Status Exam
MRI
Magnetic resonance imaging
MSGV1
Murine stem cell virus-based vector
NaCl
Sodium chloride
NCI
National Cancer Institute
NHL
Non-Hodgkin lymphoma
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
PMBCL
Primary mediastinal B-cell lymphoma
PR
Partial response
RCR
Replication-competent retrovirus
qPCR
Quantitative polymerase chain reaction
SAE
Serious adverse event
scFv
Single-chain variable fragment
SD
Stable disease
SMS
Safety management study
SOA
Schedule of assessment
SPD
Sum of the product of diameters
SRT
Safety review team
SUSAR
Suspected unexpected serious adverse reaction


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Abbreviation or Term
Definition/Explanation
Study Day 0
Defined as the first day that axicabtagene ciloleucel is administered to the subject
TFL
Transformed follicular lymphoma
ULN
Upper limit of normal
VAS
Visual analogue scale
WBC
White blood cell


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Clinical Protocol: KTE-C19-101
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Figure 1.
Study Schema (Phase 1 and Phase 2)
Notes: Study KTE-C19-101 is a Phase 1-2 single-arm, open-label, multicenter study evaluating the safety and efficacy of KTE-C19 in subjects with refractory DLBCL, PMBCL 
and TFL.
During Phase 1, approximately 6-24 subjects with DLBCL, PMBCL or TFL will be enrolled to evaluate the safety of axicabtagene ciloleucel regimens. A safety review team 
(SRT), internal to the study sponsor, will review the safety data and make recommendations on further study conduct of Phase 1 and progression to Phase 2 as depicted in Figure 3 
and outlined in Section 9.10.
Upon SRT recommendation, the pivotal Phase 2 will commence and enroll subjects into 2 separate cohorts designated as Cohort 1 and Cohort 2.

Cohort 1 will enroll adult subjects with refractory DLBCL.

Cohort 2 will enroll adult subjects with refractory PMBCL and TFL. Refer to entrance criteria for TFL eligibility requirements.
Upon completion of enrollment of the Phase 2 pivotal study, the Phase 2 Safety Management Study will commence and enroll subjects into 4 separate cohorts designated as 
Cohort 3, Cohort 4, Cohort 5, and Cohort 6.

Cohort 3 will enroll adult subjects with relapsed or refractory transplant ineligible DLBCL, PMBCL, and TFL.

Cohort 4 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL and HGBCL after 2 systemic lines of therapy.

Cohort 5 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy.

Cohort 6 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy.
Independent of the phase of the study each subject will follow the same study treatment schedule and procedural requirements. Each subject will follow through the following 
study periods: a screening period, an enrollment/leukapheresis period, a conditioning chemotherapy period, an IP treatment period, a post treatment assessment period and a 
long-term follow-up period.
Cohort 6 is not open for enrollment in Germany.
After the end of KTE-C19-101, subjects who received an infusion of axicabtagene ciloleucel will complete the remainder of the 15-year follow-up assessments in a separate 
long-term follow-up study, KT-US-982-5968.
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS
SPONSOR AND INVESTIGATOR SIGNATURE PAGE............................................................................................2
PROTOCOL SYNOPSIS................................................................................................................................................3
STUDY GLOSSARY ...................................................................................................................................................14
TABLE OF CONTENTS..............................................................................................................................................18
LIST OF APPENDICES...............................................................................................................................................20
LIST OF IN-TEXT FIGURES......................................................................................................................................21
1.
OBJECTIVES.......................................................................................................................................................22
2.
DISEASE BACKGROUND AND RATIONALE...............................................................................................23
2.1.
Diffuse Large B-cell Lymphoma.............................................................................................................23
2.2.
Primary Mediastinal B-cell Lymphoma and Transformed Follicular Lymphoma..................................24
2.3.
High Grade B-cell Lymphoma ................................................................................................................25
2.4.
Study Rationale .......................................................................................................................................25
2.4.1.
CD19 and Expression............................................................................................................26
2.4.2.
Anti-CD19 CAR T-cell Product............................................................................................26
2.4.3.
Prior Experience with Axicabtagene Ciloleucel and other Anti-CD19 
CAR T Cells..........................................................................................................................27
2.4.4.
Axicabtagene Ciloleucel........................................................................................................27
3.
STUDY DESIGN.................................................................................................................................................28
3.1.
General Study Design..............................................................................................................................28
3.2.
Participating Sites....................................................................................................................................31
3.3.
Number of Subjects .................................................................................................................................31
3.4.
Replacement of Subjects .........................................................................................................................32
3.5.
Study Duration.........................................................................................................................................32
3.5.1.
Study Duration for Individual Subjects.................................................................................32
3.5.2.
Completion of the Study (Phase 1/Phase 2) ..........................................................................32
3.5.3.
Long-term Follow-up ............................................................................................................32
4.
SUBJECT SCREENING AND ENROLLMENT................................................................................................33
5.
SUBJECT ELIGIBILITY.....................................................................................................................................34
5.1.
Inclusion Criteria.....................................................................................................................................34
5.2.
Exclusion Criteria....................................................................................................................................36
6.
PROTOCOL TREATMENT................................................................................................................................38
6.1.
Treatment Terminology...........................................................................................................................38
6.2.
Study Treatment ......................................................................................................................................38
6.2.1.
Bridging Therapy for Phase 2 Safety Management Study, Cohort 3 
(retreatment), Cohort 4, and Cohort 6...................................................................................38
6.2.2.
Debulking Therapy for Phase 2 Safety Management Study, Cohort 5 .................................39
6.2.3.
Conditioning Chemotherapy .................................................................................................40
6.2.4.
Axicabtagene Ciloleucel........................................................................................................41
6.2.5.
Concomitant Therapy ............................................................................................................42
6.2.6.
Excluded Medications ...........................................................................................................42
6.2.7.
Subsequent Therapy ..............................................................................................................43
6.3.
Study Treatment Schedule.......................................................................................................................43
6.3.1.
Leukapheresis (Within Approximately 5 Days of Eligibility 
Confirmation)........................................................................................................................43
6.3.2.
Study Treatment ....................................................................................................................43


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6.3.3.
Rationale for Study Treatment Dosing..................................................................................45
6.3.4.
Study Treatment by Phase.....................................................................................................50
6.4.
Toxicity Management..............................................................................................................................53
6.4.1.
Phase 2 Safety Management Study (Cohort 4 and Cohort 6 only)........................................53
6.4.2.
Phase 2 Safety Management Study (Cohort 5)......................................................................57
7.
STUDY PROCEDURES......................................................................................................................................58
7.1.
Informed Consent ....................................................................................................................................58
7.2.
Demographic Data...................................................................................................................................58
7.3.
Medical and Treatment History...............................................................................................................58
7.4.
Physical Exam, Vital Signs, Performance Status, and EQ-5D................................................................59
7.5.
Neurological Assessment ........................................................................................................................59
7.6.
Cardiac Function .....................................................................................................................................60
7.7.
Magnetic Resonance Imaging .................................................................................................................60
7.8.
Bone Marrow Biopsy ..............................................................................................................................60
7.9.
Lumbar Puncture .....................................................................................................................................60
7.10.
Disease Response Assessment ................................................................................................................61
7.11.
Laboratory ...............................................................................................................................................62
7.12.
Biomarkers ..............................................................................................................................................63
7.13.
Description of Study Periods...................................................................................................................65
7.13.1.
Screening ...............................................................................................................................65
7.13.2.
Rescreening ...........................................................................................................................67
7.13.3.
Enrollment/Leukapheresis.....................................................................................................67
7.13.4.
Bridging Therapy Phase 2 Safety Management Study..........................................................68
7.13.5.
Debulking Therapy Phase 2 Safety Management Study, Cohort 5.......................................68
7.13.6.
Conditioning Chemotherapy Period......................................................................................69
7.13.7.
Investigational Product Treatment Period.............................................................................71
7.13.8.
Post-treatment Assessment Period ........................................................................................75
7.13.9.
Long-term Follow-up Period.................................................................................................76
7.13.10.
Retreatment............................................................................................................................78
8.
SUBJECT WITHDRAWAL ................................................................................................................................84
8.1.
Reasons for Removal from Treatment ....................................................................................................84
8.2.
Reasons for Removal from Study............................................................................................................85
9.
SAFETY REPORTING........................................................................................................................................86
9.1.
Adverse Events........................................................................................................................................86
9.2.
Reporting of Adverse Events...................................................................................................................86
9.2.1.
Reporting Abnormal Laboratory Findings ............................................................................87
9.3.
Definition of Serious Adverse Events .....................................................................................................88
9.4.
Reporting of Serious Adverse Events......................................................................................................89
9.5.
Reporting Deaths.....................................................................................................................................90
9.6.
Diagnosis versus Signs and Symptoms...................................................................................................90
9.7.
Pregnancy and Lactation .........................................................................................................................90
9.8.
Hospitalization and Prolonged Hospitalization.......................................................................................91
9.9.
Abnormal Vital Sign Values ...................................................................................................................91
9.10.
Safety Review Team and Dose-limiting Toxicity...................................................................................91
9.11.
Data Safety Monitoring Board ................................................................................................................93
9.12.
Criteria to Pause Enrollment ...................................................................................................................93
10.
STATISTICAL CONSIDERATIONS.................................................................................................................95
10.1.
Hypothesis ...............................................................................................................................................95
10.2.
Study Endpoints.......................................................................................................................................95
10.2.1.
Primary ..................................................................................................................................95
10.2.2.
Secondary ..............................................................................................................................95


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10.3.
Sample Size Considerations ....................................................................................................................96
10.3.1.
Phase 2 Pivotal Study, Cohort 1, and Cohort 2 .....................................................................97
10.3.2.
Phase 2 Safety Management Study .......................................................................................98
10.4.
Statistical Assumptions ...........................................................................................................................98
10.5.
Analysis Subsets......................................................................................................................................99
10.5.1.
Phase 1 Study ........................................................................................................................99
10.5.2.
Phase 2 Study ......................................................................................................................100
10.6.
Access to Individual Subject Treatment Assignments ..........................................................................100
10.7.
Interim Analysis ....................................................................................................................................100
10.7.1.
Interim Analysis and Early Stopping Rules ........................................................................100
10.7.2.
Safety Interim Analysis .......................................................................................................101
10.7.3.
Efficacy Interim Analysis....................................................................................................101
10.8.
Planned Method of Analysis .................................................................................................................102
10.8.1.
Objective Response Rate.....................................................................................................102
10.8.2.
Duration of Response ..........................................................................................................102
10.8.3.
Progression-free Survival ....................................................................................................103
10.8.4.
Overall Survival...................................................................................................................103
10.8.5.
Safety...................................................................................................................................103
10.8.6.
Long-term Data Analysis ....................................................................................................103
11.
REGULATORY OBLIGATIONS.....................................................................................................................104
11.1.
Independent Review Board/Independent Ethics Committee.................................................................104
11.2.
Subject Confidentiality..........................................................................................................................104
11.3.
Investigator Signatory Obligations........................................................................................................105
12.
PROTOCOL AMENDMENTS AND TERMINATION ...................................................................................106
13.
STUDY DOCUMENTATION AND ARCHIVE ..............................................................................................107
14.
STUDY MONITORING AND DATA COLLECTION....................................................................................108
15.
PUBLICATION .................................................................................................................................................109
16.
COMPENSATION.............................................................................................................................................110
17.
REFERENCES...................................................................................................................................................111
18.
APPENDICES....................................................................................................................................................117
LIST OF APPENDICES
Appendix 1.
Revised IWG Response Criteria for Malignant Lymphoma {Cheson 2007} .......................118
Appendix 2.
Monitoring of subjects after IP administration per country regulatory agencies: .................120
LIST OF IN-TEXT TABLES
Table 1.
Historical Responses in Refractory NHL (SD or PD to Last Line of Therapy)......................24
Table 2.
Bridging Therapy Regimens....................................................................................................39
Table 3.
Debulking Therapy Regimens.................................................................................................40
Table 4.
Incidence of DLT and Response among Subjects with B-cell Lymphomas and 
Dosed with Group 2 and Group 3 Conditioning Chemotherapy and ≤ 2.5 x 106 anti-
CD19 CAR T Cells..................................................................................................................46
CCI


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Table 5.
DLTa Events among Subjects with B-cell Lymphomas and Dosed with ≤ 1-2.0 x 106 
anti-CD19 CAR T Cells and Cyclosphosphamide 30 mg/kg x 2 Days-Fludarabine 
25 mg/m2 x 5 Days ..................................................................................................................46
Table 6.
Tocilizumab and Corticosteroids Use in ZUMA-1 Phase 2 Pivotal Study Primary 
Analysis ...................................................................................................................................48
Table 7.
Rates of Neurologic Toxicities and CRS in the Phase 1 and 2 Pivotal Study versus 
Phase 2 Safety Management Study Cohort 3 ..........................................................................49
Table 8.
Grading and Management of CRS in Cohort 4 and Cohort 6 .................................................53
Table 9.
Grading and Management of Neurologic Toxicities in Cohort 4 and Cohort 6......................55
Table 10.
Management of Cerebral Edema in Cohort 4 and Cohort 6....................................................57
Table 11.
Schedule of Assessments.........................................................................................................80
Table 12.
Schedule of Assessments (Long-term Follow-up Period).......................................................83
LIST OF IN-TEXT FIGURES
Figure 1.
Study Schema (Phase 1 and Phase 2) ......................................................................................17
Figure 2.
Axicabtagene Ciloleucel..........................................................................................................27
Figure 3.
Phase 1 Dosing Cohorts and Regimens...................................................................................29
Figure 4
Axicabtagene Ciloleucel Expansion and Correlations with Response and Adverse 
Events ......................................................................................................................................48


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1.
OBJECTIVES
The primary objective of Phase 1 study is to evaluate the safety of axicabtagene ciloleucel 
regimens.
The primary objective of Phase 2 pivotal study is to evaluate the efficacy of axicabtagene 
ciloleucel, as measured by objective response rate (ORR) in subjects with diffuse large B-cell 
lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed 
follicular lymphoma (TFL). Secondary objectives will include assessing the safety and 
tolerability of axicabtagene ciloleucel and additional efficacy endpoints.
The primary objective of the Phase 2 safety management study is to assess the impact of a 
prophylactic regimen, earlier interventions, debulking therapy, or prophylactic steroid use on the 
rate and severity of cytokine release syndrome (CRS) and neurologic toxicities. The key 
secondary objectives include assessment of efficacy, levels of anti-CD19 chimeric antigen 
receptor (CAR) T cells, cytokines in blood/serum, and the change in European Quality of Life-5 
Dimensions (EQ-5D) scores from baseline to Month 6.


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2.
DISEASE BACKGROUND AND RATIONALE
Non-Hodgkin lymphoma (NHL) is a heterogeneous group of cancers originating in B 
lymphocytes, T lymphocytes or natural killer cells. In the United States, B cell lymphomas 
represent 80-85% of cases reported. In 2013, approximately 69,740 new cases of NHL and over 
19,000 deaths related to the disease were estimated to occur. Non-Hodgkin lymphoma is the 
most prevalent hematological malignancy and is the seventh leading site of new cancers among 
men and women and account for 4% of all new cancer cases and 3% of deaths related to cancer 
{Howlader 2017}. Large B-cell lymphomas represent the most common sub-group of NHL 
{Rodriguez-Abreu 2007}.
2.1.
Diffuse Large B-cell Lymphoma
DLBCL is the most common subtype of large B-cell lymphoma, accounting for approximately 
30% of NHL cases. There are approximately 22,000 new diagnoses of DLBCL in the United 
States each year. In the past two decades, progress has been made in understanding the biological 
heterogeneity of DLBCL and in improving survival with combinations of CHOP and 
immunotherapy. The addition of rituximab into combination therapies for DLBCL have greatly 
improved patient outcomes. However, patients with chemotherapy-refractory DLBCL following 
treatment under the current standards of care still have a particularly dire prognosis, with no 
curative treatment options {Flowers 2010}.
The population with the highest unmet need continues to consist of patients who do not respond 
to first line combination chemotherapy (typically R-CHOP) or who do not respond to their last 
course of combination chemotherapy, as the disease is mostly insensitive to subsequent 
combination chemotherapy (typically R-ICE, R-ESHAP) (Table 1). In a review of 64 patients 
with DLBCL with disease progression during first line chemotherapy or only transient response 
(≤90 days) after end of induction treatment, the response rate to second line therapy was 
15% and the median overall survival (OS) was 6 months, and no patient survived more than 
26 months after first diagnosis {Josting 2000}. An analysis of outcome in 1126 patients with 
DLBCL after first line R-CHOP included 33 patients with primary refractory DLBCL who 
received second line therapy with curative intent. Only 3 (9%) patients were able to receive 
autologous stem cell transplantation (ASCT), and only 1 (3%) patient achieved long-term 
survival {Hitz 2010}. Seshadri et al analyzed 120 patients who did not respond to second line 
platinum-based chemotherapy regimens (e.g., R-ICE) and showed that only 14% responded to 
their third line therapy {Seshadri 2008}. Ardeshna et al followed 19 patients with large B-cell 
lymphoma, and 9 patients with TFL who did not respond to second line chemotherapy. Only 5 of 
the 28 total patients (18%) responded to third line chemotherapy {Ardeshna 2005}.


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Table 1.
Historical Responses in Refractory NHL (SD or PD to Last Line of 
Therapy)
Setting
Outcome to Subsequent Therapy
Refractory to 1st line
{Philip 1995}
ORR 21%
{Josting 2000}
ORR 15%, median OS 6 mos
{Ardeshna 2005}
ORR 0%
{Hitz 2010}
Proceeded to ASCT 9%, 3% survived > 1 year
{Telio 2012}
ORR 23%, median OS 10 mos
{Matasar 2013}
ORR 10%
Refractory to 2nd line
{Moskowitz 1999}
Median OS 5 mos
{Ardeshna 2005}
ORR 18%, median OS (large B-cell lympohoma) <6 mos
{Seshadri 2008}
ORR 14%
Relapsed After ASCT
{Nagle 2013}
Median OS 8 mos
Abbreviations: ASCT, autologous stem cell transplant; mos, months; NHL, non-Hodgkin lymphoma; ORR, objective response 
rate; OS, overall survival; PD, progressive disease; SD, stable disease.
These consistently discouraging results demonstrate that new treatment options are urgently 
needed for patients whose tumors have demonstrated a lack of response to chemotherapy.
This trial will enroll patients with chemo-refractory lymphoma, as evidenced by failure to 
achieve even a transient or partial response to prior biologic and combination chemotherapy or 
by early recurrence after ASCT.
2.2.
Primary Mediastinal B-cell Lymphoma and Transformed Follicular 
Lymphoma
PMBCL has distinct clinical, pathological, and molecular characteristics compared to DLBCL. 
PMBCL is thought to arise from thymic (medullary) B cells and represents approximately 3% of 
patients diagnosed with large B-cell lymphoma. PMBCL is typically identified in the younger 
adult population in the fourth decade of life with a slight female predominance {Savage 2006, 
Sehn 1998}. Gene expression profiling suggests deregulated pathways in PMBCL overlap with 
Hodgkin lymphoma. Initial therapy of PMBCL generally includes anthracycline-containing 
regimens with rituximab with or without involved field radiotherapy. A recent Phase 2, 
prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide 
with vincristine, prednisone, and rituximab (DA-EPOCH-R) demonstrated radiotherapy may not 
be required {Dunleavy 2013}.


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Follicular lymphoma (FL), a B cell lymphoma, is the most common indolent (slow-growing) 
form of NHL, accounting for approximately 20% to 30% of all NHLs. Some patients with FL 
will transform (TFL) histologically to DLBCL which is more aggressive and associated with a 
poor outcome. Histological transformation to DLBCL occurs at an annual rate of approximately 
3% for 15 years with the risk of transformation continuing to drop in subsequent years. The 
biologic mechanism of histologic transformation is unknown. Initial treatment of TFL is 
influenced by prior therapies for follicular lymphoma but generally includes 
anthracycline-containing regimens with rituximab to eliminate the aggressive component of the 
disease {National Comprehensive Cancer Network 2014}.
Treatment options for relapsed/refractory PMBCL and TFL are similar to those in DLBCL. 
Given the low prevalence of these diseases, no large prospective randomized studies in these 
patient populations have been conducted. Patients with chemotherapy refractory disease have a 
similar or worse prognosis {Kuruvilla 2008} to those with refractory DLBCL.
In addition, the international, multicohort retrospective non-Hodgkin lymphoma research 
(SCHOLAR-1) study retrospectively evaluated outcomes in patients with chemorefractory 
DLBCL, PMBCL, and TFL. SCHOLAR-1 integrated data from two Phase 3 studies 
(LYSARC-CORAL and Canadian Cancer Trials Group LY.12) and 2 observational cohorts 
(MD Anderson Cancer Center and Mayo Clinic/University of Iowa Specialized Program of 
Research Excellence). Among 861 patients, 635 were included based on chemorefractory search 
criteria. Outcomes were consistently poor, regardless of refractory subgroup and across cohorts. 
The results of SCHOLAR-1 indicated that patients with chemorefractory, aggressive DLBCL 
represent a homogenous patient population with a response rate of 26% (complete response [CR] 
rate of 7%) and median overall survival of 6.3 months {Crump 2017}.
2.3.
High Grade B-cell Lymphoma
In 2016, the World Health Organization introduced a new category of large B-cell lymphomas 
called high-grade B-cell lymphoma (HGBCL) {Swerdlow 2016}. This designation includes large 
B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements that are phenotypically 
intermediate to DLBCL or B-cell lymphoma, unclassifiable (this latter category has since been 
eliminated). MYC rearrangements in large B-cell lymphomas are associated with a poor 
prognosis that is worsened in cases of concomitant BCL2 and/or BCL6 alterations, ie, double- or 
triple-hit lymphomas. As such, patients with HGBCL are likely to face poor survival outcomes.
In summary, axicabtagene ciloleucel may provide a viable treatment option to relapsed/refractory 
large B-cell lymphoma patients with no other curative alternatives.
2.4.
Study Rationale
As most advanced cancers eventually become refractory to conventional therapies, new 
treatment modalities are needed. 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 destroying diseased cells throughout the body. Studies with 
immune checkpoint inhibitors and tumor infiltrating lymphocytes have demonstrated the 
potential of T cells to treat cancer. T cells need to possess the appropriate specificity for a tumor, 






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3.
STUDY DESIGN
3.1.
General Study Design
Study KTE-C19-101 is a Phase 1-2 multicenter, open-label study evaluating the safety and 
efficacy of axicabtagene ciloleucel in subjects with refractory NHL. Study KTE-C19-101 will be 
separated into 3 distinct phases designated as Phase 1 study, Phase 2 pivotal study (Cohort 1 and 
Cohort 2), and Phase 2 safety management study (Cohort 3,Cohort 4, Cohort 5, and Cohort 6).
NOTE: Cohort 6 is not open for enrollment in Germany.
Phase 1 Study
During Phase 1, approximately 6 to 24 subjects with DLBCL, PMBCL, or TFL will be enrolled 
to evaluate the safety of axicabtagene ciloleucel regimens. If the initial regimen is determined to 
be safe, a higher dose of conditioning chemotherapy may be investigated. If the regimen is 
determined to not be safe, reduced doses of conditioning chemotherapy and/or axicabtagene 
ciloleucel may be explored. A safety review team (SRT), internal to the study sponsor, will 
review the safety data and make recommendations on further study conduct of Phase 1 and 
progression to Phase 2 as depicted in Figure 3 and outlined in Section 9.10.


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Figure 3.
Phase 1 Dosing Cohorts and Regimens
*May be explored: see Section 9.6
 
 
 
 
   
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
  
 
 
 
 


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Phase 2 Pivotal Study
In Phase 2 pivotal study, subjects will enroll into 2 separate cohorts designated as Cohort 1 and 
Cohort 2.

Cohort 1 will enroll adult subjects with refractory DLBCL.

Cohort 2 will enroll adult subjects with refractory PMBCL and TFL.

TFL is defined as subjects who received prior chemotherapy for follicular lymphoma.
During the Phase 2 pivotal study, an independent data safety monitoring board (DSMB) will 
meet when 20 and 50 subjects in the modified intent-to-treat (mITT) set of Cohort 1 have had the 
opportunity to complete the 3 month disease assessment. The DSMB will review safety and 
efficacy data and be chartered to make trial conduct recommendations based on an analysis of 
risk vs. benefit.
Phase 2 Safety Management Study (SMS)
In the Phase 2 safety management study (SMS), subjects will enroll into 4 separate cohorts 
designated as Cohort 3, Cohort 4, Cohort 5, and Cohort 6.

Cohort 3 will enroll adult subjects with relapsed or refractory transplant ineligible DLBCL, 
PMBCL, or TFL.

Cohort 4 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, or 
HGBCL after 2 systemic lines of therapy.

Cohort 5 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, or 
HGBCL after 2 systemic lines of therapy.

Cohort 6 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, or 
HGBCL after 2 systemic lines of therapy.
NOTE: Cohort 6 is not open for enrollment in Germany.
The DSMB will meet to review safety data when 20 subjects in each Cohort 3, Cohort 4, 
Cohort 5, and Cohort 6 have been treated with axicabtagene ciloleucel and have had the 
opportunity to be followed for 30 days. The DSMB may meet more often as needed.
Independent of the phase of the study each subject will follow the same study treatment schedule 
and procedural requirements. Each subject will proceed through the following study periods:

Screening period

Enrollment/Leukapheresis period


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
Bridging therapy (if applicable, for Phase 2 SMS) or debulking therapy (if applicable, 
Phase 2 SMS, Cohort 5)

Conditioning chemotherapy period

Investigational product (IP) treatment period

Post treatment assessment period

Long-term follow-up period
For study requirements assigned to each study period, please refer to the schedule of assessments 
(SOA) and Section 7 for details.
A study schema is drawn out and described at the end of the protocol synopsis section.
3.2.
Participating Sites
Approximately 35 centers located in North America and Europe will participate in this study. 
During the conduct of the study, additional regions, countries or sites may be added as necessary.
3.3.
Number of Subjects
Participants in this trial will be referred to as “subjects”. It is anticipated that approximately 
268 to 286 subjects will be enrolled and dosed in this study as defined below:
Phase 1 study: approximately 6 to 24 subjects
Phase 2 pivotal study: approximately 92 subjects enrolled into 2 cohorts

Cohort 1: approximately 72 subjects

Cohort 2: approximately 20 subjects
Phase 2 safety management study: approximately 170 subjects enrolled and dosed within 
4 cohorts

Cohort 3: approximately 40 subjects

Cohort 4: approximately 40 subjects

Cohort 5: approximately 50 subjects

Cohort 6: approximately 40 subjects
It should be noted that Kite Pharma may choose to close enrollment at any time. Please refer to 
the statistical considerations section of the protocol for sample size estimations.
NOTE: Cohort 6 is not open for enrollment in Germany.


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3.4.
Replacement of Subjects
Subjects will continue to be enrolled until the specified number of subjects are attained in the 
dose-limiting toxicity (DLT) evaluable (Phase 1) and mITT sets (Phase 2). Subjects who have 
not received the target dose of axicabtagene ciloleucel will be retained in the analyses of 
disposition and safety, where appropriate (Section 10.5).
3.5.
Study Duration
3.5.1.
Study Duration for Individual Subjects
The duration of the study for individual subjects will vary. For a subject who completes the 
entire protocol from the date of informed consent through the completion of the long-term 
follow-up period, the duration of the study will take approximately 15 years to complete. 
However, individual study duration will vary depending on a subject’s screening requirements, 
response to treatment, survival and, if applicable, timing of transition to the separate Long-term 
Follow-up (LTFU) study, KT-US-982-5968 (discussed in Section 3.5.3).
The need for prolonged follow-up is based on the potential persistence of gene transfer vectors in 
treated subjects.
3.5.2.
Completion of the Study (Phase 1/Phase 2)
Completion of the study is defined as the time at which the last subject completes at least 
24 months of assessments, is lost to follow-up, withdraws consent, or dies. Upon activation of 
KT-US-982-5968 at the subject’s study site, the subject will be offered the opportunity to 
complete the LTFU assessments under the KT-US-982-5968 protocol.
The primary analyses will be conducted when 72 subjects in the mITT set of the Phase 2 pivotal 
Cohort 1 and 20 subjects in the mITT set of Cohort 2 have completed the 6 month disease 
response assessment, are lost to follow-up, withdraw from the study, or die, whichever occurs 
first.
3.5.3.
Long-term Follow-up
All subjects who received an infusion of axicabtagene ciloleucel will be provided the opportunity 
to transition to a separate LTFU study, KT-US-982-5968, where they will be monitored for 
occurrence of late-onset targeted adverse events (AEs) and serious adverse events (SAEs) as 
defined in KT-US-982-5968, presence of replication-competent retrovirus (RCR), and/or 
insertional mutagenesis for up to 15 years from the time of axicabtagene ciloleucel infusion (also 
refer to Section 7.13.9).
In KT-US-982-5968, subjects will continue assessments at timepoints contiguous with the LTFU 
timepoints in this study.


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4.
SUBJECT SCREENING AND ENROLLMENT
All subjects must sign and date the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) approved consent form before initiating any study specific procedures or activities 
that are not part of a subject’s routine care. Refer to Section 7 for details.
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 before any study 
specific procedures or activities are initiated. This number will be used to identify the subject 
throughout the study and must be used on all study documentation related to the subject. 
Furthermore, the subject identification number must remain constant throughout the entire 
clinical study, it must not be changed after enrollment or if the subject is rescreened or retreated.


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5.
SUBJECT ELIGIBILITY
5.1.
Inclusion Criteria
1) Histologically confirmed aggressive B cell NHL, including the following types defined by 
WHO 2008 {Campo 2011}:
a) DLBCL not otherwise specified; T cell/histiocyte rich large B cell lymphoma; 
DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL 
of the elderly;
or
i)
primary mediastinal (thymic) large B cell lymphoma
ii) transformation of follicular lymphoma to DLBCL will also be included
2) Chemotherapy-refractory disease, defined as one or more of the following:
a) No response to first-line therapy (primary refractory disease); subjects who are 
intolerant to first-line therapy chemotherapy are excluded
i)
Progressive disease (PD) as best response to first-line therapy
ii) Stable disease (SD) as best response after at least 4 cycles of first-line therapy 
(e.g., 4 cycles of R-CHOP) with SD duration no longer than 6 months from last 
dose of therapy
or
b) No response to second or greater lines of therapy
i)
PD as best response to most recent therapy regimen
ii) SD as best response after at least 2 cycles of last line of therapy with SD duration 
no longer than 6 months from last dose of therapy
or
c) Refractory post-ASCT
i)
Disease progression or relapsed ≤ 12 months of ASCT (must have biopsy proven 
recurrence in relapsed subjects)
ii) if salvage therapy is given post-ASCT, the subject must have had no response to 
or relapsed after the last line of therapy


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3) Subjects must have received adequate prior therapy including at a minimum:
a) anti-CD20 monoclonal antibody unless investigator determines that tumor is 
CD20 negative, and
b) an anthracycline containing chemotherapy regimen;
c) for subjects with transformed FL must have chemorefractory disease after 
transformation to DLBCL
4)
At least 1 measurable lesion according to the revised International Working Group (IWG) 
Response Criteria for Malignant Lymphoma {Cheson 2007}. Lesions that have been 
previously irradiated will be considered measurable only if progression has been 
documented following completion of radiation therapy
5)
Magnetic resonance imaging (MRI) of the brain showing no evidence of central nervous 
system (CNS) lymphoma
6)
At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior 
systemic therapy at the time the subject is planned for leukapheresis, except for systemic 
inhibitory/stimulatory immune checkpoint therapy. At least 3 half-lives must have 
elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule 
therapy at the time the subject is planned for leukapheresis (e.g. ipilimumab, nivolumab, 
pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc).
7)
Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for 
clinically non-significant toxicities such as alopecia)
8) Age 18 or older
9) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
10) Absolute neutrophil count (ANC) ≥ 1000/uL
11) Platelet count ≥ 75,000/uL
12) Absolute lymphocyte count ≥ 100/uL
13) Adequate renal, hepatic, pulmonary and cardiac function defined as:
a) Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min
b) Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2.5 upper 
limit of normal (ULN)
c) Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert’s syndrome


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d) Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by 
an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) 
findings
e) No clinically significant pleural effusion
f)
Baseline oxygen saturation >92% on room air
14)
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)
Additional criteria specific for Phase 2 safety management study (Cohorts 3, 4, 5 and 6):
15)
Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL, and 
HGBCL after two systemic lines of therapy
NOTE: Cohort 6 is not open for enrollment in Germany.
5.2.
Exclusion Criteria
201)
History of malignancy other than nonmelanoma skin cancer or carcinoma in situ 
(e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 
3 years
202)
History of Richter’s transformation of CLL
203)
Autologous stem cell transplant with therapeutic intent within 6 weeks of planned 
axicabtagene ciloleucel infusion
204)
History of allogeneic stem cell transplantation
205)
Prior CD19 targeted therapy with the exception of subjects who received axicabtagene 
ciloleucel in this study and are eligible for re-treatment
206)
Prior chimeric antigen receptor therapy or other genetically modified T cell therapy
207)
History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
208)
Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or 
requiring intravenous (IV) antimicrobials for management.
209)
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 (IDSA) guidelines or applicable country 
guidelines.


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210)
Presence of any indwelling line or drain (e.g., 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
211)
Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with 
a history of CNS lymphoma or primary CNS lymphoma, cerebrospinal fluid malignant 
cells or brain metastases
212)
History or presence of CNS disorder such as seizure disorder, cerebrovascular 
ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS 
involvement
213)
Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
214)
History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or 
other clinically significant cardiac disease within 12 months of enrollment
215)
Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or 
impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome)
216)
Primary immunodeficiency
217)
History of symptomatic deep vein thrombosis or pulmonary embolism requiring systemic 
anticoagulation 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
221)
Women of child-bearing 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 both genders who are not willing to practice birth control from the time of 
consent through 6 months after the completion of conditioning chemotherapy
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
224)
History of autoimmune disease (e.g. Crohn’s, rheumatoid arthritis, systemic lupus) 
resulting in end organ injury or requiring systemic immunosuppression/systemic disease 
modifying agents within the last 2 years


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6.
PROTOCOL TREATMENT
6.1.
Treatment Terminology
The following terms will be used to describe and define protocol treatment:

Bridging therapy refers to treatment used to control a subject’s disease prior to conditioning 
chemotherapy

Debulking therapy refers to treatment used to reduce a subject’s disease prior to conditioning 
chemotherapy

The conditioning chemotherapy regimen used for this study will be fludarabine and 
cyclophosphamide.

The investigational product for this study is named axicabtagene ciloleucel.

The term study treatment refers to all protocol required therapies.
6.2.
Study Treatment
6.2.1.
Bridging Therapy for Phase 2 Safety Management Study, Cohort 3 
(retreatment), Cohort 4, and Cohort 6
Bridging therapy will be supplied by the investigative site unless otherwise noted. Sites should 
refer to the current product label for guidance on packaging, storage, preparation, administration, 
and toxicity management of bridging therapy.
At the discretion of the investigator, bridging therapy may be considered for subjects retreated in 
Cohort 3 or enrolled in Cohort 4 and Cohort 6 with high disease burden at screening or baseline 
assessments (eg, bulky disease or rapidly progressing disease). Allowed bridging therapy 
regimens are outlined in Table 2. Other bridging regimens may be considered but need to be 
discussed with the medical monitor on a case-by-case basis.
NOTE: Cohort 6 is not open for enrollment in Germany.


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Table 2.
Bridging Therapy Regimens
Type
Therapy Regimensa
Timing and Washout Requirements
Corticosteroid
Dexamethasone at a dose of 20 mg to 40 
mg or equivalent, either PO or IV daily for 
1 to 4 days.
Choice of corticosteroid and dose can be 
adjusted for age/comorbidities or per local 
or institutional guidelines
May be administered after 
apheresis/enrollment and must be 
completed prior to the start of 
conditioning chemotherapy
Note: Chemistry panel and CBC with 
differential must be repeated prior to start 
of conditioning chemotherapy to confirm 
eligibility to proceed therapy.
HDMP +
Rituximab
{Castro 2009}
1 gram/m2 of high dose methylprednisolone 
(HDMP) for 3 days in combination with 
rituximab at 375 mg/m2 weekly for 3 weeks
May be administered after enrollment and 
completed at least 7 days prior to the start 
of conditioning chemotherapy
Note: Chemistry panel and CBC with 
differential must be repeated prior to start 
of conditioning chemotherapy to confirm 
eligibility to proceed.
Combination 
Chemotherapy
{Vacirca 2014}
{Ohmachi 2013}
B-R: Bendamustine (90 mg/m2, Day 1+2); 
Rituximab (375 mg/m2, Day 1)
May be administered after enrollment and 
completed at least 14 days prior to the 
start of conditioning chemotherapy, and 
subjects must remain eligible per the 
eligibility criteria outlined in Section 5 
prior to the start of conditioning 
chemotherapy
Note: Chemistry panel and CBC with 
differential must be repeated prior to start 
of conditioning chemotherapy to confirm 
eligibility to proceed.
Abbreviations: IV, intravenous; CBC, complete blood count.
a
The bridging therapy regimen may be chosen at the discretion of the investigator
6.2.2.
Debulking Therapy for Phase 2 Safety Management Study, Cohort 5
Subjects enrolled into the Phase 2 Safety Management Study, Cohort 5 should receive debulking 
therapy to reduce lymphoma burden. Debulking therapy options are outlined in Table 3. Other 
debulking treatment options may be considered in select cases and must be discussed with the 
Kite medical monitor. The goal of the debulking therapy should be to optimally reduce 
lymphoma burden.


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Table 3.
Debulking Therapy Regimens
Type
Proposed Regimena
Timing/Washout
R-CHOP
{Feugier 2005}
Rituximab 375 mg/m2 Day 1
Doxorubicin 50 mg/m2 Day 1
Prednisone 100 mg Day 1 through Day 5
Cyclophosphamide 750 mg/m2 Day 1
Vincristine 1.4 mg/m2 Day 1
R-ICE
{Gisselbrecht 2010}
Rituximab 375 mg/m2 Day 1
Ifosfamide 5 g/m2 24h-CI Day 2
Carboplatin AUC5 Day 2 maximum dose 800 mg
Etoposide 100 mg/m2 /d Days 1 through Day 3
R-GEMOX 
{Mounier 2013}
Rituximab 375 mg/m2 Day 1
Gemcitabine 1000 mg/m2 Day 2 
Oxaliplatin 100 mg/m2 Day 2
R-GDP
{Crump 2004}
{Gopal 2010}
Rituximab 375 mg/m2 Day 1 (or Day 8)
Gemcitabine 1 g/m2 on Day 1 and Day 8
Dexamethasone 40 mg on Day 1 through Day 4
Cisplatin 75 mg/m2 on Day 1 (or carboplatin AUC5 on 
Day 1)
Should be administered after 
leukapheresis/enrollment and 
should be completed at least 
14 days prior to the start of 
conditioning chemotherapy
Radiotherapyb
Per local standard up to 20 to 30 Gy
Should be administered after 
leukapheresis/enrollment and 
should be completed at least 
5 days prior to the start of 
conditioning chemotherapy
Abbreviations: AUC, area under the curve.
a
Other debulking treatment options may be used, but must be discussed with the medical monitor. Supportive care with 
hydration, anti-emesis, mesna, growth factor support, and tumor lysis prophylaxis according to local standard may be used. 
More than 1 cycle allowed.
b
At least 1 target lesion should remain outside of the radiation field to allow for tumor measurements
6.2.3.
Conditioning Chemotherapy
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.
6.2.3.1.
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.


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6.2.3.2.
Cyclophosphamide
Cyclophosphamide is a nitrogen mustard-derivative alkylating agent. Following conversion to 
active metabolites in the liver, cyclophosphamide functions as an alkylating agent; the drug also 
possesses potent immunosuppressive activity. The serum half-life after IV administration ranges 
from 3-12 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.
6.2.3.3.
Mesna
Mesna is a detoxifying agent used to inhibit the hemorrhagic cystitis induced by chemotherapy. 
The active ingredient in mesna is a synthetic sulfhydryl compound designated as 
sodium-2-mercaptoethane sulfonate with a molecular formula of C2H5NaO3S2.
Mesna should be administered per institutional guidelines. Refer to the most recent version of the 
package insert for specific details surrounding the administration of mesna.
6.2.4.
Axicabtagene Ciloleucel
Refer to the most current IB regarding axicabtagene ciloleucel and clinical experience. This 
section contains general information and is not intended to provide specific instructions. Refer to 
the investigational product manual for details and instruction on storage and administration.
Axicabtagene ciloleucel is supplied cryopreserved in cryostorage bags. 
 
. The cryostorage bags containing axicabtagene 
ciloleucel arrive frozen in a liquid nitrogen dry shipper. The bags must be stored in vapor phase 
of liquid nitrogen and the product remains frozen until the subject is ready for treatment to assure 
viable live autologous cells are administered to the subject. Several inactive ingredients are 
added to the product to assure viability and stability of the live cells through the freezing, 
thawing, and infusion process.
Axicabtagene ciloleucel is a subject-specific product and the intended subject will be identified 
by a unique subject ID number. Upon receipt, verification that the product and subject-specific 
labels match the subject’s information (e.g., initials, subject ID number) is essential. Do not 
infuse the product if the information on the subject-specific label does not match the intended 
subject. The volume of axicabtagene ciloleucel infused, the thaw start/stop time, and 
axicabtagene ciloleucel administration start/stop time, will all be noted in the subject medical 
record. The product must not be thawed until the subject is ready for the infusion. Refer to the 
Investigational Product Manual for details and instruction on storage, thawing, and 
administration of axicabtagene ciloleucel.
To date, subjects have received doses of anti-CD19 CAR T cells ranging from 
1-30 x 106 anti-CD19 CAR T cells/kg. There have been no instances of accidental overdose of 
subjects in this program. In case of accidental overdose, treatment should be supportive. 
Corticosteroid therapy may be considered if any dose is associated with severe toxicity.
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If any problems related to the use of axicabtagene ciloleucel or any products that support the 
management of axicabtagene ciloleucel (eg, cryostorage bags, subject identification labels) 
required in this study are identified, please log on to www.kitepharma.com to report the 
complaint.
6.2.5.
Concomitant Therapy
During the course of the study, investigators may prescribe any concomitant medications or 
treatment deemed necessary to provide adequate supportive care except those medications listed 
in Section 6.2.6.
All concurrent therapies, including medications, intubation, dialysis, oxygen, and blood products, 
will be recorded from the date of the informed consent through 3 months after completing 
treatment with axicabtagene ciloleucel. After 3 months of follow-up, only targeted concomitant 
medication will be collected for 24 months after axicabtagene ciloleucel infusion or disease 
progression, whichever occurs first. Targeted concomitant medications include gammaglobulin, 
immunosuppressive drugs, anti-infective drugs, and vaccinations.
For subjects who are enrolled but not dosed with axicabtagene ciloleucel, concurrent therapies 
will only be recorded from the date of the informed consent through 30 days after the last study 
specific procedure (e.g., leukapheresis, conditioning chemotherapy). For subjects who are not 
enrolled (e.g., screen failure or not leukapheresed), only concurrent therapies related to any 
SAE(s) will be recorded.
Specific concomitant medication collection requirements and instructions are included in the 
case report form (CRF) completion guidelines.
6.2.6.
Excluded Medications
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. For the prophylactic 
use of steroid for Cohort 6, refer to Section 7.13.7.
Corticosteroids and other immunosuppressive drugs should also be avoided for 3 months after 
axicabtagene ciloleucel administration, unless used to manage axicabtagene ciloleucel related 
toxicities (refer to the most current version of the IB). Other medications that might interfere 
with the evaluation of the investigational product, such as non-steroidal anti-inflammatory agents 
should also be avoided for the same time period unless medically necessary.
Treatment for lymphoma such as chemotherapy, immunotherapy, targeted agents, radiation, and 
high dose corticosteroid, other than defined/allowed in this protocol, and other investigational 
agents are prohibited, except as needed for treatment of disease progression after the 
axicabtagene ciloleucel infusion.
If permissibility of a specific medication/treatment is in question, please contact the Kite Pharma 
Medical Monitor.


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NOTE: Cohort 6 is not open for enrollment in Germany.
6.2.7.
Subsequent Therapy
Subsequent therapy administered after the axicabtagene ciloleucel infusion for a subject’s 
disease, such as non-study specified chemotherapy, immunotherapy, targeted agents, as well as 
stem cell transplant and radiation therapy, will be recorded for all subjects until one of the 
following happens: the subject transitions to the KT-US-982-5968 LTFU study, 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-cancer 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.
6.3.
Study Treatment Schedule
6.3.1.
Leukapheresis (Within Approximately 5 Days of Eligibility Confirmation)
Subjects will undergo leukapheresis to obtain leukocytes (white blood cells) for the 
manufacturing of axicabtagene ciloleucel. Leukapheresed cells obtained at participating centers 
will be shipped to the cell processing facility (CPF) overnight as described in the Investigational 
Product Manual. Once a subject commences leukapheresis, the subject is considered enrolled in 
the study.
Mononuclear cells will be obtained by leukapheresis 
 with a goal to target 
 mononuclear cells). The leukapheresed cells are then packaged for 
expedited shipment to the CPF as described in the investigational product manual.
Upon arrival at the CPF, each subject’s leukapheresed product will be processed to enrich for the 
T cells containing PBMC fraction. T cells are then stimulated to expand and transduced with a 
retroviral vector to introduce the CAR gene. The T cells are then expanded and cryopreserved to 
generate the investigational product per CPF standard operating procedures (SOPs). Once the 
product has passed certain release tests, it will be shipped back to the treating facility. Following 
completion of each subject’s conditioning chemotherapy regimen, subjects will receive their 
respective axicabtagene ciloleucel infusion.
6.3.2.
Study Treatment
6.3.2.1.
Chemotherapy General Instructions
Subjects will receive a non-myeloablative conditioning regimen consisting of cyclophosphamide 
and fludarabine in order to induce lymphocyte depletion and create an optimal environment for 
expansion of axicabtagene ciloleucel in vivo. Subjects will initiate conditioning chemotherapy 
with cyclophosphamide and fludarabine beginning on Day -5 (or Day -7 for Cohort B) through 
Day -1. The 5-day conditioning chemotherapy regimen may be administered in an outpatient 
setting. The 7-day conditioning chemotherapy regimen may be administered as an outpatient or 
inpatient regimen per investigator’s discretion.
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Subjects should be instructed to drink plenty of liquids during and for 24 hours following the 
chemotherapy. In general, subjects should be kept well-hydrated but closely monitored to 
prevent fluid overload.
For subjects enrolled into the Phase 2 Safety Management Study, Cohort 5 and Cohort 6:
Subjects who have not recovered their white blood cell (WBC) count by the time conditioning 
chemotherapy is scheduled to start, may skip the conditioning chemotherapy if the WBC is 
≤ 1000/µL at this time. This option must be discussed with the Kite medical monitor.
NOTE: Cohort 6 is not open for enrollment in Germany.
6.3.2.2.
Axicabtagene Ciloleucel General Instructions
All subjects will receive axicabtagene ciloleucel infusion at a healthcare facility, followed by 
daily monitoring at a healthcare facility for at least 7 days unless otherwise required by country 
regulatory agencies (refer to Appendix 2) to monitor for signs and symptoms of CRS and 
neurologic toxicities. Subjects should be instructed to remain within proximity of the clinical 
study site for at least 4 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.
Alternatively, subjects may be hospitalized to receive their axicabtagene ciloleucel infusion and 
be observed for CRS and neurologic toxicities in the hospital setting, if deemed appropriate by 
the investigator.
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 return to 
baseline. Subjects may be discharged with non-critical and clinically stable or improving 
toxicities (e.g., renal insufficiency) even if > 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 toxicities > Grade 1, or if deemed necessary by the 
investigator.
The following medications should be administered approximately 1 hour prior to axicabtagene 
ciloleucel infusion. Alternatives to the recommendations below should be discussed with the 
medical monitor.

Acetaminophen 
 PO

Diphenhydramine (
 PO)
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 Investigational Product Manual. The Investigational 
Product Manual must be reviewed prior to administration of axicabtagene ciloleucel.
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Research sites should follow institutional guidelines for the infusion of cell products.
6.3.3.
Rationale for Study Treatment Dosing
6.3.3.1.
Rationale for Conditioning Chemotherapy Dose in Phase 1 Cohort A1
Increasing levels of conditioning chemotherapy correlates with clinical responses to adoptive cell 
therapy {Dudley 2008}. Specifically, there appears to be a link between adequate 
lymphodepletion and adoptively transferred T cell expansion and function in pre-clinical models. 
The depth and duration of the lymphodepletion in preclinical models correlate with anti-tumor 
activity of the adoptively transferred tumor-specific CD8+ T cells {Gattinoni 2005}. 
Lymphodepletion may function by eradicating cytokine sinks for the transferred cells, 
eliminating T regulatory cells, or enhancing antigen presenting cell activation {Klebanoff 2005}. 
Cyclophosphamide and fludarabine is a potent lymphodepleting regimen. Optimizing the doses 
of cyclophosphamide and fludarabine to improve the depth and duration of lymphodepletion may 
enhance the activity of axicabtagene ciloleucel.
As described in the IB, the NCI study (09-C-0082; IND 13871) evaluated three groups of 
subjects based on conditioning regimens. Group 3 evaluated cyclophosphamide (300 mg/m2) and 
fludarabine (30 mg/m2), both given for 3 concurrent days followed by 1-2 x 106 anti-CD19 CAR 
T cells. Eleven subjects were treated with this regimen.
The DLT definition in the KTE-C19-101 study was applied to the NCI study (09-C-0082; 
IND 13871) data in group 3. There were no DLTs. The subject incidences of Grade 3, 4, 5, and 
serious adverse events attributed to CAR+ T-cells were 3 (27%), 0 (0%), 0 (0%), and 1 (9%). 
The ORR in this cohort was 60%, including 10% complete responses. Many subjects, however, 
did not achieve blood lymphocyte counts of zero with this conditioning regimen.
To improve the depth and duration of lymphocyte depletion, the conditioning chemotherapy dose 
in Phase 1 Cohort A1 will be cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) both 
given for 3 concurrent days with the target dose of 2 x 106 anti-CD19 CAR T cells/kg. This 
regimen is currently being evaluated in the NCI study (09-C-0082; IND 13871). 
Cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) both given for 3 concurrent days 
has been studied and tolerated in subjects with B cell malignancies {O'Brien 2001}. Similar total 
doses of cyclophosphamide (900 to 2,000 mg/m2) and fludarabine (90 to 150 mg/m2) have been 
given as a reduced non-myeloblative conditioning regimen in subjects with B cell malignancies 
receiving allogeneic stem cell transplants {Khouri 1998}. The cyclophosphamide dose used in 
this regimen (Cohort A1 and currently in the NCI study 09-C-0082; IND 1387) is approximately 
38% lower than that used in the Group 2 cyclophosphamide 30 mg/kg conditioning regimen 
from the NCI study (incidence of DLT 29%), with the same lower dose of fludarabine dose as 
Group 3. Evaluation of higher conditioning chemotherapy doses and/or varying anti-CD19 CAR 
T cell doses would proceed based on the incidence of DLT and evaluation of benefit-risk.
6.3.3.2.
Rationale for Conditioning Chemotherapy Dose in Phase 1 Cohort B1
Fifteen subjects were treated in the NCI protocol (09-C-0082; IND 13871) in group 2. Group 2 
included subjects with leukemia and lymphoma, 2 different doses of cyclophosphamide 




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6.3.3.3.
Rationale for Patient Population to be Included in Phase 2 Pivotal Study Cohort 1 
and Cohort 2
In the multicenter randomized Phase 3 CORAL study where subjects were randomized to R-ICE 
or R-DHAP second-line therapy followed by ASCT with or without rituximab maintenance, 
203 subjects across both arms did not proceed with ASCT. These subjects were ineligible for 
ASCT for multiple reasons including chemorefractory disease, early relapsed disease, residual 
masses after salvage therapy and intolerance to therapy. The median overall survival of these 
203 ASCT ineligible subjects after salvage chemotherapy was only 4.4 months {Van Den Neste 
2016}. Therefore, the efficacy of axicabtagene ciloleucel will be estimated in this population 
which represents a significant unmet need for more effective therapies.
6.3.3.4.
Rationale for Including Phase 2 Safety Management Study Cohort 3, Cohort 4, 
Cohort 5, and Cohort 6
6.3.3.4.1.
Cohort 3
CRS and neurologic toxicities are two identified risks associated with axicabtagene ciloleucel. 
Both CRS and neurologic toxicities have led to Grade 4 or Grade 5 events in the context of 
anti-CD19 CAR T cells {Schuster 2015, Turtle 2016}. The pathophysiology of CRS is well 
described, but the etiology of the neurologic toxicities remains unclear. Currently it is 
hypothesized that there are two potential mechanisms of the pathophysiology of neurologic 
toxicities: 1) peripheral systemic cytokine release followed by cytokine diffusion across the 
blood brain barrier (BBB) and/or 2) peripherally activated anti-CD19 CAR T cells translocate 
across the BBB and elicits a local inflammatory effect. The later hypothesis is supported by 
emerging evidence of CAR T-cells trafficking to the CSF. To further elucidate the 
pathophysiology of neurologic toxicities, serial CSF collections will be analyzed in this study for 
cytokines/chemokines/effector molecules and anti-CD19 CAR T cells. In addition, in an attempt 
to mitigate the onset and severity of CRS and neurologic toxicities, prophylactic tocilizumab and 
levetiracetam will be administered in Cohort 3 (see Section 6.3.4). It is hypothesized that 
tocilizumab may lead to fewer activated CAR T-cells trafficking to the CNS and levetiracetam 
may reduce the risk of clinical or subclinical seizures. Lastly, in an effort to mitigate the severity 
and/or duration of the neurologic toxicities, IT-Ara C with corticosteroids is recommended to be 
administered at the onset of Grade 3 neurologic toxicities (see Section 6.4.1).
6.3.3.4.2.
Cohort 4 and Cohort 6
In the Phase 2 pivotal study portion of ZUMA-1 (n = 101), CAR T-cell levels were associated 
with response (P = 0.0002), with a 5.4-fold higher area under the curve (AUC) within the first 
28 days post-treatment for responders versus non-responders. However, CAR T-cell levels and 
specific cytokines, including IL-2, GM-CSF, and ferritin, were only associated with Grade 3 or 
higher neurologic toxicity suggesting that distinct mechanisms may underlie the pathogenesis of 
these adverse events, as shown in Figure 4 and {Locke 2017}. While there is a theoretical 
concern for the use of immunosuppressive agents to manage CRS or neurologic toxicities, 
tocilizumab and/or corticosteroids usage did not appear to affect negatively the overall response 
in ZUMA-1 and CAR T-cell levels (Table 6). Prophylactic tocilizumab use in Cohort 3 appeared 
to lower the rate of Grade 3 or higher CRS but not neurologic toxicities (Table 7). To further 


Axicabtagene ciloleucel; KTE-C19
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Clinical Protocol: KTE-C19-101
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refine the use of corticosteroids to treat CRS and neurologic toxicities, Cohort 4 and Cohort 6 
will recommend corticosteroids at lower toxicity grades to determine the impact on incidence 
and severity of CRS and neurologic toxicities (Section 6.4.1). Cohort 6 will further build on this 
rationale by initiating corticosteroids as prophylactic treatment on Day 0, Day 1, and Day 2. 
Prophylactic tocilizumab will not be used in Cohort 4, Cohort 5, or Cohort 6 (Section 6.3.4).
NOTE: Cohort 6 is not open for enrollment in Germany.
Figure 4
Axicabtagene Ciloleucel Expansion and Correlations with Response 
and Adverse Events
Table 6.
Tocilizumab and Corticosteroids Use in ZUMA-1 Phase 2 Pivotal Study 
Primary Analysis
No Tocilizumab
n = 58
Tocilizumab
n = 43
P
Value
No 
corticosteroids
n = 74
Corticosteroids
n = 27
P
Value
ORR, n (%)
47 (81.0)
36 (83.7)
.8
62 (83.8)
21 (77.8)
.56
CR, n (%)
33 (56.9)
22 (51.2)
.69
40 (54.1)
15 (55.6)
1
Ongoing, n (%)
28 (48.3)
16 (37.2)
.31
33 (44.6)
11 (40.7)
.82
Median peak 
CAR levels, 
cells/μL (range)
26.52
(1.25-1226.36)
61.06
(0.84-1513.69)
.0011
32.2
(1.25-1226.36)
49.69
(0.84-1513.69)
.0618
Median CAR 
AUC, cells/μL 
days (range)
289.49
(16.82-14329.29)
743.85
(5.09-11506.59)
.0022
407.53
(16.82-14329.29)
724.98
(5.09-11506.59)
.0967
{Neelapu 2017}
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
  
 


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Table 7.
Rates of Neurologic Toxicities and CRS in the Phase 1 and 2 Pivotal 
Study versus Phase 2 Safety Management Study Cohort 3
ZUMA-1
Phase 1+ Phase 2 
Pivotal Cohorts 1+2
(N = 108)
ZUMA-1
SMS Cohort 3
(N = 34)
Any Neurologic toxicitya
70 (65)
29 (85)
Worst Grade 1
23 (21)
9 (26)
Worst Grade 2
15 (14)
6 (18)
Worst Grade 3
29 (27)
12 (35)
Worst Grade 4
3 (3)
1 (3)
Worst Grade 5
0 (0)
1 (3)
due to disease progression
0 (0)
0 (0)
Worst Grade >= 3
32 (30)
14 (41)
Any CRSb
101(94)
32 (94)
Worst Grade 1
41 (38)
12 (35)
Worst Grade 2
45 (42)
19 (56)
Worst Grade 3
9 (8)
0 (0)
Worst Grade 4
4 (4)
1 (3)
Worst Grade 5
1 (1)
0 (0)
due to disease progression
0 (0)
0 (0)
Worst Grade >= 3
14 (13)
1 (3)
Data cut for Phase 1, Phase 2 Cohort 1 and 2: Primary Analysis, DCO 
Data cut of SMS Cohort 3: Updated Analysis, DCO 
Neurologic events are graded per CTCAE 4.03; CRS events are graded per Lee grade {Lee 2014}.
a
Neurologic AEs were identified with a search strategy based on known neurologic toxicities associated with anti-CD19 
immunotherapy {Topp 2015}. For Phase 1, Phase 2 Cohort 1 and 2, the neurologic toxicities included events with onset 
between date of first axicabtagene ciloleucel infusion (Day 0) and Day 56; for SMS Cohort 3, the neurologic toxicities 
included events with onset on or after the date of first conditioning chemotherapy.
b
One subject in Phase 1 had CRS symptoms reported but not graded for CRS at the time at the Primary Analysis data cut. 
This subject was counted in the “Any CRS” row but not by the worst grade.
6.3.3.4.3.
Cohort 5
In the pivotal cohorts of ZUMA-1, Phase 2 (Cohorts 1 and 2; n = 101), subjects with relapsed 
and refractory aggressive B-cell lymphoma were not permitted to receive anti-cancer therapy 
between leukapheresis and conditioning chemotherapy. However, a subsequent retrospective 
analysis suggested a relationship between lymphoma burden (estimated by the sum of the 
product of diameters [SPD] of index lesions) and clinical outcomes {Locke 2018}. Subjects with 
the lowest SPD had the highest rates of ongoing response at 1 year and the lowest rates of CRS 
and neurological events. Thus, Cohort 5 will be used to prospectively assess the impact of 
debulking therapy, administered after leukapheresis but prior to conditioning chemotherapy, on 
the safety and efficacy of axicabtagene ciloleucel. The goal of the debulking therapy will be to 
reduce lymphoma burden and assess clinical outcomes.
PPD
PPD


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Furthermore, the majority (90%) of patients with relapsed/refractory (r/r) DLBCL who were 
included in another CAR T-cell therapy study {KYMRIAH 2018} received the investigator’s 
choice of bridging therapy that may have had a debulking effect. Although debulking was not 
explicitly tested, 8 of these patients had no measurable disease following bridging therapy. The 
overall results from this study suggested that the inclusion of the investigator’s choice of 
bridging therapy was well-tolerated, as no new safety signals were identified using this approach. 
Toxicities observed within the JULIET study were consistent with other CD19-targeted CAR 
T-cell therapies.
In conclusion, the goal of Cohort 5 is to improve the benefit-risk ratio of axicabtagene ciloleucel 
by reducing lymphoma burden prior to administration of axicabtagene ciloleucel. This approach 
is justified by a retrospective analysis of outcome by tumor burden in ZUMA-1 and data from 
other CD19-targeting CAR T-cell products. The specific safety regimens studied in Cohorts 3 
and 4 will not be continued in Cohort 5.
6.3.4.
Study Treatment by Phase
Phase 1 Study
The study will begin with Cohort A1. Subsequent cohorts may be explored as depicted in 
Figure 3 and outlined in Section 9.10.
Conditioning Chemotherapy
Cohorts A1/A2: Subjects will receive the following 5-day chemotherapy regimen:

IV hydration with 
 given prior to cyclophosphamide on 
the day of infusion followed by:

Cyclophosphamide 500 mg/m2 IV over 60 minutes on Day -5, Day -4, and Day -3 followed 
by:

Fludarabine 30 mg/m2 IV over 30 minutes on Day -5, Day -4, and Day -3 followed by:

An additional 
 at the completion of the fludarabine infusion

Add mesna (sodium 2-mercaptoethanesulfonate) per institutional guidelines
Cohort A3: Subjects will receive the following 
 chemotherapy regimen:

The IV hydration is 
 given prior to cyclophosphamide on the day of 
infusion followed by:

Cyclophosphamide 300 mg/m2 IV over 60 minutes on Day -5, Day -4, and Day -3 followed 
by:

Fludarabine 30 mg/m2 IV over 30 minutes on Day -5, Day -4, and Day -3 followed by:
CCI
CCI
CCI
CCI




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In Phase 2, subjects will receive the 5-day conditioning chemotherapy regimen used in Cohort 
A1 of the Phase 1 portion of the study:

IV hydration with 
 given prior to 
cyclophosphamide on the day of infusion followed by:

Cyclophosphamide 500 mg/m2 IV over approximately 60 minutes on Day -5, Day -4, and 
Day -3 followed by:

Fludarabine 30 mg/m2 IV over approximately 30 minutes on Day -5, Day -4, and Day -3 
followed by:

An additional 
 at the completion of the 
fludarabine infusion

Add mesna (sodium 2-mercaptoethanesulfonate) per institutional guidelines
Axicabtagene ciloleucel will be administered at a target dose of 2 x 106 anti-CD19 CAR T 
cells/kg. In addition, subjects who receive doses between 1-2 x 106 anti-CD19 CAR T cells/kg 
will be included in the mITT analysis set. For subjects weighing greater than 
 
 anti-CD19 CAR T cells will be administered.
Phase 2 Safety Management Study:
For Cohort 3, subjects will receive conditioning chemotherapy and axicabtagene ciloleucel as 
described above. In addition, subjects will receive levetiracetam (750 mg PO or IV BID) starting 
on Day 0. At the onset of ≥ Grade 2 neurologic toxicities, levetiracetam should be administered. 
If a subject does not experience any ≥ Grade 2 neurologic toxicities, levetiracetam should be 
tapered and discontinued as clinically indicated. Subjects will also receive tocilizumab 
(8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2. Further tocilizumab 
(± corticosteroids) is recommended to be administered at the onset of ≥ Grade 2 CRS.
For Cohorts 4 and 6, subjects will receive bridging therapy (if applicable, refer to Section 6.2.1), 
conditioning chemotherapy, axicabtagene ciloleucel, and levetiracetam, as described above. 
Tocilizumab will not be administered as prophylaxis, but will be administered based on toxicity 
management guidance (eg, tocilizumab and corticosteroids) as described in Section 6.4.1, 
Table 8, Table 9, and Table 10. Corticosteroids will be initiated for toxicity management for 
Grade 2 CRS and for Grade 1 neurologic toxicities per Table 8 and Table 9, respectively, as 
described in Section 6.4.1. In addition, in Cohort 6, subjects will receive corticosteroids on 
 
NOTE: Cohort 6 is not open for enrollment in Germany.
For Cohort 5, subjects should receive debulking therapy (refer to Section 6.2.2), conditioning 
chemotherapy, axicabtagene ciloleucel, and levetiracetam, as described above. Toxicity 
management guidance is provided in Section 6.4.
CCI
CCI
CCI
CCI


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6.4.
Toxicity Management
To date, the following important risks have been identified with axicabtagene ciloleucel: CRS, 
neurologic toxicities, infections, hypogammaglobulinemia, and cytopenias. 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.
6.4.1.
Phase 2 Safety Management Study (Cohort 4 and Cohort 6 only)
To date, the following risks have been identified with axicabtagene ciloleucel: CRS, neurologic 
events, infections, hypogammaglobulinemia, and cytopenias. For CRS and neurological 
toxicities, the treatment guidance outlined in Table 8, Table 9, and Table 10 will be used for 
Cohort 4 and Cohort 6 of the Phase 2 safety management study. Additional safety information 
and management recommendations for the other identified risks can also be found in the most 
current version of the IB.
Table 8.
Grading and Management of CRS in Cohort 4 and Cohort 6
CRS Grade
Supportive Care
Tocilizumab
Steroids
Follow up
Grade 1:
Symptoms are not life 
threatening and 
require symptomatic 
treatment only (eg, 
fever, nausea, fatigue, 
headache, myalgia, 
malaise)
Supportive care 
per institutional 
standard of 
care
N/A
N/A
Not improving after 
24 hours:
Tocilizumab as per 
Grade 2 guidance 
(below)
Not improving after 
3 days:
Dexamethasone 10 mg 
x1




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Table 9.
Grading and Management of Neurologic Toxicities in Cohort 4 and 
Cohort 6
Neurologic Toxicities
Supportive Care
Tocilizumab
Corticosteroids
Follow up
Grade 1 examples 
include:

Somnolence-mild 
drowsiness or 
sleepiness

Confusion-mild 
disorientation

Encephalopathy-mild 
limiting of ADLs

Dysphagia-not 
impairing ability to 
communicate

Supportive care 
per institutional 
standard of care

Closely 
monitor 
neurologic 
status

Consider 
prophylactic 
levetiracetam
N/A

Dexamethasone 
Not improving after 
2 days:

Repeat 
dexamethasone 

Continue 
supportive care
Grade 2 examples 
include:

Somnolence-moderate, 
limiting instrumental 
ADLs

Confusion-moderate 
disorientation

Encephalopathy-limiti
ng instrumental ADLs

Dysphagia-moderate 
impairing ability to 
communicate 
spontaneously

Seizure(s)

Continuous 
cardiac 
telemetry and 
pulse oximetry 
as indicated

Closely 
monitor 
neurologic 
status with 
serial neuro 
exams to 
include 
fundoscopy and 
Glasgow Coma 
Score. Consider 
neurology 
consult

Perform brain 
imaging 
(eg, MRI), 
EEG, and 
lumbar 
puncture (with 
opening 
pressure) if no 
contraindicatio
ns

Levetiracetam/ 
antiepileptics if 
subject has 
seizures

Only in 
case of 
concurrent 
CRS:

Tocilizuma
b 8 mg/kg 
IV over 
1 hour (not 
to exceed 
800 mg)

Repeat 
tocilizumab 
every 4 to 
6 hours as 
needed if 
not 
responsive 
to IV fluids 
or 
increasing 
supplement
al oxygen; 
maximum 
of 3 doses 
in a 24-hour 
period.

Maximum 
total of 
4 doses if 
no clinical 
improveme
nt in the 
signs and 
symptoms 
of CRS

Dexamethasone 
Improving:

Discontinue 
tocilizumab

Taper 
corticosteroids

Not improving:

Manage as Grade 
3 (below)
CCI
CCI
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7.
STUDY PROCEDURES
Research staff should refer to the SOAs for an outline of the procedures required. The visit 
schedule is calculated from axicabtagene ciloleucel infusion on Day 0.
An overview of study assessments/procedures is outlined below. A description for each period of 
the study is provided in Section 7. Refer to the CRF completion guidelines for data collection 
requirements and documentation of study procedures.
NOTE: Cohort 6 is not open for enrollment in Germany.
7.1.
Informed Consent
Before a subject’s participation in the clinical study, the investigator is responsible for obtaining 
written informed consent from the subject after adequate explanation of the study design, 
anticipated benefits and the potential risks. Subjects should sign the most current IRB/IEC 
approved ICF prior to any study specific activity or procedure is performed.
The consent process and the subject’s agreement or refusal to participate in the study is to be 
documented in the subject’s medical records. If the subject agrees to participate, the ICF is to be 
signed and personally dated by the subject and by the person who conducted the informed 
consent discussion. The original signed ICF will be retained in accordance with institution policy 
and IRB/IEC requirements with a copy of the ICF provided to the subject.
All subjects who are enrolled into the study should be re-consented with any updated version of 
the IRB/IEC approved ICF if relevant to their participation in the study.
7.2.
Demographic Data
Demographic data will be collected to include sex, age, race, ethnicity, and country of enrollment 
to study their possible association with subject safety and treatment effectiveness.
7.3.
Medical and Treatment History
Relevant medical history prior to the start of adverse event reporting will be collected. Relevant 
medical history is defined as data on the subject’s concurrent medical condition that would be 
typically shared in a referral letter. All findings will be recorded in the CRFs.
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.
For subjects who are being referred from another clinic or institution to the participating research 
center, copies from the subjects chart should be obtained.


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7.4.
Physical Exam, Vital Signs, Performance Status, and EQ-5D
Physical exams will be performed during screening and at times noted in the SOA. Changes 
noted in subsequent exams when compared to the baseline exam will be reported as an adverse 
event.
During IP administration, vital signs including blood pressure, heart rate, oxygen saturation, and 
temperature will be monitored before and after the axicabtagene ciloleucel infusion and then 
routinely per institutional guidelines. If the subject has a fever (temperature 38.3oC or greater), 
vital signs will be monitored more frequently 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.
For subjects enrolled in Cohort 3, Cohort 4, Cohort 5 or, Cohort 6, EQ-5D will be completed by 
the subject, prior to any other assessment, at the screening visit and at other times noted in the 
SOA. Subjects who are blind or illiterate may have the EQ-5D questions read to them by the 
study staff. The study staff, however, cannot interpret any of the questions for the subject. A 
subject may be exempt from completing the questionnaire if he or she is unable to read the 
questionnaire in one of the country languages available.
The EQ-5D is a 2 page generic patient questionnaire for assessing the overall health status of a 
subject. The EQ-5D consists of a 5 dimension descriptive system including questions on 
mobility, self-care, usual activities, pain/comfort, and anxiety/depression and a visual analogue 
scale (EQ VAS) which allows the respondent to record health on a vertical scale (eg, best health 
to worst health) thus allowing a quantitative measure of health outcome.
7.5.
Neurological Assessment
For subjects enrolled in Cohort 1, Cohort 2, or Cohort 3, neurological assessments will be 
standardized by using the Mini-Mental State Examination (MMSE) standard version 2.0. The 
MMSE neurological assessment will not be required for Phase 2 SMS Cohort 4, Cohort 5, and 
Cohort 6. The MMSE is a 5-10 minute, 11-question measure that examines various areas of 
cognitive function: orientation, attention, immediate recall, short-term recall, language, and the 
ability to follow simple verbal and written commands.
The MMSE is divided into two sections. The first part requires vocal responses to the examiner's 
questions. In the second part of the exam, the subject is asked to follow verbal and written 
instructions, write a sentence spontaneously, and copy a geometric figure. Every attempt should 
be made to dedicate a single research staff member trained in the administration of the MMSE to 
conduct the assessment to minimize variability among different assessors.
A full neurological assessment will be completed during screening to establish a baseline. 
Subsequent assessments will be performed before axicabtagene ciloleucel administration on 
Day 0, on Day 1, and then every other day during the 7-day post-infusion monitoring period, as 
well as at the Week 4 and Month 3 visits.


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7.6.
Cardiac Function
Each subject’s cardiac function, as measured by ECHO will be assessed during the screening 
period to confirm study eligibility. Both left ventricular ejection fraction (LVEF) and pericardial 
effusion will be assessed prior to study entrance by ECHO. An ECHO performed following the 
subject’s last chemotherapy treatment and within 28 days prior to signing the consent may be 
used for confirmation of eligibility.
To establish a baseline, an ECG will also be performed during the screening period.
7.7.
Magnetic Resonance Imaging
Each subject will undergo a screening brain MRI, with contrast whenever possible or without 
contrast in case of contraindication, to rule out CNS metastasis during the screening period of the 
study. An MRI performed following the subject’s last chemotherapy treatment and ≤ 28 days 
before signing the consent may be used for confirmation of eligibility.
Evaluation of any new onset of ≥ Grade 2 neurologic toxicities should include a brain MRI as 
described in Section 6.4.
7.8.
Bone Marrow Biopsy
Bone marrow aspirate/biopsy will be performed at screening if not previously performed to 
assess bone marrow involvement. For subjects with a potential complete response to 
axicabtagene ciloleucel, a follow-up bone marrow aspirate/biopsy will be performed in subjects 
presenting with bone marrow involvement prior to therapy or if new abnormalities in the 
peripheral blood counts or blood smear cause clinical suspicion of bone marrow involvement 
with lymphoma after treatment. To confirm a complete response, the bone marrow aspirate and 
biopsy must show no evidence of disease by morphology or if indeterminate by morphology it 
must be negative by immunohistochemistry. Refer to Section 7.10 and 
Appendix 1 for treatment response assessment requirements per the revised IWG Response 
Criteria for Malignant Lymphoma {Cheson 2007}. Bone marrow aspirate/biopsy should also be 
considered to evaluate hemophagocytic lymphohistiocytosis (HLH) as indicated in the IB. A 
portion of the bone marrow sample collected to evaluate HLH or other toxicities should be 
submitted to the central laboratory as outlined in the central laboratory manual.
7.9.
Lumbar Puncture
Subjects with symptoms of central nervous system malignancy such as new onset severe 
headaches, neck stiffness, or any focal neurologic findings on physical exam will have lumbar 
puncture performed at the screening visit for examination of cerebral spinal fluid. In addition, 
lumbar puncture may be performed as applicable for subjects with new onset of ≥ Grade 2 
neurologic toxicities after axicabtagene ciloleucel infusion (see Section 6.4).




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If the subject is eligible for retreatment with axicabtagene ciloleucel, the last scan prior to 
retreatment will be considered the baseline for the purpose of evaluating the response to 
retreatment.
Requirements for PET-CT scans and shipping requirements will be outlined in the study imaging 
manual.
7.11.
Laboratory
The below samples will be collected at the time points indicated in the SOA. Additional samples 
(eg, blood, urine, CSF, tissue, etc) may be collected as needed for further safety testing.
Local lab analysis:

Sodium (Na), potassium (K), chloride (Cl), total CO2 (bicarbonate), creatinine, glucose, 
blood urea nitrogen (BUN) or urea (if BUN test cannot be analyzed by the local lab), 
albumin, calcium total, magnesium total (Mg), inorganic phosphorus, alkaline phosphatase, 
ALT/glutamic-pyruvic transaminase (GPT), AST/glutamic-oxaloacetic transaminase (GOT), 
total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), uric acid

C-reactive protein (CRP)

Complete blood count (CBC) with differential

A urine or serum sample will be collected and assessed locally for females of childbearing 
potential. If the screening pregnancy test is positive, the subjects should not be enrolled. If a 
standard of care pregnancy test is collected during the course of the study, and the result is 
positive, the investigator should contact the Kite Pharma medical monitor for instructions. If 
a female partner of a male subject becomes pregnant during the conduct of the study, it must 
be reported by contacting Kite Pharma Medical Monitor for instructions.

For EU sites, a serology (eg, HIV, hepatitis B, hepatitis C, syphilis) test will be carried out 
per institutional guidelines and EU regulations. This may be administered within the 30 days 
prior to leukapheresis and/or on the day of leukapheresis.
Central lab analysis:

Blood draws for PBMC (lymphocyte subsets, replication-competent retrovirus [RCR], and 
anti-CD19 CAR T-cell levels) and cytokine analysis will be performed at intervals outlined 
in the SOA.

Serum samples will also be evaluated centrally for anti-axicabtagene ciloleucel antibodies.

For serum samples that demonstrate increased anti-axicabtagene ciloleucel antibodies at the 
Month 3 visit over baseline values, attempts should be made to obtain and test additional 
serum samples approximately every 3 months until the antibody levels return to baseline (or 
becomes negative) or up to 1 year from the completion of treatment, whichever occurs first.








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Clinical Protocol: KTE-C19-101
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
Medical history and disease assessment

Physical examination including height and weight

Subjects with symptoms of central nervous system malignancy such as new onset severe 
headaches, neck stiffness, or any focal neurologic findings on physical exam will have 
lumbar puncture for examination of cerebral spinal fluid.

Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature

ECOG performance status

For subjects enrolled in Cohort 3, Cohort 4, Cohort 5, and Cohort 6, EQ-5D questionnaire 
(prior to any other assessments/procedures being performed)

For subjects enrolled in Cohort 1, Cohort 2, or Cohort 3, neurological assessment including 
MMSE

ECG

ECHO for LVEF and pericardial effusion assessment

An ECHO performed following the subjects last chemotherapy treatment and within 28 days 
prior to signing the consent may be used for confirmation of eligibility

Imaging Studies

Brain MRI

Baseline PET-CT of the neck, chest, abdomen and pelvis

PET-CT performed following the subjects last line of therapy and prior to signing the consent 
may be used for confirmation of eligibility.

If PET CT is performed > 28 days prior to the initiation of conditioning chemotherapy or if 
subject receives any anti-cancer therapy between screening and conditioning chemotherapy, 
the scans must be repeated to establish a new baseline. For subjects in Cohort 5, if no 
conditioning chemotherapy is being administered, a PET-CT must be repeated to establish a 
new baseline prior to the axicabtagene ciloleucel infusion. PET-CT should be performed as 
close to enrollment as possible.

Bone marrow aspirate/biopsy as needed (if not done at initial diagnosis or between diagnosis 
and screening)

Labs

Chemistry panel




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Clinical Protocol: KTE-C19-101
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The following procedures/requirements will occur on the leukapheresis collection day and as 
outlined in the SOA:

Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature

Weight

Labs (to be drawn prior to leukapheresis, on the day of or day before leukapheresis)

Chemistry panel

CBC with differential

CRP; if CRP is ≥ 100 mg/L a call must be made to the Kite medical monitor before 
proceeding with conditioning chemotherapy

Anti-CD19 CAR T cells

Lymphocyte subsets

Cytokine levels

Anti-axicabtagene ciloleucel antibodies

Leukapheresis

Adverse/Serious Adverse Event reporting

Concomitant medications documentation
7.13.4.
Bridging Therapy Phase 2 Safety Management Study
If prescribed, bridging therapy must be administered after enrollment and completed prior to 
initiating conditioning chemotherapy per the specifications outlined in Section 6 for bridging 
therapy.

Adverse/Serious Adverse Event reporting

Concomitant medications documentation
7.13.5.
Debulking Therapy Phase 2 Safety Management Study, Cohort 5
Debulking chemotherapy must be administered after enrollment and should be completed at least 
14 days prior to initiating conditioning chemotherapy or at least 14 days prior to axicabtagene 
ciloleucel administration in case conditioning chemotherapy is omitted. Radiotherapy must be 
administered after enrollment and should be completed at least 5 days prior to initiating 
conditioning chemotherapy or at least 5 days prior to axicabtagene ciloleucel administration in 
case conditioning chemotherapy is omitted.


Axicabtagene ciloleucel; KTE-C19
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Clinical Protocol: KTE-C19-101
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7.13.6.
Conditioning Chemotherapy Period
If any screening assessments or procedures are repeated between screening and the start of 
conditioning chemotherapy and results are outside the eligibility criteria (Section 5), contact the 
Kite medical monitor for approval prior to proceeding with conditioning chemotherapy.
If PET-CT will be older than 28 days at the initiation of conditioning chemotherapy or if the 
subject receives any anti-cancer therapy with therapeutic intent (eg, radiation, supraphysiologic 
doses of steroids, chemotherapy) between the last PET-CT and initiation of conditioning 
chemotherapy, the PET-CT must be repeated to establish a new baseline.
Subjects in Cohort 5 and Cohort 6 may proceed with conditioning chemotherapy in absence of 
measurable disease in the new baseline PET-CT if they have received preceding bridging or 
debulking therapy (Cohort 5).
The investigational product (axicabtagene ciloleucel) must be available before initiation of 
conditioning chemotherapy.
7.13.6.1.
Requirements for Initiating Conditioning Chemotherapy
Administration of anti-CD19 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 (eg “tumor fever,” elevated CRP) are 
diagnoses of exclusion that require a documented workup to establish. Conditioning 
chemotherapy and axicabtagene ciloleucel infusion should only be initiated after it is reasonably 
assured that cell infusion can safely proceed.
If any of the following criteria are met prior to initiation of conditioning chemotherapy, then the 
work-up listed in Section 7.13.7.3 must be performed to determine the potential cause if there is 
no identified source of infection.

Temperature > 38°Celsius within 72 hours of conditioning chemotherapy

CRP > 100 mg/L anytime between enrollment to start of conditioning chemotherapy

WBC count or WBC differential that is suggestive of infectious process, and is observed 
between enrollment and the initiation of conditioning chemotherapy (eg WBC > 20,000/µL, 
rapidly increasing WBC, or differential with high percentage of segments/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.


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
Complete history and physical exam including head, ears, eyes, nose, and throat (HEENT) 
exam, 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 known or 
suspected infection within 48 hours before conditioning chemotherapy (prophylactic use of 
antimicrobials is allowed).

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 the 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 and in consultation with infectious disease service (if applicable).

The 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 (eg, bacterial, viral 
serologies, PCR, stood 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.
7.13.6.2.
Conditioning Chemotherapy Administration
The following procedures will be completed during Day –5 to Day –3 at the time points outlined 
in the SOA:

Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature

Labs (to be drawn prior to chemotherapy)

Chemistry Panel

CBC with differential

Fludarabine and cyclophosphamide administration

Adverse/Serious Adverse Event reporting

Concomitant medications documentation

Cytokine levels (Cohort 5 only)


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Clinical Protocol: KTE-C19-101
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7.13.7.
Investigational Product Treatment Period
7.13.7.1.
Requirements for Initiating Axicabtagene Ciloleucel Infusion
If any of the following criteria are met prior to the initiation of axicabtagene ciloleucel infusion, 
then the work-up listed in Section 7.13.7.3 must be performed to determine the potential cause if 
there is no identified source of infection.

Temperature > 38°Celsius within 72 hours of axicabtagene ciloleucel infusion.

CRP > 100 mg/L anytime between enrollment to start of conditioning chemotherapy

WBC count or WBC differential, that is suggestive of infectious process, and is observed 
between enrollment and the initiation of axicabtagene ciloleucel infusion (eg, WBC 
> 20,000/µL, rapidly increasing WBC, or differential with high percentage or 
segments/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 exam, 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 infusion (prophylactic use 
of antimicrobials is allowed)

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 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 (eg, 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.


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Clinical Protocol: KTE-C19-101
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After the above criteria are met, then the subject can proceed with administration of axicabtagene 
ciloleucel. For Cohort 6 only, dexamethasone 
 should be given prior to axicabtagene 
ciloleucel infusion (refer to Section 7.13.7.2).
If the axicabtagene ciloleucel infusion is delayed > 2 weeks from the planned infusion date, 
protocol guidelines should be followed regarding the need for repeat conditioning chemotherapy.
7.13.7.2.
Monitoring After Axicabtagene Ciloleucel Infusion
All subjects will receive axicabtagene ciloleucel infusion at a healthcare facility followed by 
daily monitoring at a healthcare facility for at least 7 days unless otherwise required by country 
regulatory agencies (refer to Appendix 2) to monitor for signs and symptoms of CRS and 
neurologic toxicities. Alternatively, subjects may be hospitalized to receive their axicabtagene 
ciloleucel infusion and be observed for CRS and neurologic toxicities in the hospital setting, if 
deemed appropriate by the investigator.
If subjects are hospitalized, subjects should not be discharged from the hospital until all 
axicabtagene ciloleucel related non-hematological toxicities return to ≤ Grade 1 or return to 
baseline. Subjects may be discharged with non-critical and clinically stable or improving 
toxicities (eg, renal insufficiency) even if > Grade 1, if deemed appropriate by the investigator. 
Subjects should remain in a hospital for ongoing axicabtagene ciloleucel-related fever, 
hypotension, hypoxia, or ongoing central neurologic toxicities > 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 and their family 
members/caregivers should be educated on potential CRS and neurologic symptoms, such as 
fever, dyspnea, confusion, aphasia, dysphagia, 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.
During this period, the following procedures will be completed at the time points outlined in the 
SOA:

Neurological assessment including MMSE for subjects enrolled in Cohort 1, Cohort 2, or 
Cohort 3

MMSE will be administered before treatment with axicabtagene ciloleucel on Day 0, and 
then on Day 1 and every other day during the 7-day post-infusion monitoring period.

Vital signs including blood pressure, heart rate, oxygen saturation, and temperature, daily at a 
health care facility for at least 7 days

Labs (before axicabtagene ciloleucel infusion, as described in the SOA)

Chemistry Panel
CCI




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7.13.7.3.
Requirements for 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 the following:

Call Kite medical monitor

Infectious disease service consult (if available)

CT imaging of the chest, abdomen, and pelvis with IV contrast. If there is a medical 
contraindication to contrast, then non-contrast 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 (eg, galactomannan, fungitell)
Collection of appropriate serum viral studies (eg, cytomegalovirus [CMV])

If a central nervous system 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 and/or axicabtagene ciloleucel infusion, the 
above workup must not suggest the presence of an active infection and all requirements for 
conditioning chemotherapy and/or axicabtagene ciloleucel infusion must be satisfied. If the 
axicabtagene ciloleucel infusion is delayed > 2 weeks following conditioning chemotherapy, 
protocol guidelines should be followed regarding the need for repeat conditioning chemotherapy.
If the above workup was triggered due to CRP > 100 mg/L, CRP should be repeated. If CRP 
continues to increase significantly, an evaluation should be performed for any other potential 
infectious or inflammatory condition that was not previously evaluated.


Axicabtagene ciloleucel; KTE-C19
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Clinical Protocol: KTE-C19-101
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7.13.8.
Post-treatment Assessment Period
After completing axicabtagene ciloleucel infusion and completing the minimum 7-day 
observation period, all subjects will be followed in the post-treatment assessment period. 
Counting from Day 0 (axicabtagene ciloleucel infusion), subjects will return to the clinic at the 
following intervals.

Week 2 (± 2 days)

Week 3 (± 2 days) for subjects enrolled in Cohort 4 only

Week 4 (± 3 days)

Month 2 (± 1 week)

Month 3 (± 1 week)
Subject will allow key sponsor contacts to continue to access medical records so that information 
related to subjects health condition and initial treatment response may be obtained. The 
following procedures will be completed for subjects as outlined in the SOA:

For subjects enrolled in Cohort 3, Cohort 4, Cohort 5, and Cohort 6, EQ-5D questionnaire 
(prior to any other assessments/procedures being performed)

For subjects enrolled in Cohort 1, Cohort 2, or Cohort 3, neurological assessment including 
MMSE

PET-CT for disease assessment: If the PET-CT is not of high enough resolution, the scan 
must be repeated. Refer to the imaging charter for detailed instructions.

As applicable, bone marrow aspirate/biopsy to confirm response (i.e., for subjects presenting 
with bone marrow involvement prior to therapy or if new abnormalities in the peripheral 
blood counts or blood smear cause clinical suspicion of bone marrow involvement with 
lymphoma after treatment)

Physical exam

Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature

Labs

Chemistry Panel

CBC with differential

β-HCG pregnancy test (serum or urine) on all women of child-bearing potential

Anti-axicabtagene ciloleucel antibodies




Axicabtagene ciloleucel; KTE-C19
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Clinical Protocol: KTE-C19-101
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
Beginning with year 6, Month 72 (± 3 months), subjects will return to the clinic 1 time 
annually up to 15 years.
Subjects will be given the opportunity to transition to the separate LTFU study, 
KT-US-982-5968, after providing signed informed consent for the LTFU study and after 
completing at least 24 months of assessments in the parent study. 
The following procedures will be completed for subjects who are enrolled and receive 
axicabtagene ciloleucel at the time points outlined in the SOA (Table 11):

For subjects enrolled in Cohort 3, Cohort 4, Cohort 5, and Cohort 6, EQ-5D questionnaire 
(prior to any other assessments/procedures being performed)

Physical exam

PET-CT/ Disease assessment through 24 months or until disease progression, whichever 
occurs first. If subject’s disease has not progressed by Month 24, disease assessments will 
continue to be performed per institutional standard of care.

Survival status

Labs

CBC with differential

Anti-axicabtagene ciloleucel antibodies (refer to Section 7.11)

Lymphocyte subsets

Anti-CD19 CART-cell levels

RCR analysis

Subsequent therapy for the treatment of NHL

Refer to Sections 9.2 and 9.4 for targeted adverse/serious adverse event reporting

Neurological, hematological, infections, autoimmune disorders, and secondary malignancies

Targeted concomitant medication documentation (for 24 months or until disease progression, 
whichever occurs first)

Gammaglobulins, immunosuppressive drugs, anti-infectives, and vaccinations
Subjects may be contacted by telephone to confirm survival status and report targeted 
concomitant medication use.






Axicabtagene ciloleucel; KTE-C19
Kite Pharma, Inc.
Clinical Protocol: KTE-C19-101
Final
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14 June 2022
Table 11.
Schedule of Assessments
Procedures
Screening
Enrollment/
Leukapheresis
Debulking 
Therapy
(Cohort 5)
Conditioning 
Chemotherapy
Period
IP 
Administration 
Period12
Post Treatment Follow-up
(each visit calculated from Day 0)
Day
Within 28 
days of 
enrollment
Within approx. 
5 days of 
eligibility 
confirmation
After 
enrollment 
and at least 
14 days 
prior to 
Day -5
-
5
-4
-3
-2
-1
0
1 - 7
Week 
2
(± 2 
days)
Week 
3
(± 2 
days)
Week 
4
(± 3 
days)
Month 
2
(± 1 
week)
Month 
3
(± 1 
week)
Medical history
X
ECOG Performance Status
X
EQ-5D Questionnaire (Cohort 
3,4, 5, and 6 only)14
X
X
X
Neurological assessment 
including Mini Mental Status 
Exam (MMSE)5,14
X
X
QOD 5
X
X
ECG
X
ECHO
X
Archival/Fresh tumor1,14
X
between Day 7 & 
Day 14
Brain MRI
X
PET-CT/ disease assessment 2
X
X
X
Physical exam
X
X
X
X
X
Vital signs (BP, HR, O2 sat, temp)
X
X
X
X
X
X
X
X
X
X
X
Weight (plus Height at screening)
X
X
Pregnancy test (serum or urine)
X
X
Lumbar Puncture6,14
X
X
X
Blood draw for Chemistry panel
X
X
X
X
X
X
X
X
X
X
X
Blood draw for CBC 
w/differential
X
X
X
X
X
X
X
X
X
X
X
Blood draw for C-reactive protein 
(CRP)
X
Blood draw for Anti-axicabtagene 
ciloleucel antibodies 3
X
X
X
Blood draw for Lymphocyte 
subsets
X
X
X
X


Axicabtagene ciloleucel; KTE-C19
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Clinical Protocol: KTE-C19-101
Final
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Procedures
Screening
Enrollment/
Leukapheresis
Debulking 
Therapy
(Cohort 5)
Conditioning 
Chemotherapy
Period
IP 
Administration 
Period12
Post Treatment Follow-up
(each visit calculated from Day 0)
Day
Within 28 
days of 
enrollment
Within approx. 
5 days of 
eligibility 
confirmation
After 
enrollment 
and at least 
14 days 
prior to 
Day -5
-
5
-4
-3
-2
-1
0
1 - 7
Week 
2
(± 2 
days)
Week 
3
(± 2 
days)
Week 
4
(± 3 
days)
Month 
2
(± 1 
week)
Month 
3
(± 1 
week)
Blood draw for Cytokines 7, 11,14
X
X 
11
X
QOD 11
X
X
Blood draw for Anti-CD19 CAR 
T cells7, 10,14
X
X
Day110,210, 
3, 7, 10
X
X
X
X
Blood draw for RCR analysis 4
X
X
Leukapheresis
X
Debulking Therapy (Cohort 5 
only)
X
Fludarabine/Cyclophosphamide
X
X
X
Prophylactic Steroid13 (Cohort 6 
only)14
X13
X13
Axicabtagene ciloleucel infusion 
IV
X
Tocilizumab8
Day 2
Levetiracetam9,14
Starting on Day 0
Adverse events/ Concomitant 
medication
X
X
1.
Archival/Fresh tumor sample: Either FFPE tumor block or up to 20 unstained slides. For subjects enrolled in Cohort 4 Cohort 5, and Cohort 6, a block or 30 unstained slides. 
. Archived and fresh tumor samples (if applicable) will be submitted to central laboratory after 
eligibility has been confirmed and prior to start of conditioning chemotherapy. Post treatment fresh tumor samples (if applicable) will be collected/submitted anytime between 
Day 7 and Day 14. See Section 7.11 and 7.12 and central laboratory manual for details
2.
PET-CT (Neck-Chest-Abdomen-Pelvis)/disease assessment PET-CT performed following last line of therapy (>28 days from enrollment) may be used for confirmation of 
eligibility. If PET-CT performed > 28 days prior to the initiation of conditioning chemotherapy or if subject receives any anti-cancer therapy between screening and 
conditioning chemotherapy, baseline scans must be repeated. Screening PET-CT should be completed as close to enrollment as possible. As applicable, bone marrow 
aspirate/biopsy will be performed to confirm response (i.e., for subjects presenting with bone marrow involvement prior to therapy or if new abnormalities in the peripheral 
blood counts or blood smear cause clinical suspicion of bone marrow involvement with lymphoma after treatment). Bone marrow samples may also be collected and analyzed 
centrally for subjects who develop toxicities post axicabtagene ciloleucel. See Section 7.10 and Section 7.12
3.
Blood draw for Anti-axicabtagene ciloleucel antibodies: Baseline antibody sample to be collected prior to start of leukapheresis. Post axicabtagene ciloleucel antibody sample 
to be collected at Week 4 and Month 3 visits. See Section 7.11 for further details
4.
Blood draw for RCR: on Day 0 prior to administration of axicabtagene ciloleucel and at Month 3, 6 and 12; then collect yearly for up to 15 years. Yearly samples will only be 
analyzed if positive at Month 3, 6, or 12.
CCI




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Table 12.
Schedule of Assessments (Long-term Follow-up Period)
Procedure
Long-Term Follow-up Period10
(Each visit calculated from Day 0)
Visit Frequency
Month 
6
Month 
9
Month 
12
Month 
15
Month 
18
Month 
24
Month 
30
Month 
36
Month 
42
Month 
48
Month 
54
Month 
60
Month 72 and 
Annually 
Thereafter
EQ-5D Questionnaire (Cohorts 3, 
4, 5, and 6 only)9
X
Physical exam1
X
X
X
X
X
X
PET-CT/disease assessment2
X
X
X
X
X
X
X2
X2
X2
X2
X2
X2
X2
Survival Status
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood draw for CBC 
w/differential 3
X
X
X
X
X
X
Blood draw for Anti-axicabtagene 
ciloleucel antibodies 4
X
X
X
Blood draw for Lymphocyte 
subsets 3
X
X
X
X
X
X
Blood draw for anti-CD19 CAR T 
cells3
X
X
X
Blood draw for RCR analysis 5
X
X
X
X
X
X
X
Targeted AE/SAEs 6
X
X
X
X
X
X
Targeted concomitant medication 
7
X
X
X
X
X
X
Subsequent therapy for NHL8
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Physical exams will continue through Month 24
2.
PET-CTs/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.
3.
Subjects will continue to provide samples for CBC w/diffs, lymphocyte subsets and anti-CD19 CAR T cells through Month 24
4.
Anti-axicabtagene ciloleucel antibody samples: refer to Section 7.11
5.
RCR samples: collect and measured at Month 3, 6 and 12, then collect yearly for up to 15 years. Yearly samples will only be analyzed if positive at Month 3, 6, or 12.
6.
Targeted AEs/SAEs will be collected for 24 months or until disease progression (whichever occurs first)
7.
Targeted concomitant medications will be collected for 24 months or until disease progression (whichever occurs first)
8.
Subsequent therapy administered after axicabtagene ciloleucel infusion for a subjects’ disease such as non-study specified chemotherapy, immunotherapy, targeted agents, as 
well as stem cell transplant and radiation therapy must be collected until subject completes the long-term follow up 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.
9.
Cohort 6 is not open for enrollment in Germany.
10. After completion of at least 24 months of assessments in the KTE-C19-101 study, subjects who received an infusion of axicabtagene ciloleucel will be provided an 
opportunity to transition to the LTFU study (KT-US-982-5968) after providing signed informed consent, to complete the remainder of the 15-year LTFU period.


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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 but continue 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 investigational product, study treatment or other 
protocol required therapies and must 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 or undergo procedures and the subject does not wish to continue 
further study follow-up. Subject data collected up to withdrawal of consent will be retained and 
included in the analysis of the study, and where permitted by local regulations, publically 
available data (death records) can be included after withdrawal of consent. 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 also 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 or 
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:

Adverse Event

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 adverse event 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 adverse events observed by the investigator or reported by the 
subject are recorded in the subject’s medical record.
The definition of adverse events 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. 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 adverse event.
Interventions for pretreatment conditions (such as elective cosmetic surgery) or medical 
procedures that were planned before study participation are not considered adverse events. 
Hospitalization for study treatment infusions or precautionary measures per institutional policy 
are not considered adverse events.
The term “disease progression” as assessed by measurement of malignant lesions on radiographs 
or other methods should not be reported as adverse events. Death due to disease progression in 
the absence of signs and symptoms should be reported as the primary tumor type 
(e.g., B-Cell Lymphoma).
For situations when an adverse event or serious adverse event is due to the disease under 
investigation report the signs and symptoms. Worsening of signs and symptoms of the 
malignancy under study should also be reported as adverse events in the appropriate section of 
the CRF.
The investigators clinical judgment is used to determine whether a subject is to be removed from 
treatment due to an adverse event. In the event a subject requests to withdraw from protocol 
required therapies or the study due to an adverse event, 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 adverse events observed by the investigator or 
reported by the subject that occur from enrollment (ie, commencement of leukapheresis) through 
3 months after treatment with axicabtagene ciloleucel infusion or until the initiation of another 
anti-cancer therapy, whichever occurs first. After 3 months, targeted adverse events including 
(eg, neurological, hematological, infections, autoimmune disorders, and secondary malignancies) 
will be monitored and reported for 24 months after treatment with axicabtagene ciloleucel or 
until disease progression, whichever occurs first.


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For subjects who are enrolled, but do not receive axicabtagene ciloleucel, the adverse event 
reporting period ends 30 days after the last study-specific procedure (eg, leukapheresis, 
conditioning chemotherapy).
The investigator must address the below for adverse events:

Adverse event diagnosis or syndrome (if not known, signs or symptoms)

Dates of onset and resolution

Severity

Assessment of relatedness to investigational product, conditioning chemotherapy or study 
procedures

Action taken
Adverse event grading scale used will be the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. A copy of the grading scale can be downloaded from the CTEP 
home page (http://ctep.cancer.gov). Cytokine Release Syndrome events will also be reported 
using the grading scale outlined in Section 6.4.
In reviewing adverse events, investigators must assess whether the adverse event is possibly 
related to 1) the investigational product (axicabtagene ciloleucel), 2) conditioning chemotherapy, 
or 3) any protocol-required study procedure. 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 adverse event. Additional 
relevant data with respect to describing the adverse event will be collected in the CRFs.
The investigator is expected to follow reported adverse events until stabilization or resolution. If 
a subject begins a new anticancer therapy, the adverse event reporting period for non-serious 
adverse events 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.


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An abnormal laboratory test result must be reported as an adverse event if it is a change from 
baseline and meets any of the following criteria:

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

Clinically significant in the investigator’s judgment
9.3.
Definition of Serious Adverse Events
A serious adverse event is defined as an adverse event that meets at least 1 of the following 
serious criteria:

Fatal

Life threatening (places the subject at immediate risk of death)

Requires in-patient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Congenital anomaly/birth defect

Other medically important serious event
An adverse event 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 a serious adverse event. Examples of such events include movement from routine 
care in the hospital to the intensive care unit (ICU) 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 a serious adverse event with the criterion of 
“other medically important serious event.”
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an 
adverse event 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 adverse event recorded on the electronic 
CRF.


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9.4.
Reporting of Serious Adverse Events
The investigator is responsible for reporting all serious adverse events observed by the 
investigator or reported by the subject that occur after signing of the consent through 3 months 
after the axicabtagene ciloleucel infusion or until the initiation of another anti-cancer therapy, 
whichever occurs first. After 3 months, only serious targeted adverse events (e.g., neurological, 
hematological, infections, autoimmune disorders, and secondary malignancies) observed by the 
investigator or reported by the subject will be reported for 24 months after axicabtagene 
ciloleucel infusion or until disease progression, whichever occurs first. For subjects who screen 
fail or are enrolled but do not receive axicabtagene ciloleucel, the reporting period for serious 
adverse events ends 30 days after the last procedure (e.g., screen procedure, leukapheresis, 
conditioning chemotherapy).
Serious events that the investigator assesses as related to axicabtagene ciloleucel should be 
reported regardless of the study period.
All SAEs must be submitted via email to 
 within 24 hours following the 
investigator’s knowledge of the event and using a SAE Report Form.
Subsequently, all serious adverse events will be reported to the health authorities per local 
reporting guidelines.
Progression of the malignancy during the study should not be reported as a serious adverse event. 
Adverse events associated with disease progression may be reported as serious adverse events. If 
the malignancy has a fatal outcome within 3 months of the last day of the conditioning therapy or 
axicabtagene ciloleucel, then the event leading to death must be recorded as a serious adverse 
event with CTCAE Grade 5.
Death must be reported if it occurs during the serious adverse event 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 the axicabtagene ciloleucel infusion, regardless of attribution to 
treatment, requires expedited reporting within 24 hours. Any death occurring greater than 
3 months after the axicabtagene ciloleucel infusion requires expedited reporting within 24 hours 
only if it is considered related to treatment.
Following the completion of KTE-C19-101, any relevant information on ongoing SAEs must be 
submitted to Kite Safety and Pharmacovigilance 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: 
PPD
PPD


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9.5.
Reporting Deaths
Deaths that occur during the protocol-specified adverse event 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. The term “unexplained death” should be 
captured if the cause of death is not known. However, every effort should be made to capture the 
established cause of death, which may become available later on (eg, after autopsy). Deaths 
during the post-study survival follow-up due to underlying cancer should be recorded only on the 
Survival Status CRF.
9.6.
Diagnosis versus Signs and Symptoms
For adverse events, 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 signs and 
symptoms will be captured on the CRF 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.
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%) through at least 6 months 
after conditioning chemotherapy dosing or axicabtagene ciloleucel dosing, whichever is longer. 
Male subjects are recommended not to father a child for at least 6 months after completing 
conditioning chemotherapy dosing or axicabtagene ciloleucel dosing, whichever is longer.
If a pregnancy occurs in a female subject enrolled into the study, or a female partner of a male 
subject, within 6 months of completing the conditioning chemotherapy or axicabtagene 
ciloleucel dosing (whichever is longer), the pregnancy must be reported to the key sponsor 
contact. Information regarding the pregnancy and/or the outcome may be requested by the key 
sponsor.
The pregnancy should be reported to the key sponsor contact within 24 hours of the 
investigator’s knowledge of the pregnancy event.
If a lactation case occurs while the female subject is taking protocol required therapies report the 
lactation case to the key sponsor contact.


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In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of protocol required therapies through 6 months.
Any lactation case should be reported to the key sponsor contact within 24 hours of the 
investigator’s knowledge of the event.
9.8.
Hospitalization and Prolonged Hospitalization
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event as described in Section 9.4.
The following hospitalization scenarios are not considered to be serious adverse events:

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
9.9.
Abnormal Vital Sign Values
Not all vital sign abnormalities qualify as an adverse event. A vital sign result must be reported 
as an adverse event 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 whether an isolated vital sign abnormality should be 
classified as an adverse event. However, if a clinically significant vital sign abnormality is a sign 
of a disease or syndrome (eg, high blood pressure), only the diagnosis (ie, hypertension) should 
be recorded on the CRF.
9.10.
Safety Review Team and Dose-limiting Toxicity
Phase 1 Study
The SRT will be specifically chartered to review safety data during Phase 1 of the study and 
make recommendations on further study conduct in Phase 1 and progression to Phase 2 based on 
the incidence of axicabtagene ciloleucel DLT and review of serious adverse events.


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Dose-limiting toxicity is defined as the following axicabtagene ciloleucel-related events with 
onset within the first 30 days following axicabtagene ciloleucel infusion:

Grade 4 neutropenia lasting longer than 21 days from the day of cell transfer

Grade 4 thrombocytopenia lasting longer than 35 days from the day of cell transfer

Any axicabtagene ciloleucel-related adverse event requiring intubation, including Grade 4 
confusion requiring intubation for airway protection is considered to be a DLT.

All other Grade 3 toxicities lasting more than 3 days and all Grade 4 toxicities, with the 
exception of the following conditions which are not considered DLTs:

Aphasia/dysphasia or confusion/cognitive disturbance which resolves to Grade 1 or less 
within 2 weeks and to baseline within 4 weeks

Fever Grade 3

Myelosuppression (includes bleeding in the setting of platelet count less than 50 x109/L and 
documented bacterial infections in the setting of neutropenia), defined as lymphopenia, 
decreased hemoglobin, neutropenia and thrombocytopenia unless neutropenia and 
thrombocytopenia meet the DLT definition described above

Immediate hypersensitivity reactions occurring within 2 hours of cell infusion (related to cell 
infusion) that are reversible to a Grade 2 or less within 24 hours of cell administration with 
standard therapy

Hypogammaglobulinemia Grade 3 or 4
As noted in Section 6.4 CRS will be graded according to a revised grading system {Lee 2014}. 
Adverse events attributed to CRS will be mapped to the overall CRS grading assessment for the 
determination of DLT.
During Phase 1, approximately 6 to 24 subjects with DLBCL, PMBCL, or TFL will be enrolled 
to evaluate the safety of axicabtagene ciloleucel regimens.
Subjects in each cohort will be evaluated for DLTs within the first 30 days following the 
completion of their respective axicabtagene ciloleucel infusion. The analysis of DLTs will be 
based on the DLT evaluable set as defined in Section 10.5 . The SRT will make 
recommendations based on the incidence of DLT and overall safety profile of the axicabtagene 
ciloleucel regimen. If the subject incidence of DLT is ≤ 1 of 6 subjects, Cohort B1 may be 
explored or the study may proceed to Phase 2 of the trial. This decision will be based on overall 
benefit/risk and available biomarker data.




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
CRS (per Lee 2014 criteria) {Lee 2014}

Other non-hematological serious adverse event

Infection (treatment-related)


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10.
STATISTICAL CONSIDERATIONS
The primary objective of the Phase 1 Study is to evaluate the safety of axicabtagene ciloleucel 
regimens. The primary objective of the pivotal Phase 2 portion is to evaluate the efficacy of 
axicabtagene ciloleucel, as measured by ORR in subjects with DLBCL, PMBCL, and TFL. 
Secondary objectives will include assessing the safety and tolerability of axicabtagene ciloleucel 
and additional efficacy endpoints. Inferential testing will only be performed for efficacy for 
Phase 2 pivotal study Cohort 1 and Cohort 2. For the Phase 2 safety management study, 
Cohort 3, Cohort 4, Cohort 5, and Cohort 6, the primary objective is to assess the impact of 
prophylactic regimens, earlier interventions, debulking therapy, or prophylactic steroids on the 
rate and severity of CRS and neurologic toxicities.
NOTE: Cohort 6 is not open for enrollment in Germany.
10.1.
Hypothesis
Phase 2 pivotal study Cohort 1 and Cohort 2: This study is designed to differentiate between a 
treatment that has a true response rate of 20% or less and a treatment with a true response rate of 
40% or more. The hypothesis is that the ORR to axicabtagene ciloleucel in Cohort 1 and 
Cohort 2 is significantly greater than 20%.
Phase 2 safety management study Cohort 3, Cohort 4, Cohort 5, and Cohort 6: No hypothesis 
will be tested in Cohort 3, Cohort 4, Cohort 5, and Cohort 6, which will be used to assess the 
impact of prophylactic regimens, earlier interventions, debulking therapy, or prophylactic 
steroids on the rate and severity of CRS and neurologic toxicities.
10.2.
Study Endpoints
10.2.1.
Primary
Phase 1 study: Incidence of adverse events defined as DLT.
Phase 2 pivotal study: ORR, defined as the incidence of either a complete response or a partial 
response by the revised IWG Response Criteria for Malignant Lymphoma {Cheson 2007} as 
determined by the study investigators. All subjects who do not meet the criteria for an objective 
response by the analysis data cutoff date will be considered non-responders.
Phase 2 safety management study: incidence and severity of CRS and neurologic toxicities.
10.2.2.
Secondary
Duration of response (DOR): Among subjects who experience an objective response, DOR is 
defined as the date of their first objective response (which is subsequently confirmed) to disease 
progression per the revised IWG Response Criteria for Malignant Lymphoma {Cheson 2007} or 
death regardless of cause. Subjects not meeting the criteria for progression or death by the 
analysis data cutoff date will be censored at their last evaluable disease assessment date and their 
response will be noted as ongoing.










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If needed, more subjects will be enrolled to achieve 6 DLT evaluable subjects at the target dose 
for each cohort.
Safety set: the safety set is defined as all subjects treated with any dose of axicabtagene 
ciloleucel.
10.5.2.
Phase 2 Study
In the Phase 2 portion of the study (including the Phase 2 pivotal study and SMS), subjects are to 
be dosed at a target of 2 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 greater than 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 1 x 106 anti-CD19 CAR T cells/kg up to 
 anti-CD19 CAR T cells/kg or, if the subject 
, the subject 
receives 
 anti-CD19 CAR T cells.
Modified Intent-to-Treat Set: the mITT set will consist of all subjects enrolled and treated with 
axicabtagene ciloleucel at a dose of at least 1 x 106 anti-CD19 CAR T cells/kg.
This analysis set will be used for all analyses of objective response and endpoints based on 
objective response (objective response, duration of response, progression-free survival) for both 
the Phase 1 and Phase 2 portions of the study (including both pivotal and SMS).
Safety analysis set: the safety analysis set is defined as all subjects treated with any dose of 
axicabtagene ciloleucel.
Full Analysis set (FAS): the full analysis set will consist of all enrolled subjects and will be used 
for the summary of subject disposition, sensitivity analyses of ORR and DOR, and subject 
listings of deaths.
10.6.
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 Phase 2 portion of 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 analysis plan, DSMB charter, and Trial Integrity 
Document.
10.7.
Interim Analysis
10.7.1.
Interim Analysis and Early Stopping Rules
Phase 1 Study
The SRT will be chartered to review safety during Phase 1 of the study only and make 
recommendations on further study conduct in Phase 1 and progression to Phase 2.
CCI
CCI
CCI




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10.8.
Planned Method of Analysis
Phase 1 Study
Descriptive analysis of the Phase 1 portion of the study may occur at any time.
Phase 2 Pivotal Study
The primary efficacy analyses of Cohort 1 will be performed when 72 subjects in the mITT set 
of Cohort 1 have had the opportunity to be evaluated for response 6 months after the 
axicabtagene ciloleucel infusion. The primary analysis of Cohorts 1 and 2 combined will be 
performed when 72 subjects in the mITT set of Cohort 1 and 20 subjects in the mITT set of 
Cohort 2 have had the opportunity to be evaluated for response at 6 months after the target 
axicabtagene ciloleucel infusion. Additional analyses may occur after the primary analysis. 
These additional analyses will be descriptive and will occur after inferential testing has been 
performed. The final analysis will occur when all subjects have completed the study.
The primary endpoint of ORR for all analyses (
) will be based on 
investigator review of disease assessments in the mITT set. For Cohorts 1 and 2, sensitivity 
analyses of ORR based on central radiologic review of disease assessments will be performed.
Analyses of efficacy endpoints will be summarized by study phase, for Cohort 1 alone, for 
Cohort 1 and Cohort 2 combined, and for Cohort 3 alone. Analyses of safety endpoints will be 
evaluated by study phase, cohort, Cohort 1 and 2 combined.
Phase 2 Safety Management Study
The primary analysis of Cohort 3, Cohort 4, Cohort 5, and Cohort 6 will occur after all treated 
subjects in each cohort have had the opportunity to be followed for 6 months, respectively. The 
ORR in Cohort 3, Cohort 4, Cohort 5, and Cohort 6 will be based on investigator review of 
disease assessment in the mITT set. No central radiologic review of disease assessment will be 
performed for these cohorts.
Descriptive analyses of the Phase 2 SMS Cohort 3, Cohort 4, Cohort 5, and Cohort 6 may occur 
at any time.
10.8.1.
Objective Response Rate
The incidence of objective response and exact 2-sided 95% confidence intervals will be 
generated. For the Phase 2 pivotal study, Cohort 1 and Cohort 2, an exact binomial test will be 
used to compare the observed response rate to a response rate of 20%.
10.8.2.
Duration of Response
Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for duration of 
response. Estimates of the proportion of subjects in response at 3-month intervals from the first 
response will be provided. The competing-risk analysis method {Fine 1999, Pepe 1991} may be 
used to estimate the cumulative incidence of relapse. The cumulative incidence of relapse in the 
presence of non-disease related mortality (the competing risk) may be estimated along with 
2-sided 95% confidence intervals at 3-month intervals.
CCI




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11.
REGULATORY OBLIGATIONS
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 sites respective IRB/IEC for approval. Once 
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 are to submit site specific and study serious adverse 
events (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 contained at all material submitted to the key sponsor contact. 
The following rules are to be applied.

Subjects will be identified by a unique identification number

Date of birth or year of birth/age at time of enrollment will be reported according with local 
laws and regulations
For reporting of serious adverse events, subjects will be identified by their respective subject 
identification number, initials and data of birth or year of birth (as per their local reporting 
requirements for both initials and date of birth)
Per federal regulations and International Conference on Harmonisation/Good Clinical Practice 
(ICH/GCP) guidelines, investigators and institutions are required to permit authorization to the 
sponsor, contract research organization (CRO), 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.


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11.3.
Investigator Signatory Obligations
Each clinical study report will be signed by the coordinating investigator. The coordinating 
investigator will be identified by Kite Pharma under the following criteria:

A recognized expert in the disease setting

Provided significant contributions to the design or analysis of study data

Participate 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 investigators 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 of the trial completion or early termination 
and provide the CRO with a copy of the correspondence.
Kite Pharma reserves the unilateral right, at is sole discretion, to determine whether to 
manufacture axicabtagene ciloleucel T cells and provide them to sites and subjects after the 
completion of the study and before treatment becomes commercially available.


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13.
STUDY DOCUMENTATION AND ARCHIVE
The investigator will maintain a list of qualified staff to whom study responsibilities have been 
delegated. These 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, radiology and 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, use of the CRFs as source 
documentation as a routine practice is not recommended.
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, regulatory authorities and IRB/IECs. The filing system will 
include at minimum:

Subject content including ICFs and subject identification 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 Pharma and the investigator. Should storage no longer be available to 
archive source documents or must be moved to an alternative location, the research staff should 
notify the key sponsor contact prior to the 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 assuring that subject confidentially is respected.
The monitor is responsible for source document verification of CRF data at regular intervals 
during the study. Protocol adherence, 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 medications 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-C19-101 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:

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 re appropriately investigated or resolved
When a large, multicenter group has conducted the work, the group should identify the 
individual who accepts 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 Pharma 
for review and approval. The study contract between the institution, principal investigation and 
Kite Pharma or its delegate will outline the requirements for publication review.


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16.
COMPENSATION
Kite Pharma 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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Khouri IF, Keating M, Körbling M, Przepiorka D, Anderlini P, O'Brien S, et al. Transplant-lite: 
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lymphoma. Leuk Lymphoma 2008;49 (7):1329-36.
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Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T 
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18.
APPENDICES
Appendix 1.
Revised IWG Response Criteria for Malignant Lymphoma {Cheson 2007}
Appendix 2.
Monitoring of subjects after IP administration per country regulatory agencies:


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Appendix 1.
Revised IWG Response Criteria for Malignant Lymphoma {Cheson 
2007}
Complete Remission (CR): CR requires all of the following:

Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy.

Typically FDG-avid lymphoma (large cell, mantle cell and follicular lymphomas are all 
typically FDG-avid): in subjects with no pretreatment PET scan or when the PET scan was 
positive before therapy, a post-treatment residual mass of any size is permitted as long as it is 
PET negative.

Variably FDG-avid lymphomas/FDG avidity unknown: in subjects without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses 
must have regressed to normal size (≤ 1.5 cm in greatest diameter if > 1.5 cm before 
therapy). Previously involved nodes that were 1.1 to 1.5 cm in their long axis and more than 
1 cm in their short axis before treatment must have decreased to ≤ 1.0 cm in their short axis 
after treatment.

The spleen and/or liver, if considered to be enlarged before therapy on basis of physical exam 
or CT scan, must should be normal size on CT scan and not be palpable on physical 
examination and nodules thought to represent lymphoma must no longer be present.

A bone marrow aspirate and biopsy is performed only when the patient had bone marrow 
involvement with lymphoma prior to therapy or if new abnormalities in the peripheral blood 
counts or blood smear cause clinical suspicion of bone marrow involvement with lymphoma 
after treatment. The bone marrow aspirate and biopsy must show no evidence of disease by 
morphology or if indeterminate by morphology it must be negative by 
immunohistochemistry. The biopsy core sample must be a minimum of 20 mm in length.
Partial Remission (PR): PR requires all of the following:

≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest 
dominant nodes or nodal masses. Dominant nodes or nodal masses should be clearly 
measurable in at least 2 perpendicular dimensions, should be from different regions of the 
body if possible and should include mediastinal and retroperitoneal nodes if possible.

No increase in size of nodes, liver or spleen and no new sites of disease.

If multiple splenic and hepatic nodules are present, they must regress by ≥ 50% in the SPD. 
There must be a > 50% decrease in the greatest transverse diameter for single nodules.


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
Bone marrow is irrelevant for determination of a PR. If patient has persistent bone marrow 
involvement and otherwise meets criteria for CR the patient will be considered a PR.

Typically FDG-avid lymphoma: for subjects with no pretreatment PET scan or if the PET 
scan was positive before therapy, the post-treatment PET scan should be positive in at least 
one previously involved site. Note: in subjects with follicular lymphoma or mantle-cell 
lymphoma, a PET scan is only indicated in subjects with one or at most two residual masses 
that have regressed by 50% on CT scan.
Stable Disease (SD):

Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PET 
should be positive in typically FDG-avid lymphomas.
Progressive Disease:
Defined by at least one of the following:

≥ 50% increase from nadir in the sum of the products of at least two lymph nodes, or if a 
single node is involved at least a 50% increase in the product of the diameters of this one 
node.

Appearance of a new lesion greater than 1.5 cm in any axis even if other lesions are 
decreasing in size

Greater than or equal to a 50% increase in size of splenic or hepatic nodules

At least a 50% increase in the longest diameter of any single previously identified node more 
than 1 cm in its short axis.

Lesions should be PET positive in typically FDG-avid lymphomas unless the lesion is too 
small to be detected by PET (< 1.5 cm in its long axis by CT)


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Appendix 2.
Monitoring of subjects after IP administration per country regulatory 
agencies:
Germany:
The post-infusion monitoring of subjects, described in Section 7.13.7.2 in this protocol, will be 
extended by monitoring on Day 8, Day 9, and Day 10, according to procedures outlined in 
Table 11, column “IP administration period, 1-7”. 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 7.4), blood draw for chemistry panel 
with CRP, blood draw for CBC w/differential (see Section 7.11), and neurological assessment. 
Any observed toxicity will be managed according to Section 6.4 of this protocol.
France:
The post-infusion monitoring of subjects in this protocol will be extended by monitoring on 
Day 8, Day 9, and Day 10, according to procedures outlined in Table 11, column “IP 
administration period, 1-7.” The L'Agence nationale de sécurité du médicament et des produits 
de santé (ANSM) recommends a 10-day hospitalization after infusion of any CAR T-cell 
product.
The daily monitoring will include vital signs (see Section 6.4), blood draw for chemistry panel 
with CRP, blood draw for CBC w/differential (see Section 7.11), and neurological assessment. 
Any observed toxicity will be evaluated according to Section 6.4 of this protocol.

Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Title:  
A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of 
KTE-C19 in Subjects with Refractory Aggressive Non-Hodgkin 
Lymphoma (ZUMA-1) 
Protocol Number:  
KTE-C19-101 
IND Number: 
016278 
EudraCT Number: 
2015-005007-86  
Clinical Study Sponsor:  
Kite Pharma, Inc. 
2400 Broadway 
Santa Monica, CA 90404 
United States of America 
Key Sponsor Contacts: 
, Clinical Development 
Kite Pharma, Inc.  
2 Roundwood Avenue 
Stockley Park 
Uxbridge, Middlesex 
Phone: 
 
Email: 
 
 
 Clinical Development 
Kite Pharma Inc.  
2400 Broadway 
Santa Monica, CA 90404 
Phone: 
 
Email: 
  
 
 Clinical Operations 
Kite Pharma, Inc.  
2400 Broadway 
Santa Monica, CA 90404 
Phone: 
 
Email: 
 
Version: 
1.0 (Amendment # 8) 
Date: 
11 February 2019 
 
Confidentiality Notice 
This document contains proprietary and confidential information of Kite Pharma Inc., a wholly 
owned subsidiary of Gilead Sciences, Inc.  The information must not be disclosed to any third 
party without the prior written consent of Kite Pharma, Inc.  Questions regarding how this 
document should be used or the conduct of the clinical trial should be directed to the key sponsor 
contacts. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 2 of 118 
 
11 February 2019 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol titled: A Phase 1/2 Multicenter Study Evaluating the Safety and 
Efficacy of KTE-C19 in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) 
(ZUMA-1) dated 11 Feb 2019 and agree to abide by all provisions set forth therein.  
I agree to comply with the International Conference on Harmonisation Tripartite Guideline on 
Good Clinical Practice and applicable national or regional regulations and guidelines.  
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 one 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. 
 
 
 
____________________________________ 
Signature 
____________________________________ 
Name of investigator 
____________________________________ 
Date 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 3 of 118 
 
11 February 2019 
PROTOCOL SYNOPSIS 
Title 
A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of 
KTE-C19 in Subjects with Refractory Aggressive Non-Hodgkin 
Lymphoma (ZUMA-1). 
Indication 
The indication is for the treatment of adult subjects with relapsed or 
refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal 
B-cell lymphoma (PMBCL), transformed follicular lymphoma (TFL), 
and high grade B-cell lymphoma (HGBCL) after two or more lines of 
systemic therapy. 
Study Design 
Study KTE-C19-101 is a Phase 1/2 multicenter, open-label study 
evaluating the safety and efficacy of axicabtagene ciloleucel in subjects 
with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL).  
The trial will be separated into 3 distinct phases designated as the 
Phase 1 study, Phase 2 pivotal study (Cohort 1 and Cohort 2), and 
Phase 2 safety management study (Cohort 3, Cohort 4, Cohort 5, and 
Cohort 6). 
Phase 1 Study 
During Phase 1 study, approximately 6 to 24 subjects with DLBCL, 
PMBCL, or TFL will be enrolled to evaluate the safety of axicabtagene 
ciloleucel regimens.  A safety review team (SRT), internal to the study 
sponsor, will review the safety data and make recommendations on 
further study conduct of Phase 1 and progression to Phase 2 pivotal study 
as depicted in Figure 3 and outlined in Section 9.10.  
Phase 2 Pivotal Study 
In the Phase 2 pivotal study, approximately 92 subjects will enroll into 
2 separate cohorts designated as Cohort 1 and Cohort 2: 
 Cohort 1 will enroll approximately 72 adult subjects with refractory 
DLBCL. 
 Cohort 2 will enroll approximately 20 adult subjects with refractory 
PMBCL and TFL. TFL is defined as subjects who received prior 
therapy for follicular lymphoma. 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 4 of 118 
 
11 February 2019 
 
Phase 2 Safety Management Study 
In the Phase 2 safety management study (SMS), approximately 
170 subjects will enroll into 4 separate cohorts designated as Cohort 3, 
Cohort 4, Cohort 5, and Cohort 6. 
 Cohort 3 will enroll approximately 40 adult subjects with relapsed or 
refractory transplant ineligible DLBCL, PMBCL, or TFL. 
 Cohort 4 will enroll and dose approximately 40 adult subjects with 
relapsed or refractory DLBCL, PMBCL, TFL or HGBCL after 2 or 
more lines of systemic therapy. 
 Cohort 5 will enroll and dose approximately 50 adult subjects with 
relapsed or refractory DLBCL, PMBCL, TFL or HGBCL after 2 or 
more lines of systemic therapy. 
 Cohort 6 will enroll and dose approximately 40 adult subjects 
with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL 
after 2 or more lines of systemic therapy. 
Independent of the phase of the study each subject will follow the same 
study treatment schedule and procedural requirements. Each subject will 
proceed through the following study periods: 
 Screening 
 Enrollment/Leukapheresis period 
 Bridging therapy (if applicable; safety management study only) or 
debulking therapy (if applicable, safety management study, Cohort 5 
only) 
 Conditioning chemotherapy period  
 Investigational product (IP) treatment period 
 Post-treatment assessment period 
 Long-term follow-up period 
For study requirements assigned to each study period, refer to Section 7 
for details. 
Study Objectives 
Phase 1 Study 
The primary objective of Phase 1 is to evaluate the safety of 
axicabtagene ciloleucel regimens. 
Phase 2 Pivotal Study 
The primary objective of the Phase 2 pivotal study is to evaluate the 
efficacy of axicabtagene ciloleucel, as measured by objective response 
rate (ORR) in subjects with DLBCL, PMBCL, and TFL.  Secondary 
objectives will include assessing the safety and tolerability of 
axicabtagene ciloleucel and additional efficacy endpoints. 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 5 of 118 
 
11 February 2019 
Phase 2 Safety Management Study 
The primary objective of the Phase 2 safety management study is to 
assess the impact of prophylactic regimens, earlier interventions, tumor 
debulking, and prophylactic steroid use on the rate and severity of 
cytokine release syndrome (CRS) and neurologic toxicity.  Secondary 
objectives will include assessment of efficacy, levels of anti-CD19 
chimeric antigen receptor (CAR) T cells, cytokines in blood/serum, and 
the change in European Quality of Life-5 Dimensions (EQ-5D) scores 
from baseline to Month 6. 
Study Hypothesis 
and Endpoints 
Phase 1 Study 
Primary Endpoint 
 Incidence of adverse events defined as dose-limiting toxicities (DLT) 
Secondary Endpoints 
 Objective response rate (complete response [CR] + partial response 
[PR]) per the revised International Working Group (IWG) Response 
Criteria for Malignant Lymphoma  
 Duration of response (DOR) 
 Overall survival (OS) 
 Progression-free survival (PFS) 
 Incidence of adverse events and clinical significant changes in safety 
lab values 
 Incidence of adverse events and clinical significant changes in safety 
lab values 
 Levels of anti-CD19 CAR T cells in blood 
 Levels of cytokines in serum 
 Incidence of anti-axicabtagene ciloleucel antibodies 
 
 
 
 
 
 
 
 
  
 
 
 
 
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Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 6 of 118 
 
11 February 2019 
 
 
Phase 2 Pivotal Study 
This study is designed to differentiate between a treatment that has a true 
response rate of 20% or less and a treatment with a true response rate of 
40% or more.  The hypothesis is that the objective response rate to 
axicabtagene ciloleucel in Cohort 1 and Cohort 2 is significantly greater 
than 20%. 
Primary Endpoint 
 Objective response rate (CR + PR) per the revised IWG Response 
Criteria for Malignant Lymphoma (Cheson et al, 2007) as determined 
by study investigators. 
Secondary Endpoints  
 Objective response rate per Independent Radiology Review 
Committee (IRRC)  
 DOR 
 PFS 
 OS  
 Incidence of adverse events and clinical significant changes in safety 
lab values 
 Levels of anti-CD19 CAR T cells in blood 
 Levels of cytokines in serum 
Incidence of anti-axicabtagene ciloleucel antibodies 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 7 of 118 
 
11 February 2019 
 
Phase 2 Safety Management Study 
No hypothesis will be tested in Cohort 3, Cohort 4, Cohort 5, and 
Cohort 6.  
Primary Endpoint 
 Incidence and severity of CRS and neurologic toxicities. 
Secondary Endpoints  
 Objective response rate (complete response [CR] + partial response 
[PR]) per the revised IWG Response Criteria for Malignant 
Lymphoma (Cheson et al, 2007) as determined by study 
investigators. 
 DOR 
 PFS 
 OS  
 Incidence of adverse events and clinically significant changes in 
safety lab values 
 Levels of anti-CD19 CAR T cells in blood  
 Levels of cytokines in blood 
 Incidence of anti-axicabtagene ciloleucel antibodies 
 Changes over time in the EQ-5D scale score and visual analogue 
scale (VAS) score (Phase 2 SMS only) 
  
 
 
 
Sample Size 
Approximately 268 to 286 subjects 
Phase 1 Study:  approximately 6 to 24 subjects 
Phase 2 Pivotal Study: approximately 92 subjects enrolled into 2 cohorts 
 Cohort 1:  approximately 72 subjects 
 Cohort 2:  approximately 20 subjects 
Phase 2 Safety Management Study:  approximately 170 subjects enrolled 
and dosed within 4 cohorts 
 Cohort 3:  approximately 40 subjects 
 Cohort 4:  approximately 40 subjects 
 Cohort 5: approximately 50 subjects 
 Cohort 6: approximately 40 subjects 
 
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Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 8 of 118 
 
11 February 2019 
Study Eligibility 
Please refer to Section 5 for a complete and detailed list of inclusion and 
exclusion criteria for both phases of the study.  
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 CAR T cells/kg.  For subjects 
weighing greater than 100 kg, a maximum flat dose of 
2 x 108 anti-CD19 CAR T cells will be administered.  Under 
circumstances where subjects initially respond and subsequently 
relapse, subjects may be eligible for a second course of conditioning 
chemotherapy and axicabtagene ciloleucel.  Refer to Section 6 for 
treatment and Section 7.13.9 for retreatment details. 
Bridging Therapy (Phase 2 Safety Management Study) 
 At the discretion of the investigator, bridging therapy may be 
considered for subjects particularly with high disease burden at 
screening or baseline assessment (eg, bulky disease or rapidly 
progressing disease). 
 For subjects receiving bridging therapy, refer to Section 6 for 
bridging therapy details. 
Debulking Therapy (Phase 2 Safety Management Study, Cohort 5) 
 Debulking therapy should be applied to all subjects enrolled in 
Cohort 5 with the aim of reducing lymphoma burden. Debulking 
therapy is to be administered after leukapheresis and prior to 
administration of conditioning chemotherapy or axicabtagene 
ciloleucel. 
 Refer to Section 6.2.2 for debulking therapy details 
Conditioning Chemotherapy 
 Axicabtagene ciloleucel is administered after a conditioning 
chemotherapy regimen consisting of fludarabine 30 mg/m2/day and 
cyclophosphamide 500 mg/m2/day, administered x 3 days.  Refer to 
Section 6 for chemotherapy treatment details. 
Additional axicabtagene ciloleucel regimens may be explored in Phase 1 
per Section 9.10. 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 9 of 118 
 
11 February 2019 
 
Phase 2 Safety Management Study 
 Subjects assigned to Cohort 3 will receive the same conditioning 
chemotherapy and axicabtagene ciloleucel regimen as described above 
and will also receive prophylactic tocilizumab and levetiracetam for 
toxicity management as outlined in Section 6.3.4 and Section 6.4. 
 Subjects assigned to Cohort 4 will receive the same conditioning 
chemotherapy and axicabtagene ciloleucel regimen as described 
above, but toxicity management will intervene at lower grades of CRS 
and neurologic toxicities as outlined in Section 6.4.1. 
 Subjects assigned to Cohort 5 will receive the same conditioning 
chemotherapy and axicabtagene ciloleucel regimen as other safety 
management cohorts; toxicity management will be completed as 
outlined in Section 6.4.2. 
 Subjects assigned to Cohort 6 will receive the same conditioning 
chemotherapy and axicabtagene ciloleucel regimen as described 
above 
;  toxicity management 
will intervene at lower grades of CRS and neurologic toxicities as 
outlined in Section 6.4.1. 
Procedures 
At specific time points as outlined in the schedule of assessments, subjects 
will undergo the following assessments/procedures: collection of informed 
consent, general medical history including previous treatments for NHL, 
physical exam including vital signs and performance status, neurologic 
assessments, blood draws for complete blood count (CBC), chemistry 
panels, cytokines, C-reactive protein, lymphocyte subsets, anti-
axicabtagene ciloleucel antibodies, replication-competent retrovirus 
(RCR) and anti-CD19 CAR T cell analysis. Women of childbearing 
potential will undergo a urine or serum pregnancy test.  
Subjects will also undergo a baseline electrocardiogram (ECG), 
echocardiogram (ECHO), brain magnetic resonance image (MRI), a 
positron emission tomography–computed tomography (PET-CT), possible 
bone marrow aspirate/biopsy and leukapheresis. 
Subjects assigned to Cohort 3, Cohort 4, Cohort 5, and Cohort 6 will 
complete the EQ-5D questionnaire at baseline and after axicabtagene 
ciloleucel (see Section 7.4 and schedule of assessments [SOA]) infusion 
and will have lumbar punctures performed for the collection of 
cerebrospinal fluid (CSF) (see Section 7.9 and SOA) before and after 
axicabtagene ciloleucel infusion. 
Routinely throughout the conduct of the study, subjects will be asked to 
report concomitant medications and adverse events and will have their 
disease assessed. 
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Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 10 of 118 
 
11 February 2019 
Safety Review 
Team and Data 
Safety Monitoring 
Board 
An SRT, that is internal to the study sponsor and in collaboration with at 
least one study investigator, will review safety data in Phase 1 of the 
study.  The SRT will review the safety data and make recommendations 
on further study conduct of Phase 1 and progression to Phase 2 as depicted 
in Figure 3 and outlined in Section 9.10.   
Phase 2 Pivotal Study:  An independent Data Safety Monitoring Board 
(DSMB) will meet when 20 and 50 subjects in the modified intent-to-treat 
(mITT) set of Cohort 1 have had the opportunity to complete their 3 
month disease assessment. The DSMB will review safety and efficacy 
data and be chartered to make trial conduct recommendations based on an 
analysis of risk vs. benefit.  
Phase 2 Safety Management Study:  The DSMB will meet to review 
Cohort 3, Cohort 4, Cohort 5, and Cohort 6 safety data when 20 subjects 
in each cohort have been treated with axicabtagene ciloleucel and have 
had the opportunity to be followed for 30 days. The DSMB may meet 
more often as needed. Refer to Section 9.11 and Section 9.12. 
Statistical 
Considerations 
Phase 1 Study 
The primary endpoint for the Phase 1 study is the incidence of DLT. 
Phase 2 Pivotal Study 
The primary endpoint for the Phase 2 pivotal study (Cohort 1 and 
Cohort 2) of the study is objective response rate per the revised IWG 
Response Criteria for Malignant Lymphoma (Cheson et al, 2007) as 
determined by the study investigators. This endpoint will be based on a 
modified intent-to-treat (mITT) population consisting of all subjects 
enrolled and treated with axicabtagene ciloleucel at a dose of at least 
1 X 106 anti-CD19 CAR T cells/kg. 
This study uses a single-arm design to test for an improvement in response 
rate 
 
.  For the test of efficacy this study has ≥ 90% power to distinguish 
between an active therapy with a 40% true response rate from a therapy 
with a response rate of 20% or less with a 1-sided alpha level of 0.025.   
 
 
 
 
 
 
 
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Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 11 of 118 
 
11 February 2019 
 
Within Cohort 1, 
 one primary analyses will be performed. 
 
 
 
 
  
 
 
 
 
   
 The primary analysis of Cohort 1 will occur after 72 subjects in the 
mITT set have had the opportunity to be assessed for response 
6 months after the axicabtagene ciloleucel infusion. 
 
 
For Cohort 1 and Cohort 2 combined, 1 primary analysis will be 
performed when 72 subjects in the mITT set in Cohort 1 and 20 subjects 
in the mITT set in Cohort 2 have had the opportunity to be assessed for 
response 6 months after the axicabtagene ciloleucel infusion. 
Phase 2 Safety Management Study  
The primary objective of Cohort 3 is to assess the impact of prophylactic 
regimens on the rate and severity of CRS and neurologic toxicities. 
The primary objective of Cohort 4 is to assess the impact of earlier 
interventions on the incidence and severity of CRS and neurologic 
toxicities. 
The primary objective of Cohort 5 is to assess the impact of debulking 
therapy on the incidence and severity of CRS and neurologic toxicities. 
The primary objective of Cohort 6 is to assess the impact of 
prophylactic steroid use and earlier interventions on the incidence 
and severity of CRS and neurologic toxicities. 
The secondary objectives of Cohort 3, Cohort 4, Cohort 5, and Cohort 6 
include assessment of efficacy endpoints (ORR, DOR, PFS, OS) and 
levels of anti-CD19 CAR T cells and cytokines in the blood.  
Analyses of the safety and efficacy endpoints of this portion of the study 
will be entirely descriptive, with no formal statistical testing being 
performed.  
 
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Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 12 of 118 
 
11 February 2019 
STUDY GLOSSARY 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse event 
ALL 
Acute lymphoblastic leukemia 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCT 
Autologous stem cell transplant 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BBB 
Blood brain barrier 
BUN 
Blood urea nitrogen 
CAR 
Chimeric antigen receptor  
CBC 
Complete blood count 
CLL 
Chronic lymphocytic leukemia 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CPF 
Cell processing facility 
CR 
Complete response 
CRF 
Case report form 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
CSF 
Cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
DSMB 
Data Safety Monitoring Board 
eACT™ 
Engineered autologous cell therapy  
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EQ-5D 
European Quality of Life-5 Dimensions 
FAS 
Full analysis set 
FL 
Follicular lymphoma  
GCP 
Good Clinical Practice 
GOT 
Glutamic-oxaloacetic transaminase 
GPT 
Glutamic-pyruvic transaminase 
HGBCL 
High grade B-cell lymphoma  
HIV 
Human immunodeficiency virus 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 13 of 118 
 
11 February 2019 
Abbreviation or Term 
Definition/Explanation 
HLH 
Hemophagocytic lymphohistiocytosis 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation  
ICU 
Intensive care unit 
ID 
Identification 
IP 
Investigational product 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IRRC 
Independent Radiological Review Committee 
IV 
Intravenous 
IWG 
International Working Group  
LDH 
Lactate dehydrogenase 
LTFU 
Long-term follow-up 
LVEF 
Left ventricular ejection fraction 
mITT 
Modified intent-to-treat 
MMSE 
Mini-Mental Status Exam 
MRI 
Magnetic resonance imaging 
MSGV1 
Murine stem cell virus-based vector 
NaCl 
Sodium chloride 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin lymphoma 
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 
PMBCL 
Primary mediastinal B-cell lymphoma  
PR 
Partial response 
RCR  
Replication-competent retrovirus 
qPCR 
Quantitative polymerase chain reaction 
SAE 
Serious adverse event 
scFv 
Single-chain variable fragment 
SD 
Stable disease 
SMS 
Safety management study 
SOA 
Schedule of assessment 
SPD 
Sum of the product of diameters 
SRT 
Safety review team 
SUSAR 
Suspected unexpected serious adverse reaction 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 14 of 118 
 
11 February 2019 
Abbreviation or Term 
Definition/Explanation 
Study Day 0 
Defined as the first day that axicabtagene ciloleucel is administered to the subject 
TFL 
Transformed follicular lymphoma 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
WBC 
White blood cell 
 


Axicabtagene ciloleucel; KTE-C19 
 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
 
Final 
CONFIDENTIAL 
 
Page 15 of 118 
 
11 February 2019 
Figure 1. 
Study Schema (Phase 1 and Phase 2) 
 
Study KTE-C19-101 is a Phase 1-2 single-arm, open-label, multicenter study evaluating the safety and efficacy of KTE-C19 in subjects with refractory DLBCL, PMBCL and TFL.  
During Phase 1, approximately 6-24 subjects with DLBCL, PMBCL or TFL will be enrolled to evaluate the safety of axicabtagene ciloleucel regimens. A safety review team 
(SRT), internal to the study sponsor, will review the safety data and make recommendations on further study conduct of Phase 1 and progression to Phase 2 as depicted in Figure 3  
and outlined in Section 9.10.   
Upon SRT recommendation, the pivotal Phase 2 will commence and enroll subjects into 2 separate cohorts designated as Cohort 1 and Cohort 2.  
 
Cohort 1 will enroll adult subjects with refractory DLBCL.  
 
Cohort 2 will enroll adult subjects with refractory PMBCL and TFL. Refer to entrance criteria for TFL eligibility requirements. 
Upon completion of enrollment of the Phase 2 pivotal study, the Phase 2 Safety Management Study will commence and enroll subjects into 4 separate cohorts designated as Cohort 
3, Cohort 4, Cohort 5, and Cohort 6. 
 
Cohort 3 will enroll adult subjects with relapsed or refractory transplant ineligible DLBCL, PMBCL, and TFL. 
 
Cohort 4 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL and HGBCL after 2 systemic lines of therapy. 
 
Cohort 5 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy. 
 
Cohort 6 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, or HGBCL after 2 systemic lines of therapy. 
Independent of the phase of the study each subject will follow the same study treatment schedule and procedural requirements. Each subject will follow through the following 
study periods: a screening period, an enrollment/leukapheresis period, a conditioning chemotherapy period, an IP treatment period, a post treatment assessment period and a long 
term follow-up period. 
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Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final 
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TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ............................................................................................................................. 2 
PROTOCOL SYNOPSIS .............................................................................................................................................. 3 
STUDY GLOSSARY .................................................................................................................................................. 12 
TABLE OF CONTENTS ............................................................................................................................................ 16 
LIST OF IN-TEXT TABLES ...................................................................................................................................... 18 
LIST OF IN-TEXT FIGURES .................................................................................................................................... 19 
1. 
OBJECTIVES ..................................................................................................................................................... 20 
2. 
DISEASE BACKGROUND AND RATIONALE .............................................................................................. 21 
2.1. 
Diffuse Large B-cell Lymphoma ........................................................................................................... 21 
2.2. 
Primary Mediastinal B-cell Lymphoma and Transformed Follicular Lymphoma ................................. 22 
2.3. 
High Grade B-cell Lymphoma ............................................................................................................... 23 
2.4. 
Study Rationale ...................................................................................................................................... 23 
2.4.1. 
CD19 and Expression ........................................................................................................... 24 
2.4.2. 
Anti-CD19 CAR T-cell Product ........................................................................................... 24 
2.4.3. 
Prior Experience with Axicabtagene Ciloleucel and other Anti-CD19 
CAR T Cells ......................................................................................................................... 25 
2.4.4. 
Axicabtagene Ciloleucel ....................................................................................................... 25 
3. 
STUDY DESIGN ................................................................................................................................................ 26 
3.1. 
General Study Design ............................................................................................................................ 26 
3.2. 
Participating Sites................................................................................................................................... 29 
3.3. 
Number of Subjects ................................................................................................................................ 29 
3.4. 
Replacement of Subjects ........................................................................................................................ 30 
3.5. 
Study Duration ....................................................................................................................................... 30 
3.5.1. 
Study Duration for Individual Subjects ................................................................................ 30 
3.5.2. 
Completion of the Phase 2 Pivotal Study ............................................................................. 30 
4. 
SUBJECT SCREENING AND ENROLLMENT ............................................................................................... 31 
5. 
SUBJECT ELIGIBILITY ................................................................................................................................... 32 
5.1. 
Inclusion Criteria .................................................................................................................................... 32 
5.2. 
Exclusion Criteria................................................................................................................................... 34 
6. 
PROTOCOL TREATMENT .............................................................................................................................. 37 
6.1. 
Treatment Terminology.......................................................................................................................... 37 
6.2. 
Study Treatment ..................................................................................................................................... 37 
6.2.1. 
Bridging Therapy for Phase 2 Safety Management Study, Cohort 3 
(retreatment), Cohort 4, and Cohort 6 .................................................................................. 37 
6.2.2. 
Debulking Therapy for Phase 2 Safety Management Study, Cohort 5 ................................. 38 
6.2.3. 
Conditioning Chemotherapy ................................................................................................ 39 
6.2.4. 
Axicabtagene Ciloleucel ....................................................................................................... 40 
6.2.5. 
Concomitant Therapy ........................................................................................................... 41 
6.2.6. 
Excluded Medications .......................................................................................................... 41 
6.2.7. 
Subsequent Therapy ............................................................................................................. 42 
6.3. 
Study Treatment Schedule ..................................................................................................................... 42 
6.3.1. 
Leukapheresis (Within Approximately 5 Days of Eligibility 
Confirmation) ....................................................................................................................... 42 
6.3.2. 
Study Treatment ................................................................................................................... 43 
6.3.3. 
Rationale for Study Treatment Dosing ................................................................................. 44 


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6.3.4. 
Study Treatment by Phase .................................................................................................... 50 
6.4. 
Toxicity Management ............................................................................................................................ 53 
6.4.1. 
Phase 2 Safety Management Study (Cohort 4 and Cohort 6 only) ....................................... 53 
6.4.2. 
Phase 2 Safety Management Study (Cohort 5) ..................................................................... 57 
7. 
STUDY PROCEDURES .................................................................................................................................... 58 
7.1. 
Informed Consent ................................................................................................................................... 58 
7.2. 
Demographic Data ................................................................................................................................. 58 
7.3. 
Medical and Treatment History .............................................................................................................. 58 
7.4. 
Physical Exam, Vital Signs, Performance Status, and EQ-5D ............................................................... 58 
7.5. 
Neurological Assessment ....................................................................................................................... 59 
7.6. 
Cardiac Function .................................................................................................................................... 60 
7.7. 
Magnetic Resonance Imaging ................................................................................................................ 60 
7.8. 
Bone Marrow Biopsy ............................................................................................................................. 60 
7.9. 
Lumbar Puncture .................................................................................................................................... 60 
7.10. 
Disease Response Assessment ............................................................................................................... 61 
7.11. 
Laboratory .............................................................................................................................................. 62 
7.12. 
Biomarkers ............................................................................................................................................. 63 
7.13. 
Description of Study Periods .................................................................................................................. 65 
7.13.1. 
Screening .............................................................................................................................. 65 
7.13.2. 
Rescreening .......................................................................................................................... 67 
7.13.3. 
Enrollment/Leukapheresis .................................................................................................... 67 
7.13.4. 
Bridging Therapy Phase 2 Safety Management Study ......................................................... 68 
7.13.5. 
Debulking Therapy Phase 2 Safety Management Study, Cohort 5 ...................................... 68 
7.13.6. 
Conditioning Chemotherapy Period ..................................................................................... 69 
7.13.7. 
Investigational Product Treatment Period ............................................................................ 71 
7.13.8. 
Post-treatment Assessment Period ....................................................................................... 74 
7.13.9. 
Long-term Follow-up Period ................................................................................................ 76 
7.13.10. 
Retreatment .......................................................................................................................... 78 
8. 
SUBJECT WITHDRAWAL ............................................................................................................................... 84 
8.1. 
Reasons for Removal from Treatment ................................................................................................... 84 
8.2. 
Reasons for Removal from Study .......................................................................................................... 85 
9. 
SAFETY REPORTING ...................................................................................................................................... 86 
9.1. 
Adverse Events....................................................................................................................................... 86 
9.2. 
Reporting of Adverse Events ................................................................................................................. 86 
9.2.1. 
Reporting Abnormal Laboratory Findings ........................................................................... 87 
9.3. 
Definition of Serious Adverse Events .................................................................................................... 88 
9.4. 
Reporting of Serious Adverse Events .................................................................................................... 89 
9.5. 
Reporting Deaths .................................................................................................................................... 89 
9.6. 
Diagnosis versus Signs and Symptoms .................................................................................................. 90 
9.7. 
Pregnancy and Lactation ........................................................................................................................ 90 
9.8. 
Hospitalization and Prolonged Hospitalization ...................................................................................... 90 
9.9. 
Abnormal Vital Sign Values .................................................................................................................. 91 
9.10. 
Safety Review Team and Dose-limiting Toxicity .................................................................................. 91 
9.11. 
Data Safety Monitoring Board ............................................................................................................... 93 
9.12. 
Criteria to Pause Enrollment .................................................................................................................. 93 
10. STATISTICAL CONSIDERATIONS ................................................................................................................ 94 
10.1. 
Hypothesis .............................................................................................................................................. 94 
10.2. 
Study Endpoints ..................................................................................................................................... 94 
10.2.1. 
Primary ................................................................................................................................. 94 
10.2.2. 
Secondary ............................................................................................................................. 94 
 
 
CCI-


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10.3. 
Sample Size Considerations ................................................................................................................... 95 
10.3.1. 
Phase 2 Pivotal Study, Cohort 1, and Cohort 2 .................................................................... 96 
10.3.2. 
Phase 2 Safety Management Study ...................................................................................... 97 
10.4. 
Statistical Assumptions .......................................................................................................................... 98 
10.5. 
Analysis Subsets..................................................................................................................................... 98 
10.5.1. 
Phase 1 Study ....................................................................................................................... 98 
10.5.2. 
Phase 2 Study ....................................................................................................................... 99 
10.6. 
Access to Individual Subject Treatment Assignments ........................................................................... 99 
10.7. 
Interim Analysis ................................................................................................................................... 100 
10.7.1. 
Interim Analysis and Early Stopping Rules ....................................................................... 100 
10.7.2. 
Safety Interim Analysis ...................................................................................................... 100 
10.7.3. 
Efficacy Interim Analysis ................................................................................................... 100 
10.8. 
Planned Method of Analysis ................................................................................................................ 101 
10.8.1. 
Objective Response Rate .................................................................................................... 102 
10.8.2. 
Duration of Response ......................................................................................................... 102 
10.8.3. 
Progression-free Survival ................................................................................................... 102 
10.8.4. 
Overall Survival ................................................................................................................. 102 
10.8.5. 
Safety.................................................................................................................................. 102 
10.8.6. 
Long-term Data Analysis ................................................................................................... 102 
11. REGULATORY OBLIGATIONS .................................................................................................................... 103 
11.1. 
Independent Review Board/Independent Ethics Committee ................................................................ 103 
11.2. 
Subject Confidentiality ......................................................................................................................... 103 
11.3. 
Investigator Signatory Obligations ....................................................................................................... 103 
12. PROTOCOL AMENDMENTS AND TERMINATION .................................................................................. 104 
13. STUDY DOCUMENTATION AND ARCHIVE ............................................................................................. 105 
14. STUDY MONITORING AND DATA COLLECTION ................................................................................... 106 
15. PUBLICATION ................................................................................................................................................ 107 
16. COMPENSATION ........................................................................................................................................... 108 
17. REFERENCES ................................................................................................................................................. 109 
18. APPENDICES .................................................................................................................................................. 115 
 
Appendix A 
Revised IWG Response Criteria for Malignant Lymphoma  (Cheson et al, 2007) .............. 116 
Appendix B 
Monitoring of subjects after IP administration per country regulatory agencies: ................. 118 
 
 
LIST OF IN-TEXT TABLES 
 
Table 1. 
Historical Responses in Refractory NHL (SD or PD to Last Line of Therapy) ..................... 22 
Table 2. 
Bridging Therapy Regimens ................................................................................................... 38 
Table 3. 
Debulking Therapy Regimens ................................................................................................ 39 
Table 4. 
Incidence of DLT and Response among Subjects with B-cell Lymphomas and 
Dosed with Group 2 and Group 3 Conditioning Chemotherapy and ≤ 2.5 x 106 anti-
CD19 CAR T Cells ................................................................................................................. 46 
Table 5. 
DLTa Events among Subjects with B-cell Lymphomas and Dosed with ≤ 1-2.0 x 106 
anti-CD19 CAR T Cells and Cyclosphosphamide 30 mg/kg x 2 Days-Fludarabine 
25 mg/m2 x 5 Days ................................................................................................................. 46 
Table 6. 
Tocilizumab and Corticosteroids Use in ZUMA-1 Phase 2 Pivotal Study Primary 
Analysis .................................................................................................................................. 48 


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Clinical Protocol: KTE-C19-101 
Final 
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Table 7. 
Rates of Neurologic Toxicities and CRS in the Phase 1 and 2 Pivotal Study versus 
Phase 2 Safety Management Study Cohort 3 ......................................................................... 49 
Table 8. 
Grading and Management of CRS in Cohort 4 and Cohort 6 ................................................. 53 
Table 9. 
Grading and Management of Neurologic Toxicities in Cohort 4 and Cohort 6 ...................... 55 
Table 10. 
Management of Cerebral Edema in Cohort 4 and Cohort 6 ................................................... 57 
Table 11. 
Schedule of Assessments ........................................................................................................ 80 
Table 12. 
Schedule of Assessments (Long-term Follow-up Period) ...................................................... 83 
 
 
LIST OF IN-TEXT FIGURES 
 
Figure 1. 
Study Schema (Phase 1 and Phase 2) ..................................................................................... 15 
Figure 2. 
Axicabtagene Ciloleucel ......................................................................................................... 25 
Figure 3. 
Phase 1 Dosing Cohorts and Regimens .................................................................................. 27 
Figure 4 
Axicabtagene Ciloleucel Expansion and Correlations with Response and Adverse 
Events ..................................................................................................................................... 48 
 


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1. 
OBJECTIVES 
The primary objective of Phase 1 study is to evaluate the safety of axicabtagene ciloleucel 
regimens.   
The primary objective of Phase 2 pivotal study is to evaluate the efficacy of axicabtagene 
ciloleucel, as measured by objective response rate (ORR) in subjects with diffuse large B-cell 
lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed 
follicular lymphoma (TFL).  Secondary objectives will include assessing the safety and 
tolerability of axicabtagene ciloleucel and additional efficacy endpoints.   
The primary objective of the Phase 2 safety management study is to assess the impact of a 
prophylactic regimen, earlier interventions, debulking therapy, or prophylactic steroid use on 
the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities.  The key 
secondary objectives include assessment of efficacy, levels of anti-CD19 chimeric antigen 
receptor (CAR) T cells, cytokines in blood/serum, and the change in European Quality of Life-5 
Dimensions (EQ-5D) scores from baseline to Month 6. 


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2. 
DISEASE BACKGROUND AND RATIONALE 
Non-Hodgkin lymphoma (NHL) is a heterogeneous group of cancers originating in B 
lymphocytes, T lymphocytes or natural killer cells.  In the United States, B cell lymphomas 
represent 80-85% of cases reported.  In 2013, approximately 69,740 new cases of NHL and over 
19,000 deaths related to the disease were estimated to occur.  Non-Hodgkin lymphoma is the 
most prevalent hematological malignancy and is the seventh leading site of new cancers among 
men and women and account for 4% of all new cancer cases and 3% of deaths related to cancer 
(Howlader et al, 2017).  Large B-cell lymphomas represent the most common sub-group of NHL 
(Rodriguez-Abreu et al, 2007). 
2.1. 
Diffuse Large B-cell Lymphoma 
DLBCL is the most common subtype of large B-cell lymphoma, accounting for approximately 
30% of NHL cases.  There are approximately 22,000 new diagnoses of DLBCL in the United 
States each year.  In the past two decades, progress has been made in understanding the 
biological heterogeneity of DLBCL and in improving survival with combinations of CHOP and 
immunotherapy.  The addition of rituximab into combination therapies for DLBCL have greatly 
improved patient outcomes.  However, patients with chemotherapy-refractory DLBCL following 
treatment under the current standards of care still have a particularly dire prognosis, with no 
curative treatment options (Flowers et al, 2010). 
The population with the highest unmet need continues to consist of patients who do not respond 
to first line combination chemotherapy (typically R-CHOP) or who do not respond to their last 
course of combination chemotherapy, as the disease is mostly insensitive to subsequent 
combination chemotherapy (typically R-ICE, R-ESHAP) (Table 1).  In a review of 64 patients 
with DLBCL with disease progression during first line chemotherapy or only transient response 
(≤90 days) after end of induction treatment, the response rate to second line therapy was 
15% and the median overall survival (OS) was 6 months, and no patient survived more than 
26 months after first diagnosis (Josting et al, 2000).  An analysis of outcome in 1126 patients 
with DLBCL after first line R-CHOP included 33 patients with primary refractory DLBCL who 
received second line therapy with curative intent.  Only 3 (9%) patients were able to receive 
autologous stem cell transplantation (ASCT), and only 1 (3%) patient achieved long term 
survival (Hitz et al, 2010).  Seshadri et al analyzed 120 patients who did not respond to 
second line platinum-based chemotherapy regimens (e.g., R-ICE) and showed that only 
14% responded to their third line therapy (Seshadri et al, 2008).  Ardeshna et al followed 
19 patients with large B-cell lymphoma, and 9 patients with TFL who did not respond to 
second line chemotherapy.  Only 5 of the 28 total patients (18%) responded to third line 
chemotherapy (Ardeshna et al, 2005).  


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Table 1. 
Historical Responses in Refractory NHL (SD or PD to Last Line of 
Therapy) 
Setting 
Outcome to Subsequent Therapy 
Refractory to 1st line 
 
     (Philip et al, 1995) 
ORR 21% 
     (Josting et al, 2000) 
ORR 15%, median OS 6 mos 
     (Ardeshna et al, 2005) 
ORR 0% 
     (Hitz et al, 2010) 
Proceeded to ASCT 9%, 3% survived > 1 year 
     (Telio et al, 2012) 
ORR 23%, median OS 10 mos 
     (Matasar et al, 2013) 
ORR 10% 
      
 
Refractory to 2nd line 
 
     (Moskowitz et al, 1999) 
Median OS 5 mos 
     (Ardeshna et al, 2005) 
ORR 18%, median OS (large B-cell lympohoma) <6 mos 
     (Seshadri et al, 2008) 
ORR 14% 
 
 
Relapsed After  ASCT 
 
     (Nagle et al, 2013) 
Median OS 8 mos 
Abbreviations: ASCT, autologous stem cell transplant; mos, months; NHL, non-Hodgkin lymphoma; ORR, objective response 
rate; OS, overall survival; PD, progressive disease; SD, stable disease. 
These consistently discouraging results demonstrate that new treatment options are urgently 
needed for patients whose tumors have demonstrated a lack of response to chemotherapy.   
This trial will enroll patients with chemo-refractory lymphoma, as evidenced by failure to 
achieve even a transient or partial response to prior biologic and combination chemotherapy or 
by early recurrence after ASCT. 
2.2. 
Primary Mediastinal B-cell Lymphoma and Transformed Follicular 
Lymphoma 
PMBCL has distinct clinical, pathological, and molecular characteristics compared to DLBCL.  
PMBCL is thought to arise from thymic (medullary) B cells and represents approximately 3% of 
patients diagnosed with large B-cell lymphoma.  PMBCL is typically identified in the younger 
adult population in the fourth decade of life with a slight female predominance (Sehn et al, 1998; 
Savage et al, 2006).  Gene expression profiling suggests deregulated pathways in PMBCL 
overlap with Hodgkin lymphoma.  Initial therapy of PMBCL generally includes anthracycline-
containing regimens with rituximab with or without involved field radiotherapy.  A recent 
Phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and 
cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) demonstrated 
radiotherapy may not be required (Dunleavy et al, 2013). 


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Follicular lymphoma (FL), a B cell lymphoma, is the most common indolent (slow-growing) 
form of NHL, accounting for approximately 20% to 30% of all NHLs.  Some patients with FL 
will transform (TFL) histologically to DLBCL which is more aggressive and associated with a 
poor outcome.  Histological transformation to DLBCL occurs at an annual rate of approximately 
3% for 15 years with the risk of transformation continuing to drop in subsequent years.  The 
biologic mechanism of histologic transformation is unknown.  Initial treatment of TFL is 
influenced by prior therapies for follicular lymphoma but generally includes 
anthracycline-containing regimens with rituximab to eliminate the aggressive component of the 
disease (National Comprehensive Cancer Network 2014). 
Treatment options for relapsed/refractory PMBCL and TFL are similar to those in DLBCL.  
Given the low prevalence of these diseases, no large prospective randomized studies in these 
patient populations have been conducted.  Patients with chemotherapy refractory disease have a 
similar or worse prognosis (Kuruvilla et al, 2008) to those with refractory DLBCL. 
In addition, the international, multicohort retrospective non-Hodgkin lymphoma research 
(SCHOLAR-1) study retrospectively evaluated outcomes in patients with chemorefractory 
DLBCL, PMBCL, and TFL.  SCHOLAR-1 integrated data from two Phase 3 studies 
(LYSARC-CORAL and Canadian Cancer Trials Group LY.12) and 2 observational cohorts 
(MD Anderson Cancer Center and Mayo Clinic/University of Iowa Specialized Program of 
Research Excellence).  Among 861 patients, 635 were included based on chemorefractory search 
criteria.  Outcomes were consistently poor, regardless of refractory subgroup and across cohorts.  
The results of SCHOLAR-1 indicated that patients with chemorefractory, aggressive DLBCL 
represent a homogenous patient population with a response rate of 26% (complete response [CR] 
rate of 7%) and median overall survival of 6.3 months (Crump et al, 2017). 
2.3. 
High Grade B-cell Lymphoma  
In 2016, the World Health Organization introduced a new category of large B-cell lymphomas 
called high-grade B-cell lymphoma (HGBCL) (Swerdlow et al, 2016).  This designation includes 
large B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements that are 
phenotypically intermediate to DLBCL or B-cell lymphoma, unclassifiable (this latter category 
has since been eliminated).  MYC rearrangements in large B-cell lymphomas are associated with 
a poor prognosis that is worsened in cases of concomitant BCL2 and/or BCL6 alterations, 
ie, double- or triple-hit lymphomas.  As such, patients with HGBCL are likely to face poor 
survival outcomes. 
In summary, axicabtagene ciloleucel may provide a viable treatment option to relapsed/refractory 
large B-cell lymphoma patients with no other curative alternatives. 
2.4. 
Study Rationale 
As most advanced cancers eventually become refractory to conventional therapies, new 
treatment modalities are needed.  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 destroying diseased cells throughout the body.  Studies with 
immune checkpoint inhibitors and tumor infiltrating lymphocytes have demonstrated the 


Axicabtagene ciloleucel; KTE-C19 
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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.  Engineered T cells are a promising approach for cancer therapy (Kershaw et al, 2013). 
Engineered autologous cell therapy (eACT™) is a process by which a patient’s own T cells are 
collected and subsequently genetically altered to recognize and target antigens expressed on the 
cell surface of specific malignancies (Kochenderfer et al, 2013).  The ability to genetically 
engineer human T cells and use them to mediate cancer regression in patients has been 
demonstrated in a number of studies and has opened possibilities for the treatment of patients 
with a wide variety of cancer types including B cell malignancies expressing the CD19 antigen. 
2.4.1. 
CD19 and Expression 
CD19 is a 95 kDa transmembrane protein expressed only in the B cell lineage.  It is expressed in 
all normal B cells starting at the pre-B cell stage until the final differentiation stage and is not 
expressed in pluripotent hematopoietic stem cells or most plasma cells.  The pattern of CD19 
expression is maintained in B cell malignancies including all subtypes of B cell NHL, chronic 
lymphocytic leukemia (CLL), and non-T-cell acute lymphoblastic leukemia (ALL) (Blanc et al, 
2011) with the exception of multiple myeloma. 
2.4.2. 
Anti-CD19 CAR T-cell Product 
Anti-CD19 CAR T cells are autologous human T cells that have been engineered to express an 
extracellular single-chain variable fragment (scFv) with specificity for CD19 linked to an 
intracellular signaling part comprised of signaling domains from CD28 and CD3ζ (CD3-zeta) 
molecules arranged in tandem.  
An anti-CD19 CAR vector construct has been designed, optimized and initially tested at the 
Surgery Branch of the National Cancer Institute (NCI, IND 13871) (Figure 2) (Kochenderfer et 
al, 2009; Kochenderfer et al, 2010).  The scFv is derived from the variable region of the 
anti-CD19 monoclonal antibody FMC63 (Nicholson et al, 1997).  A portion of the CD28 
costimulatory molecule is added, as murine models suggest this is important for the anti-tumor 
effect and persistence of anti-CD19 CAR T cells (Kowolik et al, 2006).  The signaling domain of 
the CD3-zeta chain is essential for T cell activation.  These fragments were cloned into the 
murine stem 
 vector, utilized to genetically engineer the autologous T 
cells.  Treatment with anti-CD19 CAR T cells is currently being administered to subjects with 
CD19+ B cell malignancies in ongoing NCI protocol (09-C-0082; IND 13871).  
 
 
The CAR construct is inserted into the T cells’ genome by retroviral vector transduction.  
Briefly, peripheral blood mononuclear cells (PBMCs) are obtained by leukapheresis and Ficoll 
separation.  
 
  Stimulated cells are transduced 
with a retroviral vector containing an anti-CD19 CAR gene and propagated in culture to generate 
sufficient engineered T cells for administration.   
CCI
CCI
CCI


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Figure 2. 
Axicabtagene Ciloleucel  
 
 
2.4.3. 
Prior Experience with Axicabtagene Ciloleucel and other Anti-CD19 
CAR T Cells  
Refer to the current axicabtagene ciloleucel Investigator’s Brochure (IB) for the most current 
anti-CD19 CAR T-cell study results. 
2.4.4. 
Axicabtagene Ciloleucel 
Kite Pharma, Inc., (hereafter referred to as Kite Pharma or Kite) is developing an eACT™ 
(axicabtagene ciloleucel) that targets CD19 expression on B cell malignancies. 
 
 
  Kite Pharma in conjunction 
with the NCI Surgery Branch has developed a rapid, closed, and bead-less process for the 
generation of the anti-CD19 CAR T cells.  Closing the process retains the characteristics of the 
T cell product (Better et al, 2014).  See the investigational product manual for more details. 
CCI
CD28 
S'LTR 
scFv 
CD3{ 
3'LTR 
CAR vector construct 
Viral vector 
Target binding domain: 
antibody derived (scfv) 
CAR-engineered 
Tcell 
CAR-engineered 
Tcell 
Tumor cell 


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3. 
STUDY DESIGN 
3.1. 
General Study Design 
Study KTE-C19-101 is a Phase 1-2 multicenter, open-label study evaluating the safety and 
efficacy of axicabtagene ciloleucel in subjects with refractory NHL.  Study KTE-C19-101 will 
be separated into 3 distinct phases designated as Phase 1 study, Phase 2 pivotal study (Cohort 1 
and Cohort 2), and Phase 2 safety management study (Cohort 3,Cohort 4, Cohort 5, and 
Cohort 6). 
Phase 1 Study 
During Phase 1, approximately 6 to 24 subjects with DLBCL, PMBCL, or TFL will be enrolled 
to evaluate the safety of axicabtagene ciloleucel regimens.  If the initial regimen is determined to 
be safe, a higher dose of conditioning chemotherapy may be investigated.  If the regimen is 
determined to not be safe, reduced doses of conditioning chemotherapy and/or axicabtagene 
ciloleucel may be explored.  A safety review team (SRT), internal to the study sponsor, will 
review the safety data and make recommendations on further study conduct of Phase 1 and 
progression to Phase 2 as depicted in Figure 3 and outlined in Section 9.10. 


Axicabtagene ciloleucel; KTE-C19 
Clinical Protocol: KTE-Cl 9-101 
Figure 3. 
Phase 1 Dosing Cohorts and Regimens 
Yes* 
*May be explored: see Section 9.6 
CONFIDENTIAL 
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Kite Phanna, Inc. 
Final 
No 
11 Februaiy 2019 


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Phase 2 Pivotal Study 
In Phase 2 pivotal study, subjects will enroll into 2 separate cohorts designated as Cohort 1 and 
Cohort 2. 
 Cohort 1 will enroll adult subjects with refractory DLBCL.  
 Cohort 2 will enroll adult subjects with refractory PMBCL and TFL. 
 TFL is defined as subjects who received prior chemotherapy for follicular lymphoma. 
During the Phase 2 pivotal study, an independent data safety monitoring board (DSMB) will 
meet when 20 and 50 subjects in the modified intent-to-treat (mITT) set of Cohort 1 have had the 
opportunity to complete the 3 month disease assessment.  The DSMB will review safety and 
efficacy data and be chartered to make trial conduct recommendations based on an analysis of 
risk vs. benefit.   
Phase 2 Safety Management Study (SMS) 
In the Phase 2 safety management study (SMS), subjects will enroll into 4 separate cohorts 
designated as Cohort 3, Cohort 4, Cohort 5, and Cohort 6.  
 Cohort 3 will enroll adult subjects with relapsed or refractory transplant ineligible DLBCL, 
PMBCL, or TFL. 
 Cohort 4 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, or 
HGBCL after 2 systemic lines of therapy. 
 Cohort 5 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, or 
HGBCL after 2 systemic lines of therapy. 
 Cohort 6 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, 
or HGBCL after 2 systemic lines of therapy. 
The DSMB will meet to review safety data when 20 subjects in each Cohort 3, Cohort 4, 
Cohort 5, and Cohort 6 have been treated with axicabtagene ciloleucel and have had the 
opportunity to be followed for 30 days.  The DSMB may meet more often as needed. 
Independent of the phase of the study each subject will follow the same study treatment schedule 
and procedural requirements. Each subject will proceed through the following study periods: 
 Screening period 
 Enrollment/Leukapheresis period 
 Bridging therapy (if applicable, for Phase 2 SMS) or debulking therapy (if applicable, 
Phase 2 SMS, Cohort 5)  


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 Conditioning chemotherapy period  
 Investigational product (IP) treatment period 
 Post treatment assessment period 
 Long-term follow-up period 
For study requirements assigned to each study period, please refer to the schedule of assessments 
(SOA) and Section 7 for details. 
A study schema is drawn out and described at the end of the protocol synopsis section. 
3.2. 
Participating Sites 
Approximately 35 centers located in North America and Europe will participate in this study.  
During the conduct of the study, additional regions, countries or sites may be added as necessary. 
3.3. 
Number of Subjects 
Participants in this trial will be referred to as “subjects”.  It is anticipated that approximately 
268 to 286 subjects will be enrolled and dosed in this study as defined below: 
Phase 1 study:  approximately 6 to 24 subjects 
Phase 2 pivotal study:  approximately 92 subjects enrolled into 2 cohorts 
 Cohort 1:  approximately 72 subjects 
 Cohort 2:  approximately 20 subjects 
Phase 2 safety management study:  approximately 170 subjects enrolled and dosed within 
4 cohorts 
 Cohort 3:  approximately 40 subjects 
 Cohort 4:  approximately 40 subjects 
 Cohort 5:  approximately 50 subjects 
 Cohort 6:  approximately 40 subjects 
It should be noted that Kite Pharma may choose to close enrollment at any time.  Please refer to 
the statistical considerations section of the protocol for sample size estimations. 


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3.4. 
Replacement of Subjects 
Subjects will continue to be enrolled until the specified number of subjects are attained in the 
dose-limiting toxicity (DLT) evaluable (Phase 1) and mITT sets (Phase 2).  Subjects who have 
not received the target dose of axicabtagene ciloleucel will be retained in the analyses of 
disposition and safety, where appropriate (Section 10.5). 
3.5. 
Study Duration 
3.5.1. 
Study Duration for Individual Subjects  
The duration of the study for individual subjects will vary.  For a subject who completes the 
entire protocol from the date of informed consent through the completion of the long term 
follow-up period, the duration of the study will take approximately 15 years to complete.  
However, individual study duration will vary depending on a subject’s screening requirements, 
response to treatment and survival.  
The need for prolonged follow-up is based on the potential persistence of gene transfer vectors in 
treated subjects. 
3.5.2. 
Completion of the Phase 2 Pivotal Study 
Completion of the study is defined as the time at which the last subject completes the long-term 
follow-up period visit, is considered lost to follow-up, withdraws consent, or dies.  The primary 
analyses will be conducted when 72 subjects in the mITT set of the Phase 2 pivotal Cohort 1 and 
20 subjects in the mITT set of Cohort 2 have completed the 6 month disease response 
assessment, are lost to follow-up, withdraw from the study, or die, whichever occurs first. 


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4. 
SUBJECT SCREENING AND ENROLLMENT 
All subjects must sign and date the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) approved consent form before initiating any study specific procedures or activities 
that are not part of a subject’s routine care.  Refer to Section 7 for details. 
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 before any study 
specific procedures or activities are initiated.  This number will be used to identify the subject 
throughout the study and must be used on all study documentation related to the subject.  
Furthermore, the subject identification number must remain constant throughout the entire 
clinical study, it must not be changed after enrollment or if the subject is rescreened or retreated. 


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5. 
SUBJECT ELIGIBILITY 
5.1. 
Inclusion Criteria   
101) 
Histologically confirmed aggressive B cell NHL, including the following types defined 
by WHO 2008 (Campo et al, 2011): 
 DLBCL not otherwise specified; T cell/histiocyte rich large B cell lymphoma; DLBCL 
associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; 
or 
 primary mediastinal (thymic) large B cell lymphoma 
 transformation of follicular lymphoma to DLBCL will also be included  
102) 
Chemotherapy-refractory disease, defined as one or more of the following: 
 No response to first-line therapy (primary refractory disease); subjects who are intolerant 
to first-line therapy chemotherapy are excluded 
 Progressive disease (PD) as best response to first-line therapy 
 Stable disease (SD) as best response after at least 4 cycles of first-line therapy (e.g., 4 
cycles of R-CHOP) with SD duration no longer than 6 months from last dose of 
therapy 
or 
 No response to second or greater lines of therapy 
 PD as best response to most recent therapy regimen 
 SD as best response after at least 2 cycles of last line of therapy with SD duration no 
longer than 6 months from last dose of therapy 
or 
 Refractory post-ASCT 
 Disease progression or relapsed ≤ 12 months of ASCT (must have biopsy proven 
recurrence in relapsed subjects) 
 if salvage therapy is given post-ASCT, the subject must have had no response to or 
relapsed after the last line of therapy 


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103) 
Subjects must have received adequate prior therapy including at a minimum:  
a) anti-CD20 monoclonal antibody unless investigator determines that tumor is 
CD20 negative, and  
b) an anthracycline containing chemotherapy regimen; 
c) for subjects with transformed FL must have chemorefractory disease after transformation 
to DLBCL 
104) 
At least 1 measurable lesion according to the revised International Working Group (IWG) 
Response Criteria for Malignant Lymphoma (Cheson et al, 2007).  Lesions that have 
been previously irradiated will be considered measurable only if progression has been 
documented following completion of radiation therapy 
105) 
Magnetic resonance imaging (MRI) of the brain showing no evidence of central nervous 
system (CNS) lymphoma 
106) 
At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior 
systemic therapy at the time the subject is planned for leukapheresis, except for systemic 
inhibitory/stimulatory immune checkpoint therapy. At least 3 half-lives must have 
elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule 
therapy at the time the subject is planned for leukapheresis (e.g. ipilimumab, nivolumab, 
pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc).  
107) 
Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for 
clinically non-significant toxicities such as alopecia) 
108) 
Age 18 or older 
109) 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
110) 
Absolute neutrophil count (ANC) ≥ 1000/uL 
111) 
Platelet count ≥ 75,000/uL 
112) 
Absolute lymphocyte count ≥ 100/uL 
113) 
Adequate renal, hepatic, pulmonary and cardiac function defined as: 
a) Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min 
b) Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2.5 upper limit 
of normal (ULN) 
c) Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert’s syndrome 


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d) Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an 
echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings 
e) No clinically significant pleural effusion 
f) Baseline oxygen saturation >92% on room air  
114) 
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) 
Additional criteria specific for Phase 2 safety management study (Cohorts 3, 4, 5 and 6): 
115) 
Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL, and 
HGBCL after two systemic lines of therapy 
5.2. 
Exclusion Criteria 
201) 
History of malignancy other than nonmelanoma skin cancer or carcinoma in situ 
(e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 
3 years  
202) 
History of Richter’s transformation of CLL 
203) 
Autologous stem cell transplant with therapeutic intent within 6 weeks of planned 
axicabtagene ciloleucel infusion 
204) 
History of allogeneic stem cell transplantation 
205) 
Prior CD19 targeted therapy with the exception of subjects who received axicabtagene 
ciloleucel in this study and are eligible for re-treatment 
206) 
Prior chimeric antigen receptor therapy or other genetically modified T cell therapy 
207) 
History of severe, immediate hypersensitivity reaction attributed to aminoglycosides  
208) 
Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or 
requiring intravenous (IV) antimicrobials for management.   
209) 
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 (IDSA) guidelines or applicable country 
guidelines.  


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210) 
Presence of any indwelling line or drain (e.g., 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  
211) 
Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with 
a history of CNS lymphoma or primary CNS lymphoma, cerebrospinal fluid malignant 
cells or brain metastases 
212) 
History or presence of CNS disorder such as seizure disorder, cerebrovascular 
ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS 
involvement  
213) 
Subjects with cardiac atrial or cardiac ventricular lymphoma involvement 
214) 
History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or 
other clinically significant cardiac disease within 12 months of enrollment 
215) 
Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or 
impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome) 
216) 
Primary immunodeficiency  
217) 
History of symptomatic deep vein thrombosis or pulmonary embolism requiring 
systemic anticoagulation 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 
221) 
Women of child-bearing 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 both genders who are not willing to practice birth control from the time of 
consent through 6 months after the completion of conditioning chemotherapy 
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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224) 
History of autoimmune disease (e.g. Crohn’s, rheumatoid arthritis, systemic lupus) 
resulting in end organ injury or requiring systemic immunosuppression/systemic disease 
modifying agents within the last 2 years 


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6. 
PROTOCOL TREATMENT  
6.1. 
Treatment Terminology 
The following terms will be used to describe and define protocol treatment:  
 Bridging therapy refers to treatment used to control a subject’s disease prior to conditioning 
chemotherapy 
 Debulking therapy refers to treatment used to reduce a subject’s disease prior to conditioning 
chemotherapy 
 The conditioning chemotherapy regimen used for this study will be fludarabine and 
cyclophosphamide.   
 The investigational product for this study is named axicabtagene ciloleucel.   
 The term study treatment refers to all protocol required therapies. 
6.2. 
Study Treatment 
6.2.1. 
Bridging Therapy for Phase 2 Safety Management Study, Cohort 3 
(retreatment), Cohort 4, and Cohort 6 
Bridging therapy will be supplied by the investigative site unless otherwise noted.  Sites should 
refer to the current product label for guidance on packaging, storage, preparation, administration, 
and toxicity management of bridging therapy. 
At the discretion of the investigator, bridging therapy may be considered for subjects retreated in 
Cohort 3 or enrolled in Cohort 4 and Cohort 6 with high disease burden at screening or baseline 
assessments (eg, bulky disease or rapidly progressing disease).  Allowed bridging therapy 
regimens are outlined in Table 2. Other bridging regimens may be considered but need to be 
discussed with the medical monitor on a case-by-case basis. 


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Table 2. 
Bridging Therapy Regimens 
Type 
Therapy Regimensa 
Timing and Washout Requirements 
Corticosteroid 
Dexamethasone at a dose of 20 mg to 40 mg or 
equivalent, either PO or IV daily for 1 to 
4 days. 
 
Choice of corticosteroid and dose can be 
adjusted for age/comorbidities or per local or 
institutional guidelines 
May be administered after 
apheresis/enrollment and must be 
completed prior to the start of 
conditioning chemotherapy 
 
Note: Chemistry panel and CBC with 
differential must be repeated prior to 
start of conditioning chemotherapy to 
confirm eligibility to proceed therapy. 
HDMP + 
Rituximab 
(Castro et al, 
2009) 
1 gram/m2 of high dose methylprednisolone 
(HDMP) for 3 days in combination with 
rituximab at 375 mg/m2 weekly for 3 weeks 
May be administered after enrollment 
and completed at least 7 days prior to the 
start of conditioning chemotherapy 
 
Note: Chemistry panel and CBC with 
differential must be repeated prior to 
start of conditioning chemotherapy to 
confirm eligibility to proceed. 
Combination 
Chemotherapy 
(Vacirca et al, 
2014) 
(Ohmachi et 
al, 2013) 
B-R: Bendamustine (90 mg/m2, Day 1+2); 
Rituximab (375 mg/m2, Day 1) 
May be administered after enrollment 
and completed at least 14 days prior to 
the start of conditioning chemotherapy, 
and subjects must remain eligible per the 
eligibility criteria outlined in Section 5 
prior to the start of conditioning 
chemotherapy 
 
Note: Chemistry panel and CBC with 
differential must be repeated prior to 
start of conditioning chemotherapy to 
confirm eligibility to proceed.   
Abbreviations: IV, intravenous; CBC, complete blood count. 
a. 
The bridging therapy regimen may be chosen at the discretion of the investigator 
6.2.2. 
Debulking Therapy for Phase 2 Safety Management Study, Cohort 5 
Subjects enrolled into the Phase 2 Safety Management Study, Cohort 5 should receive debulking 
therapy to reduce lymphoma burden. Debulking therapy options are outlined in Table 3. Other 
debulking treatment options may be considered in select cases and must be discussed with the 
Kite medical monitor. The goal of the debulking therapy should be to optimally reduce 
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Table 3. 
Debulking Therapy Regimens 
Type 
Proposed Regimena 
Timing/Washout 
R-CHOP 
(Feugier et al, 2005) 
Rituximab 375 mg/m2 Day 1 
Doxorubicin 50 mg/m2 Day 1 
Prednisone 100 mg Day 1 through Day 5 
Cyclophosphamide 750 mg/m2 Day 1 
Vincristine 1.4 mg/m2 Day 1 
Should be administered after 
leukapheresis/enrollment and 
should be completed 
at least 14 days prior to the 
start of conditioning 
chemotherapy 
R-ICE 
(Gisselbrecht et al, 
2010)  
Rituximab 375 mg/m2 Day 1 
Ifosfamide 5 g/m2 24h-CI Day 2 
Carboplatin AUC5 Day 2 maximum dose 800 mg 
Etoposide 100 mg/m2 /d Days 1 through Day 3 
R-GEMOX 
(Mounier et al, 2013)  
Rituximab 375 mg/m2 Day 1 
Gemcitabine 1000 mg/m2 Day 2  
Oxaliplatin 100 mg/m2 Day 2 
R-GDP 
(Crump et al, 2004) 
(Gopal et al, 2010)  
Rituximab 375 mg/m2 Day 1 (or Day 8) 
Gemcitabine 1 g/m2 on Day 1 and Day 8 
Dexamethasone 40 mg on Day 1 through Day 4 
Cisplatin 75 mg/m2 on Day 1 (or carboplatin AUC5 on 
Day 1)  
Radiotherapyb 
Per local standard up to 20 to 30 Gy 
Should be administered after 
leukapheresis/enrollment and 
should be completed 
at least 5 days prior to the 
start of conditioning 
chemotherapy  
Abbreviations: AUC, area under the curve. 
a 
Other debulking treatment options may be used, but must be discussed with the medical monitor. Supportive care with 
hydration, anti-emesis, mesna, growth factor support, and tumor lysis prophylaxis according to local standard may be used. 
More than 1 cycle allowed. 
b 
At least 1 target lesion should remain outside of the radiation field to allow for tumor measurements 
6.2.3. 
Conditioning Chemotherapy 
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. 
6.2.3.1. 
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. 


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6.2.3.2. 
Cyclophosphamide 
Cyclophosphamide is a nitrogen mustard-derivative alkylating agent.  Following conversion to 
active metabolites in the liver, cyclophosphamide functions as an alkylating agent; the drug also 
possesses potent immunosuppressive activity.  The serum half-life after IV administration ranges 
from 3-12 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. 
6.2.3.3. 
Mesna 
Mesna is a detoxifying agent used to inhibit the hemorrhagic cystitis induced by chemotherapy.  
The active ingredient in mesna is a synthetic sulfhydryl compound designated as 
sodium-2-mercaptoethane sulfonate with a molecular formula of C2H5NaO3S2.  
Mesna should be administered per institutional guidelines.  Refer to the most recent version of 
the package insert for specific details surrounding the administration of mesna. 
6.2.4. 
Axicabtagene Ciloleucel  
Refer to the most current IB regarding axicabtagene ciloleucel and clinical experience.  This 
section contains general information and is not intended to provide specific instructions.  Refer 
to the investigational product manual for details and instruction on storage and administration.   
Axicabtagene ciloleucel is supplied cryopreserved in cryostorage bags.  
 
  The cryostorage bags containing axicabtagene 
ciloleucel arrive frozen in a liquid nitrogen dry shipper.  The bags must be stored in vapor phase 
of liquid nitrogen and the product remains frozen until the subject is ready for treatment to assure 
viable live autologous cells are administered to the subject. Several inactive ingredients are 
added to the product to assure viability and stability of the live cells through the freezing, 
thawing, and infusion process. 
Axicabtagene ciloleucel is a subject-specific product and the intended subject will be identified 
by a unique subject ID number.  Upon receipt, verification that the product and subject-specific 
labels match the subject’s information (e.g., initials, subject ID number) is essential.  Do not 
infuse the product if the information on the subject-specific label does not match the intended 
subject.  The volume of axicabtagene ciloleucel infused, the thaw start/stop time, and 
axicabtagene ciloleucel administration start/stop time, will all be noted in the subject medical 
record.  The product must not be thawed until the subject is ready for the infusion.  Refer to the 
Investigational Product Manual for details and instruction on storage, thawing, and 
administration of axicabtagene ciloleucel.   
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To date, subjects have received doses of anti-CD19 CAR T cells ranging from 1-30 x 106 
anti-CD19 CAR T cells/kg.  There have been no instances of accidental overdose of subjects in 
this program.  In case of accidental overdose, treatment should be supportive.  Corticosteroid 
therapy may be considered if any dose is associated with severe toxicity. 
If any problems related to the use of axicabtagene ciloleucel or any products that support the 
management of axicabtagene ciloleucel (eg, cryostorage bags, subject identification labels) 
required in this study are identified, please log on to www.kitepharma.com to report the 
complaint. 
6.2.5. 
Concomitant Therapy 
During the course of the study, investigators may prescribe any concomitant medications or 
treatment deemed necessary to provide adequate supportive care except those medications listed 
in Section 6.2.6. 
All concurrent therapies, including medications, intubation, dialysis, oxygen, and blood products, 
will be recorded from the date of the informed consent through 3 months after completing 
treatment with axicabtagene ciloleucel.  After 3 months of follow-up, only targeted concomitant 
medication will be collected for 24 months after axicabtagene ciloleucel infusion or disease 
progression, whichever occurs first.  Targeted concomitant medications include gammaglobulin, 
immunosuppressive drugs, anti-infective drugs, and vaccinations.   
For subjects who are enrolled but not dosed with axicabtagene ciloleucel, concurrent therapies 
will only be recorded from the date of the informed consent through 30 days after the last study 
specific procedure (e.g., leukapheresis, conditioning chemotherapy).  For subjects who are not 
enrolled (e.g., screen failure or not leukapheresed), only concurrent therapies related to any 
serious adverse event(s) will be recorded. 
Specific concomitant medication collection requirements and instructions are included in the 
case report form (CRF) completion guidelines. 
6.2.6. 
Excluded Medications 
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. For the prophylactic 
use of steroid for Cohort 6, refer to Section 7.13.7.   
Corticosteroids and other immunosuppressive drugs should also be avoided for 3 months after 
axicabtagene ciloleucel administration, unless used to manage axicabtagene ciloleucel related 
toxicities (refer to the most current version of the IB).  Other medications that might interfere 
with the evaluation of the investigational product, such as non-steroidal anti-inflammatory agents 
should also be avoided for the same time period unless medically necessary.   


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Treatment for lymphoma such as chemotherapy, immunotherapy, targeted agents, radiation, and 
high dose corticosteroid, other than defined/allowed in this protocol, and other investigational 
agents are prohibited, except as needed for treatment of disease progression after the 
axicabtagene ciloleucel infusion. 
If permissibility of a specific medication/treatment is in question, please contact the Kite Pharma 
Medical Monitor. 
6.2.7. 
Subsequent Therapy  
Subsequent therapy administered after the axicabtagene ciloleucel infusion for a subject’s 
disease, such as non-study specified chemotherapy, immunotherapy, targeted agents, as well as 
stem cell transplant and radiation therapy, will be recorded until the subject completes the 
long-term follow-up period, 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-cancer therapy will also be collected until the subject completes the long-term follow-up 
period, is considered lost to follow up, withdraws consent, or dies. 
6.3. 
Study Treatment Schedule 
6.3.1. 
Leukapheresis (Within Approximately 5 Days of Eligibility Confirmation) 
Subjects will undergo leukapheresis to obtain leukocytes (white blood cells) for the 
manufacturing of axicabtagene ciloleucel.  Leukapheresed cells obtained at participating centers 
will be shipped to the cell processing facility (CPF) overnight as described in the Investigational 
Product Manual.  Once a subject commences leukapheresis, the subject is considered enrolled in 
the study. 
Mononuclear cells will be obtained by leukapheresis (
 with a goal to target 
 mononuclear cells).  The leukapheresed cells are then packaged for 
expedited shipment to the CPF as described in the investigational product manual.  
Upon arrival at the CPF, each subject’s leukapheresed product will be processed to enrich for the 
T cells containing PBMC fraction.  T cells are then stimulated to expand and transduced with a 
retroviral vector to introduce the CAR gene.  The T cells are then expanded and cryopreserved to 
generate the investigational product per CPF standard operating procedures (SOPs).  Once the 
product has passed certain release tests, it will be shipped back to the treating facility.  Following 
completion of each subject’s conditioning chemotherapy regimen, subjects will receive their 
respective axicabtagene ciloleucel infusion.   
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6.3.2. 
Study Treatment  
6.3.2.1. 
Chemotherapy General Instructions 
Subjects will receive a non-myeloablative conditioning regimen consisting of cyclophosphamide 
and fludarabine in order to induce lymphocyte depletion and create an optimal environment for 
expansion of axicabtagene ciloleucel in vivo.  Subjects will initiate conditioning chemotherapy 
with cyclophosphamide and fludarabine beginning on Day -5 (or Day -7 for Cohort B) through 
Day -1.  The 5-day conditioning chemotherapy regimen may be administered in an outpatient 
setting.  The 7-day conditioning chemotherapy regimen may be administered as an outpatient or 
inpatient regimen per investigator’s discretion.  
Subjects should be instructed to drink plenty of liquids during and for 24 hours following the 
chemotherapy.  In general, subjects should be kept well-hydrated but closely monitored to 
prevent fluid overload.  
For subjects enrolled into the Phase 2 Safety Management Study, Cohort 5 and Cohort 6: 
Subjects who have not recovered their white blood cell (WBC) count by the time conditioning 
chemotherapy is scheduled to start, may skip the conditioning chemotherapy if the WBC is 
≤ 1000/µL at this time. This option must be discussed with the Kite medical monitor.  
6.3.2.2. 
Axicabtagene Ciloleucel General Instructions 
All subjects will receive axicabtagene ciloleucel infusion at a healthcare facility, followed by 
daily monitoring at a healthcare facility for at least 7 days unless otherwise required by country 
regulatory agencies (refer to Appendix B) to monitor for signs and symptoms of CRS and 
neurologic toxicities.  Subjects should be instructed to remain within proximity of the clinical 
study site for at least 4 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.  
Alternatively, subjects may be hospitalized to receive their axicabtagene ciloleucel infusion and 
be observed for CRS and neurologic toxicities in the hospital setting, if deemed appropriate by 
the investigator.   
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 return to 
baseline.  Subjects may be discharged with non-critical and clinically stable or improving 
toxicities (e.g., renal insufficiency) even if > 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 toxicities > Grade 1, or if deemed necessary 
by the investigator.  


Axicabtagene ciloleucel; KTE-C19 
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Clinical Protocol: KTE-C19-101 
Final 
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The following medications should be administered approximately 1 hour prior to axicabtagene 
ciloleucel infusion.  Alternatives to the recommendations below should be discussed with the 
medical monitor. 
 Acetaminophen 
 PO 
 Diphenhydramine (
 PO) 
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 Investigational Product Manual.  The Investigational 
Product Manual must be reviewed prior to administration of axicabtagene ciloleucel.   
Research sites should follow institutional guidelines for the infusion of cell products. 
6.3.3. 
Rationale for Study Treatment Dosing  
6.3.3.1. 
Rationale for Conditioning Chemotherapy Dose in Phase 1 Cohort A1 
Increasing levels of conditioning chemotherapy correlates with clinical responses to adoptive cell 
therapy (Dudley et al, 2008).  Specifically, there appears to be a link between adequate 
lymphodepletion and adoptively transferred T cell expansion and function in pre-clinical models.  
The depth and duration of the lymphodepletion in preclinical models correlate with anti-tumor 
activity of the adoptively transferred tumor-specific CD8+ T cells (Gattinoni et al, 2005).  
Lymphodepletion may function by eradicating cytokine sinks for the transferred cells, 
eliminating T regulatory cells, or enhancing antigen presenting cell activation (Klebanoff et al, 
2005).  Cyclophosphamide and fludarabine is a potent lymphodepleting regimen.  Optimizing the 
doses of cyclophosphamide and fludarabine to improve the depth and duration of 
lymphodepletion may enhance the activity of axicabtagene ciloleucel.   
As described in the IB, the NCI study (09-C-0082; IND 13871) evaluated three groups of 
subjects based on conditioning regimens.  Group 3 evaluated cyclophosphamide (300 mg/m2) 
and fludarabine (30 mg/m2), both given for 3 concurrent days followed by 1-2 x 106 anti-CD19 
CAR T cells.  Eleven subjects were treated with this regimen.   
The DLT definition in the KTE-C19-101 study was applied to the NCI study (09-C-0082; 
IND 13871) data in group 3.  There were no DLTs.  The subject incidences of Grade 3, 4, 5, and 
serious adverse events attributed to CAR+ T-cells were 3 (27%), 0 (0%), 0 (0%), and 1 (9%).  
The ORR in this cohort was 60%, including 10% complete responses.  Many subjects, however, 
did not achieve blood lymphocyte counts of zero with this conditioning regimen. 
To improve the depth and duration of lymphocyte depletion, the conditioning chemotherapy dose 
in Phase 1 Cohort A1 will be cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) both 
given for 3 concurrent days with the target dose of 2 x 106 anti-CD19 CAR T cells/kg.  This 
regimen is currently being evaluated in the NCI study (09-C-0082; IND 13871).  
Cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) both given for 3 concurrent days 
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Axicabtagene ciloleucel; KTE-C19 
Clinical Protocol: KTE-Cl 9-101 
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Final 
has been studied and tolerated in subjects with B cell malignancies (O'Brien et al, 2001). Similar 
total doses of cyclophosphamide (900 to 2,000 mg/m2) and fludarabine (90 to 150 mg/m2) have 
been given as a reduced non-myeloblative conditioning regimen in subjects with B cell 
malignancies receiving allogeneic stem cell ti·ansplants (Khouri et al, 1998). The 
cyclophosphamide dose used in this regimen (Coho1i Al and currently in the NCI study 
09-C-0082; IND 1387) is approximately 38% lower than that used in the Group 2 
cyclophosphamide 30 mg/kg conditioning regimen from the NCI study (incidence ofDLT 29%), 
with the same lower dose of fludarabine dose as Group 3. Evaluation of higher conditioning 
chemotherapy doses and/or va1ying anti-CD19 CART cell doses would proceed based on the 
incidence of DLT and evaluation of benefit-risk. 
6.3.3.2. 
Rationale for Conditioning Chemotherapy Dose in Phase 1 Coho1i B 1 
Fifteen subjects were ti·eated in the NCI protocol (09-C-0082; IND 13871) in group 2. Group 2 
included subjects with leukemia and lymphoma, 2 different doses of cyclophosphamide 
and a range of CART cell doses -
)- The DLT 
definition in the KTE-C19-101 study was applied to the NCI study data for subjects in group 2 
with B-cell lymphomas, dosed at ~ 2.5 x 106 anti-CD19 CART cells, and 
dose of cyclophosphamide to reflect the KTE-C 19-101 protocol. Seven subjects met these DLT 
criteria. 
The subject incidence of DLT was 29%. SubjectPPD 
with a best objective response of CR, 
had specific DLTs of PPD 
andPPD 
====-_---;::S--u,-bJ:-. e-c:-::t ;:;P~D;:==::---w-:".it:i"h-a~. bi""""est objective response of CR, had a 
specific DLT of PPD 
. All events were reversible. The subject incidence of 
Grade 3, 4, 5, and serious adverse events atti·ibuted to CART cells were 1 (14%), 2 (29%), 
0 (0%), and 2 (29%). The Grade 4 events were Grade 4 hypotension, Grade 4 somnolence, and 
Grade 4 aphasia/dysphasia (3 events in 2 subjects) (data on file, Kite Phanna). The subject 
incidence ORR in this coho1i was 6 (86%), including 5 (71 %) complete responses of which 4 are 
ongomg. 
The duration and depth of lymphodepletion appeared to be improved with this higher dose of 
cyclophosphamide conditioning chemotherapy (data on file, Kite Phanna). While the sample 
sizes are small, the data suggest that greater objective and complete response rates may be 
attained with a higher dose of conditioning chemotherapy regimen. Therefore, the regimen in 
Coho1i Bl may be explored if the incidence ofDLT in Coho1i Al is acceptable to fmiher 
evaluate the impact of conditioning chemotherapy on benefit/risk. 
CONFIDENTIAL 
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Axicabtagene ciloleucel; KTE-C19 
Clinical Protocol: KTE-Cl 9-101 
Kite Phanna, Inc. 
Table 4. 
Group 
Final 
Incidence of DLT and Response among Subjects with B-cell Lymphomas and 
Dosed with Group 2 and Group 3 Conditioning Chemotherapy and 
llll'fanti-CD19 CAR T Cells 
N 
Incidence 
ORR- n(%) 
ofDLT•-
n(%) 
CRRate-
n(%) 
Group 2 Conditioning 
2 (29) 
6 (86) 
5 (71) 
-) 
Group 3 conditioning 
3 days) 
a. 
DLT as detemiined by the definition proposed in the KTE-C19-101 study 
b. 
11 subjects treated in Group 3; 10 were followed through Day 30 at data cutoff 
0 (0) 
6 (60) 
1 (10) 
Table 5. 
DLTa Events among Subjects with B-cell Lymphomas and Dosed with 
_. 
anti-CD19 CART Cells and Cyclosphosphamide 
-Fludarabine 
Subject 
Event 
PPD 
I 
PPD 
I 
PPD 
I 
PPD 
I 
a. 
DLT as detemiined by the definition proposed in the KTE-C19-101 study 
6.3.3.3. 
Rationale for Patient Population to be Included in Phase 2 Pivotal Study Coho1i 1 
and Coho1i 2 
In the multicenter randomized Phase 3 CORAL study where subjects were randomized to R-ICE 
or R-DHAP second-line therapy followed by ASCT with or without rituximab maintenance, 
203 subjects across both anns did not proceed with ASCT. These subjects were ineligible for 
ASCT for multiple reasons including chemorefractory disease, early relapsed disease, residual 
masses after salvage therapy and intolerance to therapy. The median overall survival of these 
203 ASCT ineligible subjects after salvage chemotherapy was only 4.4 months (Van Den Neste 
et al, 2016). Therefore, the efficacy of axicabtagene ciloleucel will be estimated in this 
population which represents a significant unmet need for more effective therapies. 
6.3.3.4. 
6.3.3.4.1. 
Rationale for Including Phase 2 Safety Management Study Coho1i 3, Cohort 4, 
Coho1i 5, and Cohort 6 
Coho1i 3 
CRS and neurologic toxicities are two identified risks associated with axicabtagene ciloleucel. 
Both CRS and neurologic toxicities have led to Grade 4 or Grade 5 events in the context of 
anti-CD19 CART cells (Schuster et al, 2015; Turtle et al, 2016). The pathophysiology of CRS 
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Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final 
CONFIDENTIAL 
Page 47 of 118 
 
11 February 2019 
 
is well described, but the etiology of the neurologic toxicities remains unclear.  Currently it is 
hypothesized that there are two potential mechanisms of the pathophysiology of neurologic 
toxicities:  1) peripheral systemic cytokine release followed by cytokine diffusion across the 
blood brain barrier (BBB) and/or 2) peripherally activated anti-CD19 CAR T cells translocate 
across the BBB and elicits a local inflammatory effect.  The later hypothesis is supported by 
emerging evidence of CAR T-cells trafficking to the CSF.  To further elucidate the 
pathophysiology of neurologic toxicities, serial CSF collections will be analyzed in this study for 
cytokines/chemokines/effector molecules and anti-CD19 CAR T cells. In addition, in an attempt 
to mitigate the onset and severity of CRS and neurologic toxicities, prophylactic tocilizumab and 
levetiracetam will be administered in Cohort 3 (see Section 6.3.4).  It is hypothesized that 
tocilizumab may lead to fewer activated CAR T-cells trafficking to the CNS and levetiracetam 
may reduce the risk of clinical or subclinical seizures.  Lastly, in an effort to mitigate the severity 
and/or duration of the neurologic toxicities, IT-Ara C with corticosteroids is recommended to be 
administered at the onset of Grade 3 neurologic toxicities (see Section 6.4.1). 
6.3.3.4.2. 
Cohort 4 and Cohort 6 
In the Phase 2 pivotal study portion of ZUMA-1 (n = 101), CAR T-cell levels were associated 
with response (P = 0.0002), with a 5.4-fold higher area under the curve (AUC) within the first 
28 days post-treatment for responders versus non-responders.  However, CAR T-cell levels and 
specific cytokines, including IL-2, GM-CSF, and ferritin, were only associated with Grade 3 or 
higher neurologic toxicity suggesting that distinct mechanisms may underlie the pathogenesis of 
these adverse events, as shown in Figure 4 and (Locke et al, 2017).  While there is a theoretical 
concern for the use of immunosuppressive agents to manage CRS or neurologic toxicities, 
tocilizumab and/or corticosteroids usage did not appear to affect negatively the overall response 
in ZUMA-1 and CAR T-cell levels (Table 6).  Prophylactic tocilizumab use in Cohort 3 appeared 
to lower the rate of Grade 3 or higher CRS but not neurologic toxicities (Table 7).  To further 
refine the use of corticosteroids to treat CRS and neurologic toxicities, Cohort 4 and Cohort 6 
will recommend corticosteroids at lower toxicity grades to determine the impact on incidence 
and severity of CRS and neurologic toxicities (Section 6.4.1).  Cohort 6 will further build on 
this rationale by initiating corticosteroids as prophylactic treatment on Day 0, Day 1, and 
Day 2. Prophylactic tocilizumab will not be used in Cohort 4, Cohort 5, or Cohort 6 
(Section 6.3.4). 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final 
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11 February 2019 
 
Figure 4 
Axicabtagene Ciloleucel Expansion and Correlations with Response 
and Adverse Events 
 
 
Table 6. 
Tocilizumab and Corticosteroids Use in ZUMA-1 Phase 2 Pivotal Study 
Primary Analysis 
 
No 
Tocilizumab 
n = 58 
Tocilizumab 
n = 43 
P 
Value 
No 
corticosteroids 
n = 74 
Corticosteroids 
n = 27 
P 
Value 
ORR, n (%) 
47 (81.0) 
36 (83.7) 
.8 
62 (83.8) 
21 (77.8) 
.56 
CR, n (%) 
33 (56.9) 
22 (51.2) 
.69 
40 (54.1) 
15 (55.6) 
1 
Ongoing, n (%) 
28 (48.3) 
16 (37.2) 
.31 
33 (44.6) 
11 (40.7) 
.82 
Median peak CAR 
levels, cells/μL (range) 
26.52 
(1.25-1226.36) 
61.06 
(0.84-1513.69) 
.0011 
32.2 
(1.25-1226.36) 
49.69 
(0.84-1513.69) 
.0618 
Median CAR AUC, 
cells/μL days (range) 
289.49 
(16.82-
14329.29) 
743.85 
(5.09-11506.59) 
.0022 
407.53 
(16.82-14329.29) 
724.98 
(5.09-11506.59) 
.0967 
(Neelapu et al, 2017) 
100000 
AUC Fold= 5.4 
100000 
AUC Fold = 2.6 
100000 
AUC Fold= 1.3 
10000 
10000 
10000 
0 
1000 
0 
1000 
0 
1000 
=> 
=> 
=> 
<( 
<( 
<( 
a:: 
a:: 
a:: 
<( 
100 
<( 
100 
<( 
100 
0 
0 
0 
10 
10 
10 
P= .0002 
P= .0028 
P= .3379 
ORR 
No ORR 
Grade 2:3 
Grades 0-2 
Grade 2:3 
Grades 0-2 
(n = 83) 
(n = 18) 
(n = 28) 
(n = 73) 
(n = 13) 
(n = 88) 


Axicabtagene ciloleucel; KTE-C19 
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Clinical Protocol: KTE-C19-101 
Final 
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Table 7. 
Rates of Neurologic Toxicities and CRS in the Phase 1 and 2 Pivotal 
Study versus Phase 2 Safety Management Study Cohort 3 
 
ZUMA-1 
Phase 1+ Phase 2 Pivotal 
Cohorts 1+2 
(N = 108) 
ZUMA-1 
SMS Cohort 3 
(N = 34) 
   Any  Neurologic toxicitya 
70 (65) 
29 (85) 
       Worst Grade 1 
23 (21) 
9 (26) 
       Worst Grade 2 
15 (14) 
6 (18) 
       Worst Grade 3 
29 (27) 
12 (35) 
       Worst Grade 4 
3 (3) 
1 (3) 
       Worst Grade 5 
0 (0) 
1 (3) 
           due to disease progression 
0 (0) 
0 (0) 
       Worst Grade >= 3 
32 (30) 
14 (41) 
   Any CRSb 
101(94) 
32 (94) 
       Worst Grade 1 
41 (38) 
12 (35) 
       Worst Grade 2 
45 (42) 
19 (56) 
       Worst Grade 3 
9 (8) 
0 (0) 
       Worst Grade 4 
4 (4) 
1 (3) 
       Worst Grade 5 
1 (1) 
0 (0) 
           due to disease progression 
0 (0) 
0 (0) 
       Worst Grade >= 3 
14 (13) 
1 (3) 
Data cut for Phase 1, Phase 2 Cohort 1 and 2: Primary Analysis, DCO 27JAN2017. 
Data cut of SMS Cohort 3: Updated Analysis, DCO 11AUG2017. 
Neurologic events are graded per CTCAE 4.03; CRS events are graded per Lee grade (Lee et al, 2014).   
a. 
Neurologic AEs were identified with a search strategy based on known neurologic toxicities associated with anti-CD19 
immunotherapy (Topp et al, 2015). For Phase 1, Phase 2 Cohort 1 and 2, the neurologic toxicities included events with onset 
between date of first axicabtagene ciloleucel infusion (Day 0) and Day 56; for SMS Cohort 3, the neurologic toxicities 
included events with onset on or after the date of first conditioning chemotherapy. 
b. 
One subject in Phase 1 had CRS symptoms reported but not graded for CRS at the time at the Primary Analysis data cut. 
This subject was counted in the “Any CRS” row but not by the worst grade. 
6.3.3.4.3. 
Cohort 5 
In the pivotal cohorts of ZUMA-1, Phase 2 (Cohorts 1 and 2; n = 101), subjects with relapsed 
and refractory aggressive B-cell lymphoma were not permitted to receive anti-cancer therapy 
between leukapheresis and conditioning chemotherapy. However, a subsequent retrospective 
analysis suggested a relationship between lymphoma burden (estimated by the sum of the 
product of diameters [SPD] of index lesions) and clinical outcomes (Locke et al, 2018). Subjects 
with the lowest SPD had the highest rates of ongoing response at 1 year and the lowest rates of 
CRS and neurological events.  Thus, Cohort 5 will be used to prospectively assess the impact of 
debulking therapy, administered after leukapheresis but prior to conditioning chemotherapy, on 


Axicabtagene ciloleucel; KTE-C19 
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Clinical Protocol: KTE-C19-101 
Final 
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the safety and efficacy of axicabtagene ciloleucel.  The goal of the debulking therapy will be to 
reduce lymphoma burden and assess clinical outcomes.  
Furthermore, the majority (90%) of patients with relapsed/refractory (r/r) DLBCL who were 
included in another CAR T-cell therapy study (KYMRIAH™ and Novartis Pharmaceuticals 
Corporation 2018) received the investigator’s choice of bridging therapy that may have had a 
debulking effect. Although debulking was not explicitly tested, 8 of these patients had no 
measurable disease following bridging therapy. The overall results from this study suggested that 
the inclusion of the investigator’s choice of bridging therapy was well-tolerated, as no new safety 
signals were identified using this approach. Toxicities observed within the JULIET study were 
consistent with other CD19-targeted CAR T-cell therapies. 
In conclusion, the goal of Cohort 5 is to improve the benefit-risk ratio of axicabtagene ciloleucel 
by reducing lymphoma burden prior to administration of axicabtagene ciloleucel.  This approach 
is justified by a retrospective analysis of outcome by tumor burden in ZUMA-1 and data from 
other CD19-targeting CAR T-cell products.  The specific safety regimens studied in Cohorts 3 
and 4 will not be continued in Cohort 5.   
6.3.4. 
Study Treatment by Phase 
Phase 1 Study  
The study will begin with Cohort A1.  Subsequent cohorts may be explored as depicted in 
Figure 3 and outlined in Section 9.10.   
Conditioning Chemotherapy 
Cohorts A1/
: Subjects will receive the following 5-day chemotherapy regimen:  
 IV hydration with 
 given prior to cyclophosphamide on 
the day of infusion followed by: 
 Cyclophosphamide 500 mg/m2 IV over 60 minutes on Day -5, Day -4, and Day -3 followed 
by: 
 Fludarabine 30 mg/m2 IV over 30 minutes on Day -5, Day -4, and Day -3 followed by: 
 An additional 
 at the completion of the fludarabine infusion  
 Add mesna (sodium 2-mercaptoethanesulfonate) per institutional guidelines  
Cohort A3: Subjects will receive the following 
chemotherapy regimen: 
 The IV hydration is 
 given prior to cyclophosphamide on the day of 
infusion followed by: 
 Cyclophosphamide 
 IV over 60 minutes on 
 followed 
by: 
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Axicabtagene ciloleucel; KTE-C19 
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Kite Phanna, Inc. 
• 
Fludarabine-
over 30 minutes on 
followed by: 
• 
An additional 
at the completion of the fludarabine infusion 
• 
Add mesna (sodium 2-mercaptoethanesulfonate) per institutional guidelines 
For subjects enrolled into Coho1i Al/A2/A3, Day -2 and Day -1 will be rest days before 
axicabtagene ciloleucel infusion on Day 0. 
Coho1is-: 
Subjects will receive the following 7 day chemotherapy regimen: 
• 
IV hydration 
. Recommended at 
Final 
administered as a continuous infosion sta1i ing 11 hours pre-cyclophosphamide infusion and 
continue hydration until 24 hours after last cyclophosphamide infosion: 
• 
Cyclophosphamide-- administered on 
120 minutes followed by: 
• 
Fludarabine 
administered on Day 
infosion given over 30 minutes 
• 
Add mesna per institutional guidelines 
infosed over 
For subjects enrolled into Coho1i Bl/B2, there will be no rest days between the last day of 
chemotherapy (Day -1) and the axicabtagene ciloleucel infosion on Day 0. 
6.3.4.1.1. 
Axicabtagene Ciloleucel 
Each 
Coho1is Al-: Subjects will receive axicabtagene ciloleucel treatment consisting of a 
single infosion of CAR transduced autologous T cells administered intravenously at a target dose 
of 2 x 106 anti-CD19 CART cells/kg 
anti-CD19 CART cells/kg to_. 
anti-CD19 CART cells/kg). A minimum dose of 1 x 106 anti-CD19 CART cells/kg mal be 
administered. For subjects weighing greater than 100 kg, a maximum flat dose of 2 x 10 
anti-CD19 CART cells will be administered. 
Coho1is -
: Subjects will receive axicabtagene ciloleucel treatment consisting of a single 
infosion of CAR transduced autologous T cells administered intravenously at a target dose of 
' 
anti-CD19 CART cells/kg to_. 
anti-CD19 CART cells/kg). A minimum dose of_. anti-CD19 CAR T cells/kg may be 
administered. For subjects weighing greater than- a maximum flat dose oflllllllllllll' 
anti-CD19 CART cells will be administered. 
6.3.4.2. 
Phase 2 Pivotal Study: 
Based on the safety profile of the 6 DLT evaluable subjects from the Phase 1 po1i ion of the 
study, the SRT deemed the axicabtagene ciloleucel dosing regimen explored in Coho1i Al to be 
safe. 
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Final 
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In Phase 2, subjects will receive the 5-day conditioning chemotherapy regimen used in Cohort 
A1 of the Phase 1 portion of the study: 
 IV hydration with 
) given prior to 
cyclophosphamide on the day of infusion followed by: 
 Cyclophosphamide 500 mg/m2 IV over approximately 60 minutes on Day -5, Day -4, and 
Day -3 followed by: 
 Fludarabine 30 mg/m2 IV over approximately 30 minutes on Day -5, Day -4, and Day -3 
followed by: 
 An additional 
) at the completion of the 
fludarabine infusion  
 Add mesna (sodium 2-mercaptoethanesulfonate) per institutional guidelines  
Axicabtagene ciloleucel will be administered at a target dose of 2 x 106 anti-CD19 CAR T 
cells/kg.  In addition, subjects who receive doses between 1-2 x 106 anti-CD19 CAR T cells/kg 
will be included in the mITT analysis set.  For subjects weighing greater than 
 a 
 anti-CD19 CAR T cells will be administered. 
Phase 2 Safety Management Study: 
For Cohort 3, subjects will receive conditioning chemotherapy and axicabtagene ciloleucel as 
described above.  In addition, subjects will receive levetiracetam (750 mg PO or IV BID) starting 
on Day 0.  At the onset of ≥ Grade 2 neurologic toxicities, levetiracetam should be administered. 
If a subject does not experience any ≥ Grade 2 neurologic toxicities, levetiracetam should be 
tapered and discontinued as clinically indicated.  Subjects will also receive tocilizumab 
(8 mg/kg IV over 1 hour [not to exceed 800 mg]) on Day 2.  Further tocilizumab 
(± corticosteroids) is recommended to be administered at the onset of ≥ Grade 2 CRS.  
For Cohorts 4 and 6, subjects will receive bridging therapy (if applicable, refer to Section 6.2.1), 
conditioning chemotherapy, axicabtagene ciloleucel, and levetiracetam, as described above.  
Tocilizumab will not be administered as prophylaxis, but will be administered based on toxicity 
management guidance (eg, tocilizumab and corticosteroids) as described in Section 6.4.1, 
Table 8, Table 9, and Table 10.  Corticosteroids will be initiated for toxicity management for 
Grade 2 CRS and for Grade 1 neurologic toxicities per Table 8 and Table 9, respectively, as 
described in Section 6.4.1. In addition, in Cohort 6, subjects will receive corticosteroids on 
 
For Cohort 5, subjects should receive debulking therapy (refer to Section 6.2.2), conditioning 
chemotherapy, axicabtagene ciloleucel, and levetiracetam, as described above. Toxicity 
management guidance is provided in Section 6.4. 
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Final 
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6.4. 
Toxicity Management 
To date, the following important risks have been identified with axicabtagene ciloleucel:  CRS, 
neurologic toxicities, infections, hypogammaglobulinemia, and cytopenias.  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.    
6.4.1. 
Phase 2 Safety Management Study (Cohort 4 and Cohort 6 only) 
To date, the following risks have been identified with axicabtagene ciloleucel: CRS, 
neurologic events, infections, hypogammaglobulinemia, and cytopenias.  For CRS and 
neurological toxicities, the treatment guidance outlined in Table 8, Table 9, and Table 10 will be 
used for Cohort 4 and Cohort 6 of the Phase 2 safety management study.  Additional safety 
information and management recommendations for the other identified risks can also be found 
in the most current version of the IB. 
Table 8. 
Grading and Management of CRS in Cohort 4 and Cohort 6 
CRS Grade 
Supportive Care 
Tocilizumab 
Steroids 
Follow up 
Grade 1:  
 Symptoms are not 
life threatening and 
require symptomatic 
treatment only (eg, 
fever, nausea, 
fatigue, headache, 
myalgia, malaise) 
 Supportive care 
per institutional 
standard of care 
 
N/A 
N/A 
Not improving after 24 
hours: 
 Tocilizumab as per 
Grade 2 guidance 
(below) 
Not improving after 3 days: 
 Dexamethasone 10 mg 
x1  
 


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Clinical Protocol: KTE-C19-101 
Final 
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CRS Grade 
Supportive Care 
Tocilizumab 
Steroids 
Follow up 
Grade 2:  
 Symptoms require 
and respond to 
moderate 
intervention  
 Oxygen requirement 
<40% FiO2 or 
hypotension 
responsive to fluids 
or low dose of one 
vasopressora or 
Grade 2 organ 
toxicityb 
 Continuous 
cardiac telemetry 
and pulse 
oximetry as 
indicated 
 IV fluids bolus 
for hypotension 
with
 
 
 Vasopressor 
support for 
hypotension not 
responsive to IV 
fluids 
 Supplemental 
oxygen as 
indicated 
 Tocilizumab: 
8mg/kg over 1 
hour (not to 
exceed 800 mg) 
 Repeat 
tocilizumab every 
4 to 6 hours as 
needed if not 
response to IV 
fluids or 
increasing 
supplemental 
oxygen; 
maximum of 3 
doses in a 24-
hour period.  
 Maximum total 
of 4 doses if no 
clinical 
improvement in 
the signs and 
symptoms of 
CRS 
 Dexamethasone 
 
   
Improving:  
 Discontinue tocilizumab 
 Taper corticosteroids 
Not Improving: 
 Manage as Grade 3 
(below) 
Grade 3:  
 Symptoms require 
and respond to 
aggressive 
intervention 
 Oxygen requirement 
≥ 40% FiO2 or 
hypotension 
requiring high-dose 
or multiple 
vasopressorsa or 
Grade 3 organ 
toxicity or Grade 4 
transaminitisb 
 Management in 
monitored care or 
intensive care 
unit 
 Per Grade 2  
 Methylprednisolone 1 
mg/kg IV BIDc 
Improving:  
 Discontinue tocilizumab 
 Taper corticosteroids 
Not Improving: 
 Manage as Grade 4 
(below) 
Grade 4:  
 Life-threatening 
symptoms 
 Requirements for 
ventilator support or 
continuous veno-
venous 
hemodialysis 
(CVVHD) 
 Grade 4 organ 
toxicity (excluding 
transaminitis)b 
 Per Grade 3 
 Mechanical 
ventilation and/or 
renal replacement 
therapy may be 
required 
 Per Grade 2  
High-dose 
corticosteroids:  
 Methylprednisolone 
1000 mg/day 
 x 3 d
ays 
Improving: 
 Discontinue tocilizumab 
 Taper corticosteroids 
Not improving: 
 Consider 1 gram BID to 
TID of 
methylprednisolone and 
other 
immunosuppressives 
(e.g. siltuximab) and 
anti-thymocyte globulin 
 
 
a. 
High-dose vasopressor doses 
b. 
Severity based on CTCAE 
c. 
or equivalent dexamethasone 
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Table 9. 
Grading and Management of Neurologic Toxicities in Cohort 4 and 
Cohort 6 
Neurologic Toxicities 
Supportive Care 
Tocilizumab 
Corticosteroids 
Follow up 
Grade 1 examples include: 
 Somnolence-mild 
drowsiness or sleepiness 
 Confusion-mild 
disorientation 
 Encephalopathy-mild 
limiting of ADLs 
 Dysphagia-not impairing 
ability to communicate 
 Supportive care 
per institutional 
standard of care 
 Closely monitor 
neurologic status 
 Consider 
prophylactic 
levetiracetam  
N/A 
 Dexamethasone 
 
Not improving after 
2 days: 
 Repeat 
dexamethasone 
 
 
 Continue supportive 
care 
Grade 2 examples include: 
 Somnolence-moderate, 
limiting instrumental 
ADLs 
 Confusion-moderate 
disorientation 
 Encephalopathy-limiting 
instrumental ADLs  
 Dysphagia-moderate 
impairing ability to 
communicate 
spontaneously 
 Seizure(s) 
 Continuous 
cardiac telemetry 
and pulse 
oximetry as 
indicated 
 Closely monitor 
neurologic status 
with serial neuro 
exams to include 
fundoscopy and 
Glasgow Coma 
Score. Consider 
neurology 
consult 
 Perform brain 
imaging 
(eg, MRI), EEG, 
and lumbar 
puncture (with 
opening 
pressure) if no 
contraindications 
 Levetiracetam/ 
antiepileptics if 
subject has 
seizures 
 Only in case of 
concurrent CRS: 
 Tocilizumab 
8 mg/kg IV over 
1 hour (not to 
exceed 800 mg) 
 Repeat 
tocilizumab 
every 4 to 6 
hours as needed 
if not responsive 
to IV fluids or 
increasing 
supplemental 
oxygen; 
maximum of 
3 doses in a 
24-hour period.  
Maximum total of 
4 doses if no 
clinical 
improvement in the 
signs and 
symptoms of CRS 
 Dexamethasone 
 
Improving: 
 Discontinue 
tocilizumab 
 Taper corticosteroids 
 Not improving: 
 Manage as Grade 3 
(below) 
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Neurologic Toxicities 
Supportive Care 
Tocilizumab 
Corticosteroids 
Follow up 
Grade 3 examples include: 
 Somnolence-obtundation 
or stupor 
 Confusion-severe 
disorientation 
 Encephalopathy-limiting 
self-care ADLs 
 Dysphagia-severe 
receptive or expressive 
characteristics, impairing 
ability to read, write, or 
communicate intelligibly 
 Management in 
monitored care 
of intensive care 
unit 
 Per Grade 2  
 Methylprednisolone 
 
Improving: 
 Discontinue 
tocilizumab 
 Taper corticosteroids 
 Not improving: 
 Manage as Grade 4 
(below) 
Grade 4 examples include: 
 Life-threatening 
consequences 
 Urgent intervention 
indicated 
 Requirement for 
mechanical ventilation 
 Consider cerebral edema  
 Per Grade 3 
 Mechanical 
ventilation, may 
be required 
 Per Grade 2  
 Methylprednisolone 
  
Improving: 
 Taper corticosteroids 
Not improving: 
 Consider 1 gram of 
methylprednisolone 
TID,  alternative 
immunsuppressive 
(e.g. siltuximab) and 
anti-thymocyte 
globulin  
 
 
 
 
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Table 10. 
Management of Cerebral Edema in Cohort 4 and Cohort 6 
Supportive Care 
Tocilizumab 
Corticosteroids 
Follow up 
As above for neurologic toxicities Grade 
4, to include: 
 Intensive care unit supportive therapy 
 Optimal head position with elevation 
of head of bed and straight neck 
positioning 
 Administration of diuretics and 
osmotherapy (eg, mannitol, hypertonic 
saline) 
 If cerebral edema documented strongly 
suspected, recommend neurosurgical 
consult 
 Early tracheal intubation with 
controlled mechanical mild 
hyperventilation and good oxygenation 
 Maintain cerebral perfusion pressure 
with mild hypervolemia 
 Avoid hypertension with use of 
antihypertensives (labetalol, 
nicardipine) 
 Avoid potent vasodilators 
 Pharmacological cerebral metabolic 
suppression (barbiturates, sedation, 
analgesia, and neuromuscular 
paralysis, as indicated) 
 
Maintain rigorous glycemic 
control 
 Tocilizumab as above in 
Grade 4 neurologic 
toxicity management 
(tocilizumab should be 
given only if concurrent 
CRS) 
 Methylprednisone 
 
Improving: 
 Very slow steroid taper 
recommended; 
 Repeat neuro-imaging as 
indicated 
 Serial neurologic exams as 
indicated 
 Consider early neuro-
rehabilitation 
 Discontinue tocilizumab if 
started 
Not Improving 
 Consider 
Methylprednisolone 1gram 
TID, alternative 
immunosuppressive (e.g. 
siltuximab) and anti-
thymocyte globulin  
 
 
 
6.4.2. 
Phase 2 Safety Management Study (Cohort 5) 
To date, the following risks have been identified with axicabtagene ciloleucel: CRS, neurologic 
events, infections, hypogammaglobulinemia and cytopenias. Please refer to the current version of 
the IB for details and management. 
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7. 
STUDY PROCEDURES 
Research staff should refer to the SOAs for an outline of the procedures required.  The visit 
schedule is calculated from axicabtagene ciloleucel infusion on Day 0.  
An overview of study assessments/procedures is outlined below.  A description for each period 
of the study is provided in Section 7.  Refer to the CRF completion guidelines for data collection 
requirements and documentation of study procedures. 
7.1. 
Informed Consent 
Before a subject’s participation in the clinical study, the investigator is responsible for obtaining 
written informed consent from the subject after adequate explanation of the study design, 
anticipated benefits and the potential risks.  Subjects should sign the most current IRB/IEC 
approved ICF prior to any study specific activity or procedure is performed. 
The consent process and the subject’s agreement or refusal to participate in the study is to be 
documented in the subject’s medical records.  If the subject agrees to participate, the ICF is to be 
signed and personally dated by the subject and by the person who conducted the informed 
consent discussion.  The original signed ICF will be retained in accordance with institution 
policy and IRB/IEC requirements with a copy of the ICF provided to the subject. 
All subjects who are enrolled into the study should be re-consented with any updated version of 
the IRB/IEC approved ICF if relevant to their participation in the study. 
7.2. 
Demographic Data 
Demographic data will be collected to include sex, age, race, ethnicity, and country of enrollment 
to study their possible association with subject safety and treatment effectiveness. 
7.3. 
Medical and Treatment History 
Relevant medical history prior to the start of adverse event reporting will be collected.  Relevant 
medical history is defined as data on the subject’s concurrent medical condition that would be 
typically shared in a referral letter.  All findings will be recorded in the CRFs. 
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. 
For subjects who are being referred from another clinic or institution to the participating research 
center, copies from the subjects chart should be obtained. 
7.4. 
Physical Exam, Vital Signs, Performance Status, and EQ-5D 
Physical exams will be performed during screening and at times noted in the SOA.  Changes 
noted in subsequent exams when compared to the baseline exam will be reported as an adverse 
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During IP administration, vital signs including blood pressure, heart rate, oxygen saturation, and 
temperature will be monitored before and after the axicabtagene ciloleucel infusion and then 
routinely per institutional guidelines.  If the subject has a fever (temperature 38.3oC or greater), 
vital signs will be monitored more frequently 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. 
For subjects enrolled in Cohort 3, Cohort 4, Cohort 5 or, Cohort 6, EQ-5D will be completed 
by the subject, prior to any other assessment, at the screening visit and at other times noted in the 
SOA.  Subjects who are blind or illiterate may have the EQ-5D questions read to them by the 
study staff.  The study staff, however, cannot interpret any of the questions for the subject.  A 
subject may be exempt from completing the questionnaire if he or she is unable to read the 
questionnaire in one of the country languages available.  
The EQ-5D is a 2 page generic patient questionnaire for assessing the overall health status of a 
subject.  The EQ-5D consists of a 5 dimension descriptive system including questions on 
mobility, self-care, usual activities, pain/comfort, and anxiety/depression and a visual analogue 
scale (EQ VAS) which allows the respondent to record health on a vertical scale (eg, best health 
to worst health) thus allowing a quantitative measure of health outcome.   
7.5. 
Neurological Assessment  
For subjects enrolled in Cohort 1, Cohort 2, or Cohort 3, neurological assessments will be 
standardized by using the Mini-Mental State Examination (MMSE) standard version 2.0.  The 
MMSE neurological assessment will not be required for Phase 2 SMS Cohort 4, Cohort 5, and 
Cohort 6.  The MMSE is a 5-10 minute, 11-question measure that examines various areas of 
cognitive function: orientation, attention, immediate recall, short-term recall, language, and the 
ability to follow simple verbal and written commands. 
The MMSE is divided into two sections.  The first part requires vocal responses to the examiner's 
questions.  In the second part of the exam, the subject is asked to follow verbal and written 
instructions, write a sentence spontaneously, and copy a geometric figure.  Every attempt should 
be made to dedicate a single research staff member trained in the administration of the MMSE to 
conduct the assessment to minimize variability among different assessors. 
A full neurological assessment will be completed during screening to establish a baseline.  
Subsequent assessments will be performed before axicabtagene ciloleucel administration on 
Day 0, on Day 1, and then every other day during the 7-day post-infusion monitoring period, as 
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7.6. 
Cardiac Function  
Each subject’s cardiac function, as measured by ECHO will be assessed during the screening 
period to confirm study eligibility.  Both left ventricular ejection fraction (LVEF) and pericardial 
effusion will be assessed prior to study entrance by ECHO.  An ECHO performed following the 
subject’s last chemotherapy treatment and within 28 days prior to signing the consent may be 
used for confirmation of eligibility.  
To establish a baseline, an ECG will also be performed during the screening period.  
7.7. 
Magnetic Resonance Imaging 
Each subject will undergo a screening brain MRI, with contrast whenever possible or without 
contrast in case of contraindication, to rule out CNS metastasis during the screening period of the 
study.  An MRI performed following the subject’s last chemotherapy treatment and ≤ 28 days 
before signing the consent may be used for confirmation of eligibility.  
Evaluation of any new onset of ≥ Grade 2 neurologic toxicities should include a brain MRI as 
described in Section 6.4.  
7.8. 
Bone Marrow Biopsy 
Bone marrow aspirate/biopsy will be performed at screening if not previously performed to 
assess bone marrow involvement.  For subjects with a potential complete response to 
axicabtagene ciloleucel, a follow-up bone marrow aspirate/biopsy will be performed in subjects 
presenting with bone marrow involvement prior to therapy or if new abnormalities in the 
peripheral blood counts or blood smear cause clinical suspicion of bone marrow involvement 
with lymphoma after treatment.  To confirm a complete response, the bone marrow aspirate and 
biopsy must show no evidence of disease by morphology or if indeterminate by morphology it 
must be negative by immunohistochemistry.  Refer to Section 7.10 and Appendix Afor treatment 
response assessment requirements per the revised IWG Response Criteria for Malignant 
Lymphoma (Cheson et al, 2007).  Bone marrow aspirate/biopsy should also be considered to 
evaluate hemophagocytic lymphohistiocytosis (HLH) as indicated in the IB.  A portion of the 
bone marrow sample collected to evaluate HLH or other toxicities should be submitted to the 
central laboratory as outlined in the central laboratory manual.  
7.9. 
Lumbar Puncture 
Subjects with symptoms of central nervous system malignancy such as new onset severe 
headaches, neck stiffness, or any focal neurologic findings on physical exam will have lumbar 
puncture performed at the screening visit for examination of cerebral spinal fluid.  In addition, 
lumbar puncture may be performed as applicable for subjects with new onset of ≥ Grade 2 
neurologic toxicities after axicabtagene ciloleucel infusion (see Section 6.4).  
 
 
 
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Phase 2 Safety Management Study 
For subjects enrolled in Cohort 3, Cohort 4, Cohort 5, or Cohort 6, lumbar punctures for the 
collection of CSF samples will be performed pre- and post-axicabtagene ciloleucel infusion at 
times outlined in the SOA.  Samples will be submitted to the central laboratory as outlined in the 
central laboratory manual.  Adequate platelet support should be provided prior to performing a 
lumbar puncture (e.g. platelet >50,000/mm3). 
7.10. 
Disease Response 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 revised IWG Response Criteria for 
Malignant Lymphoma (Cheson et al, 2007).  Flow cytometric, molecular or cytogenetic studies 
will not be used to determine response. 
Baseline positron emission tomography-computed tomography (PET-CT) scans of the neck, 
chest, abdomen and pelvis, along with the appropriate imaging of all other sites of disease are 
required.  Subjects will undergo additional PET-CT tumor assessments after their axicabtagene 
ciloleucel infusion.  The first of these post-treatment PET-CT tumor assessments will occur 4 
weeks after infusion; subsequent assessments will occur at regular intervals throughout the post-
treatment and long-term follow-up portions of the study, as highlighted in the SOA. 
After axicabtagene ciloleucel administration, disease assessments will be used to determine the 
time when progressive disease occurs.  Subjects with symptoms suggestive of disease 
progression should be evaluated for progression at the time symptoms occur even if it is off 
schedule as per the SOA.  
A bone marrow aspirate and biopsy will be performed in subjects who are being assessed for CR.  
Per the revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007), a bone 
marrow aspirate and biopsy should be performed only when the subject had bone marrow 
involvement with lymphoma prior to therapy or if new abnormalities in the peripheral blood 
counts or blood smear cause clinical suspicion of bone marrow involvement with lymphoma 
after treatment.  The bone marrow aspirate and biopsy must show no evidence of disease by 
morphology, or if indeterminate by morphology, it must be negative by immunohistochemistry 
to assign a CR to treatment.   
In addition to the investigator’s assessment, PET-CT scans of all subjects evaluated for disease 
response for Phase 2 pivotal study (Cohort 1 and Cohort 2) will be submitted to and reviewed by 
an independent central reviewer.  For subjects who discontinue the study due to an assessment of 
progressive disease which was not subsequently confirmed by a central radiology reviewer, any 
additional imaging data, subsequent to the image in question will be submitted to the central 
reviewer to confirm disease response.  
If the subject is eligible for retreatment with axicabtagene ciloleucel, the last scan prior to 
retreatment will be considered the baseline for the purpose of evaluating the response to 
retreatment. 
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Requirements for PET-CT scans and shipping requirements will be outlined in the study imaging 
manual. 
7.11. 
Laboratory 
The below samples will be collected at the time points indicated in the SOA.  Additional samples 
(eg, blood, urine, CSF, tissue, etc) may be collected as needed for further safety testing. 
Local lab analysis:   
 Sodium (Na), potassium (K), chloride (Cl), total CO2 (bicarbonate), creatinine, glucose, 
blood urea nitrogen (BUN) or urea (if BUN test cannot be analyzed by the local lab), 
albumin, calcium total, magnesium total (Mg), inorganic phosphorus, alkaline phosphatase, 
ALT/glutamic-pyruvic transaminase (GPT), AST/glutamic-oxaloacetic transaminase (GOT), 
total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), uric acid 
 C-reactive protein (CRP)  
 Complete blood count (CBC) with differential  
 A urine or serum sample will be collected and assessed locally for females of childbearing 
potential.  If the screening pregnancy test is positive, the subjects should not be enrolled.  If a 
standard of care pregnancy test is collected during the course of the study, and the result is 
positive, the investigator should contact the Kite Pharma medical monitor for instructions.  If 
a female partner of a male subject becomes pregnant during the conduct of the study, it must 
be reported by contacting Kite Pharma Medical Monitor for instructions.  
 For EU sites, a serology (eg, HIV, hepatitis B, hepatitis C, syphilis) test will be carried out 
per institutional guidelines and EU regulations.  This may be administered within the 30 days 
prior to leukapheresis and/or on the day of leukapheresis. 
Central lab analysis: 
 Blood draws for PBMC (lymphocyte subsets, replication-competent retrovirus [RCR], and 
anti-CD19 CAR T-cell levels) and cytokine analysis will be performed at intervals outlined 
in the SOA.   
 Serum samples will also be evaluated centrally for anti-axicabtagene ciloleucel antibodies. 
 For serum samples that demonstrate increased anti-axicabtagene ciloleucel antibodies at the 
Month 3 visit over baseline values, attempts should be made to obtain and test additional 
serum samples approximately every 3 months until the antibody levels return to baseline (or 
becomes negative) or up to 1 year from the completion of treatment, whichever occurs first. 
 Archived tumor tissue 


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 For subjects enrolled in Cohort 4, Cohort 5, and Cohort 6, a block or 30 unstained slides 
should be submitted to the central laboratory for confirmatory diagnosis, CD19 expression, 
cell of origin, and determination of double/triple hit high grade lymphoma.  
 
 
 
 
 
 
 
 CSF and possibly bone marrow samples will also be collected and analyzed at the central 
laboratory as outlined in the schedule of assessments and per Section 7.12. 
 See central laboratory manual for details on sample collection, processing, and shipping 
instructions.  
7.12. 
Biomarkers 
Biomarker analysis will be performed on blood and tumor samples to evaluate pharmacodynamic 
markers for axicabtagene ciloleucel.  Prognostic markers specific for large B-cell lymphoma and 
related to the tumor immune environment may also be evaluated in archived and fresh tumor 
biopsies.  
The presence, expansion, persistence, and immunophenotype of transduced anti-CD19 
CAR T cells will be monitored in the blood primarily by polymerase chain reaction (PCR) 
analysis, complemented by flow cytometry.  Expansion and persistence in peripheral blood will 
also be monitored by a CD19 CAR specific quantitative polymerase chain reaction (qPCR) 
assay.   
Levels of serum cytokines will be evaluated in serum to characterize the pharmacodynamic and 
safety profile of axicabtagene ciloleucel.  The following pro-inflammatory, homeostatic and 
immune modulating cytokines may be included in the panel:  IL-6, IL-15, IL-17a, TNF-, 
GM-CSF, IFN-, IL-12p40/p70 and IL-13; immune effector molecules: Granzyme A, B and 
Perforin; correlates of acute phase response: CRP and SAA; Chemokines MIP-1, MIP-1β, 
MCP-1, IP-10, and IL-8.  In addition, IL1Ra, IL2Rα, and ferritin will also be measured. 
CSF, as well as additional samples (eg, pleural fluid), may be harvested from subjects who 
develop neurologic toxicities or CRS to enable evaluation of inflammatory cytokines and 
chemokine levels.  As applicable, lymphocyte populations residing in the CSF, or other subject 
samples, may also be monitored for the purpose of understanding the safety profile of 
axicabtagene ciloleucel. 
Phase 2 Pivotal Study 
 
 
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Phase 2 Safety Management Study 
For subjects enrolled in Cohort 3, Cohort 4, Cohort 5, or Cohort 6, lumbar punctures for 
collection of CSF samples will be performed at the following time points:  after eligibility is 
confirmed and prior to start of conditioning chemotherapy, after axicabtagene ciloleucel infusion 
on Day 5 (± 3 days), and at the Week 4 visit (± 3 days).  Collection of CSF samples will enable 
measurement of baseline cytokine levels prior to axicabtagene ciloleucel infusion.  Changes in 
levels of cytokines after axicabtagene ciloleucel infusion will be measured at the time of peak 
CAR T-cell expansion (Day 5) and at Week 4 when it is anticipated that cytokine levels would 
return to baseline levels.  Infiltration of CAR T cells will also be assessed by flow cytometry in 
post-axicabtagene ciloleucel infusion CSF samples.  
 
 
 
For subjects enrolled in Cohort 4, Cohort 5, and Cohort 6, additional blood will be collected on 
Day 1 (Cohort 6 only), Day 2 (Cohort 6 only), Day 3, Day 7, Day 10, and Week 3 after 
axicabtagene ciloleucel infusion.  The intent of the additional blood samples is to enable early 
monitoring of anti-CD19 CAR T-cell and serum cytokine levels in the blood of subjects treated 
more aggressively with tocilizumab and corticosteroids.  To balance the total amount of blood 
drawn over the first 3 months of therapy, blood volumes have been reduced at pre-specified time 
points (refer to the central laboratory manual for details). 
Phase 2 Pivotal Study and Safety Management Study 
Bone marrow samples may be collected for subjects who develop toxicities after axicabtagene 
ciloleucel infusion and will be analyzed centrally by immunohistochemistry for evidence of 
disease, treatment emergent toxicities (e.g. HLH, pancytopenia) and presence of anti-CD19 CAR 
T cells.  
Because axicabtagene ciloleucel comprises retroviral vector transduced T cells, the presence of 
RCR in the blood of treated subjects will be monitored.   
 
 
 
  
  
 
 
   
 
 
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7.13. 
Description of Study Periods 
Investigative sites will maintain a log of all screened subjects who were reviewed and evaluated 
for study participation.  Information collected on 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. 
7.13.1. 
Screening 
The screening period begins on the date the subject signs the IRB/IEC approved ICF and 
continues through confirmation of enrollment.  Informed consent must be obtained before 
completion of any non-standard of care study specific procedures.  Procedures that are part of 
standard of care are not considered study specific procedures and may be performed prior to 
obtaining consent and used to confirm eligibility.  Confirmation of this data must occur within 
the time allowance as outlined below and in the SOA. 
After written informed consent has been obtained, subjects will be screened to confirm study 
eligibility and participation.  Only subjects who meet the eligibility criteria listed in Section 5 
and who commence leukapheresis will be enrolled in 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 on the subject screening log with the reasons for failing screening. 
The following assessments/procedures are to be completed during the screening period at the 
time points outlined in the SOA: 
 Medical history and disease assessment 
 Physical examination including height and weight 
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 Subjects with symptoms of central nervous system malignancy such as new onset severe 
headaches, neck stiffness, or any focal neurologic findings on physical exam will have 
lumbar puncture for examination of cerebral spinal fluid. 
 Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature 
 ECOG performance status  
 For subjects enrolled in Cohort 3, Cohort 4, Cohort 5, and Cohort 6, EQ-5D questionnaire  
(prior to any other assessments/procedures being performed) 
 For subjects enrolled in Cohort 1, Cohort 2, or Cohort 3, neurological assessment including 
MMSE  
 ECG 
 ECHO for LVEF and pericardial effusion assessment 
 An ECHO performed following the subjects last chemotherapy treatment and within 28 days 
prior to signing the consent may be used for confirmation of eligibility 
 Imaging Studies 
 Brain MRI  
 Baseline PET-CT of the neck, chest, abdomen and pelvis 
 PET-CT performed following the subjects last line of therapy and prior to signing the consent 
may be used for confirmation of eligibility.  
 If PET CT is performed > 28 days prior to the initiation of conditioning chemotherapy or if 
subject receives any anti-cancer therapy between screening and conditioning chemotherapy, 
the scans must be repeated to establish a new baseline. For subjects in Cohort 5, if no 
conditioning chemotherapy is being administered, a PET-CT must be repeated to establish a 
new baseline prior to the axicabtagene ciloleucel infusion. PET-CT should be performed as 
close to enrollment as possible.   
 Bone marrow aspirate/biopsy as needed (if not done at initial diagnosis or between diagnosis 
and screening) 
 Labs  
 Chemistry panel 
 CBC with differential 
 β-HCG pregnancy test (serum or urine) on all women of child-bearing potential 


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 Serious Adverse Event reporting (refer to Section 9 for safety reporting guidelines) 
 Concomitant medications documentation and previous cancer treatment history 
 Once eligibility confirmed, collection of archived tumor sample, as well as fresh tumor 
sample(s) 
 
 For subjects assigned to Cohort 3, Cohort 4, Cohort 5, and Cohort 6, lumbar puncture for 
collection of CSF samples to be performed after eligibility confirmed and prior to start of 
conditioning chemotherapy 
7.13.2. 
Rescreening 
Subjects who are unable to complete or meet the eligibility criteria during the 28-day screening 
period will be permitted to rescreen one time.  Subjects will retain the same subject identification 
number assigned at the original screening.  If rescreening occurs within 28 days of the signing of 
the original informed consent, only the procedure(s)/assessment(s) that did not originally meet 
the eligibility criteria needs to be repeated; all other initial screening procedures/assessments do 
not need to be repeated.  If rescreening occurs, 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. 
7.13.3. 
Enrollment/Leukapheresis 
If any screening assessments or procedures are repeated between confirmation of eligibility and 
the start of leukapheresis and results are outside the eligibility criteria listed in Section 5, contact 
the Kite medical monitor prior to proceeding with leukapheresis. 
Before leukapheresis commences, the following criteria must be met.  If criteria are not met, 
leukapheresis must be delayed until the event resolves.   If leukapheresis is delayed beyond 
5 days, baseline CBC with differential and chemistry panel must be repeated.  If results are 
outside eligibility criteria listed in Section 5, contact the Kite medical monitor prior to 
proceeding with leukapheresis. 
 No evidence or suspicion of an infection 
 Corticosteroid therapy at a pharmacologic dose 
 
 
prior to leukapheresis.  
Once a subject commences leukapheresis, the subject will be considered enrolled into the study.   
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The following procedures/requirements will occur on the leukapheresis collection day and as 
outlined in the SOA: 
 Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature 
 Weight  
 Labs (to be drawn prior to leukapheresis, on the day of or day before leukapheresis) 
 Chemistry panel 
 CBC with differential 
 CRP; if CRP is ≥ 100 mg/L a call must be made to the Kite medical monitor before 
proceeding with conditioning chemotherapy 
 Anti-CD19 CAR T cells 
 Lymphocyte subsets  
 Cytokine levels 
 Anti-axicabtagene ciloleucel antibodies 
 Leukapheresis 
 Adverse/Serious Adverse Event reporting  
 Concomitant medications documentation  
7.13.4. 
Bridging Therapy Phase 2 Safety Management Study 
If prescribed, bridging therapy must be administered after enrollment and completed prior to 
initiating conditioning chemotherapy per the specifications outlined in Section 6 for bridging 
therapy. 
 Adverse/Serious Adverse Event reporting  
 Concomitant medications documentation 
7.13.5. 
Debulking Therapy Phase 2 Safety Management Study, Cohort 5 
Debulking chemotherapy must be administered after enrollment and should be completed at least 
14 days prior to initiating conditioning chemotherapy or at least 14 days prior to axicabtagene 
ciloleucel administration in case conditioning chemotherapy is omitted. Radiotherapy must be 
administered after enrollment and should be completed at least 5 days prior to initiating 
conditioning chemotherapy or at least 5 days prior to axicabtagene ciloleucel administration in 
case conditioning chemotherapy is omitted. 


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7.13.6. 
Conditioning Chemotherapy Period  
If any screening assessments or procedures are repeated between screening and the start of 
conditioning chemotherapy and results are outside the eligibility criteria (Section 5), contact the 
Kite medical monitor for approval prior to proceeding with conditioning chemotherapy. 
If PET-CT will be older than 28 days at the initiation of conditioning chemotherapy or if the 
subject receives any anti-cancer therapy with therapeutic intent (eg, radiation, supraphysiologic 
doses of steroids, chemotherapy) between the last PET-CT and initiation of conditioning 
chemotherapy, the PET-CT must be repeated to establish a new baseline. 
Subjects in Cohort 5 and Cohort 6 may proceed with conditioning chemotherapy in absence of 
measurable disease in the new baseline PET-CT if they have received preceding bridging or 
debulking therapy (Cohort 5).  
The investigational product (axicabtagene ciloleucel) must be available before initiation of 
conditioning chemotherapy. 
7.13.6.1. 
Requirements for Initiating Conditioning Chemotherapy 
Administration of anti-CD19 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 (eg “tumor fever,” elevated CRP) are 
diagnoses of exclusion that require a documented workup to establish. Conditioning 
chemotherapy and axicabtagene ciloleucel infusion should only be initiated after it is reasonably 
assured that cell infusion can safely proceed.  
If any of the following criteria are met prior to initiation of conditioning chemotherapy, then the 
work-up listed in Section 7.13.7.3 must be performed to determine the potential cause if there is 
no identified source of infection. 
 Temperature > 38°Celsius within 72 hours of conditioning chemotherapy  
 CRP > 100 mg/L anytime between enrollment to start of conditioning chemotherapy 
 WBC count or WBC differential that is suggestive of infectious process, and is observed 
between enrollment and the initiation of conditioning chemotherapy (eg WBC > 20,000/µL, 
rapidly increasing WBC, or differential with high percentage of segments/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.   


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 Complete history and physical exam including head, ears, eyes, nose, and throat (HEENT) 
exam, 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 known or 
suspected infection within 48 hours before conditioning chemotherapy (prophylactic use of 
antimicrobials is allowed). 
 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 the 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 and in consultation with infectious disease service (if applicable). 
 The 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 (eg, bacterial, viral 
serologies, PCR, stood 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. 
7.13.6.2. 
Conditioning Chemotherapy Administration 
The following procedures will be completed during Day –5 to Day –3 at the time points outlined 
in the SOA: 
 Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature 
 Labs (to be drawn prior to chemotherapy) 
 Chemistry Panel  
 CBC with differential 
 Fludarabine and cyclophosphamide administration 
 Adverse/Serious Adverse Event reporting  
 Concomitant medications documentation  
 Cytokine levels (Cohort 5 only) 


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7.13.7. 
Investigational Product Treatment Period 
7.13.7.1. 
Requirements for Initiating Axicabtagene Ciloleucel Infusion 
If any of the following criteria are met prior to the initiation of axicabtagene ciloleucel infusion, 
then the work-up listed in Section 7.13.7.3 must be performed to determine the potential cause if 
there is no identified source of infection.   
 Temperature > 38°Celsius within 72 hours of axicabtagene ciloleucel infusion. 
 CRP > 100 mg/L anytime between enrollment to start of conditioning chemotherapy  
 WBC count or WBC differential, that is suggestive of infectious process, and is observed 
between enrollment and the initiation of axicabtagene ciloleucel infusion (eg, WBC 
> 20,000/µL, rapidly increasing WBC, or differential with high percentage or 
segments/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 exam, 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 infusion (prophylactic use 
of antimicrobials is allowed)  
 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 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 (eg, 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. 
After the above criteria are met, then the subject can proceed with administration of axicabtagene 
ciloleucel. For Cohort 6 only, dexamethasone 
 should be given prior to 
axicabtagene ciloleuclel infusion (refer to Section 7.13.7.2). 
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If the axicabtagene ciloleucel infusion is delayed > 2 weeks from the planned infusion date, 
protocol guidelines should be followed regarding the need for repeat conditioning chemotherapy.  
7.13.7.2. 
Monitoring After Axicabtagene Ciloleucel Infusion 
All subjects will receive axicabtagene ciloleucel infusion at a healthcare facility followed by 
daily monitoring at a healthcare facility for at least 7 days unless otherwise required by country 
regulatory agencies (refer to Appendix B) to monitor for signs and symptoms of CRS and 
neurologic toxicities.  Alternatively, subjects may be hospitalized to receive their axicabtagene 
ciloleucel infusion and be observed for CRS and neurologic toxicities in the hospital setting, if 
deemed appropriate by the investigator.  
If subjects are hospitalized, subjects should not be discharged from the hospital until all 
axicabtagene ciloleucel related non-hematological toxicities return to ≤ Grade 1 or return to 
baseline.  Subjects may be discharged with non-critical and clinically stable or improving 
toxicities (eg, renal insufficiency) even if > Grade 1, if deemed appropriate by the investigator.  
Subjects should remain in a hospital for ongoing axicabtagene ciloleucel-related fever, 
hypotension, hypoxia, or ongoing central neurologic toxicities > 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 and their family 
members/caregivers should be educated on potential CRS and neurologic symptoms, such as 
fever, dyspnea, confusion, aphasia, dysphagia, 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. 
During this period, the following procedures will be completed at the time points outlined in the 
SOA: 
 Neurological assessment including MMSE for subjects enrolled in Cohort 1, Cohort 2, or 
Cohort 3   
 MMSE will be administered before treatment with axicabtagene ciloleucel on Day 0, and 
then on Day 1 and every other day during the 7-day post-infusion monitoring period. 
 Vital signs including blood pressure, heart rate, oxygen saturation, and temperature, daily at a 
health care facility for at least 7 days  
 Labs (before axicabtagene ciloleucel infusion, as described in the SOA) 
 Chemistry Panel  
 CBC with differential 
 Lymphocyte subsets  
 Cytokine levels  


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 Anti-CD19 CAR T cells 
 RCR analysis 
 Cohort 6 only: Dexamethasone 
 
 
 Infusion of axicabtagene ciloleucel 
 For subjects enrolled in Cohort 3, administer tocilizumab at a dose of 
 IV over 
1 hour (not to exceed 800 mg) on Day 2. See Section 6.3.4 for further details on additional 
tocilizumab administration for toxicity management. 
 For subjects enrolled in Cohort 3, Cohort 4, Cohort 5, and Cohort 6, administer 
levetiracetam at a dose of 750 mg (PO or IV) BID starting on Day 0.  See Section 6.4 for 
further details on administration and discontinuation of levetiracetam for toxicity 
management.  If subject does not experience any neurologic toxicities ≥ Grade 2, taper and 
discontinue levetiracetam as clinically indicated. 
 For subjects assigned to Cohort 3, Cohort 4, Cohort 5, and Cohort 6, lumbar puncture for 
collection of CSF samples at Day 5 (± 3 days) 
 Subjects in Cohort 5 and Cohort 6 may proceed with axicabtagene ciloleucel if the new 
baseline PET-CT shows an absence of measurable disease.  
 As applicable, lumbar puncture, for subjects with new onset Grade ≥ 2 neurologic symptoms 
after axicabtagene ciloleucel infusion 
 
 should be completed for examination of CSF.  
 
 
 
 
 Concomitant medications documentation 
Monitoring of CRP, ferritin, and LDH (only if LDH is elevated at baseline) levels may assist 
with the diagnosis and define the clinical course in regards to CRS/neurologic toxicities.  It is, 
therefore, recommended that CRP, ferritin, and LDH (if elevated at baseline) be monitored daily 
starting at Day 0 and for at least 7 days at a healthcare facility. In addition, lactate should be 
monitored as clinically indicated. 
7.13.7.3. 
Requirements for 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 the following:  
 Call Kite medical monitor 
 Infectious disease service consult (if available) 
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 CT imaging of the chest, abdomen, and pelvis with IV contrast. If there is a medical 
contraindication to contrast, then non-contrast 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 (eg, galactomannan, fungitell)  
 Collection of appropriate serum viral studies (eg, cytomegalovirus [CMV])  
 If a central nervous system 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 and/or axicabtagene ciloleucel infusion, the 
above workup must not suggest the presence of an active infection and all requirements for 
conditioning chemotherapy and/or axicabtagene ciloleucel infusion must be satisfied. If the 
axicabtagene ciloleucel infusion is delayed > 2 weeks following conditioning chemotherapy, 
protocol guidelines should be followed regarding the need for repeat conditioning chemotherapy. 
If the above workup was triggered due to CRP > 100 mg/L, CRP should be repeated. If CRP 
continues to increase significantly, an evaluation should be performed for any other potential 
infectious or inflammatory condition that was not previously evaluated. 
7.13.8. 
Post-treatment Assessment Period 
After completing axicabtagene ciloleucel infusion and completing the minimum 7-day 
observation period, all subjects will be followed in the post-treatment assessment period.  
Counting from Day 0 (axicabtagene ciloleucel infusion), subjects will return to the clinic at the 
following intervals. 
 Week 2 (± 2 days) 
 Week 3 (± 2 days) for subjects enrolled in Cohort 4 only 


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 Week 4 (± 3 days) 
 Month 2 (± 1 week) 
 Month 3 (± 1 week) 
Subject will allow key sponsor contacts to continue to access medical records so that information 
related to subjects health condition and initial treatment response may be obtained.  The 
following procedures will be completed for subjects as outlined in the SOA: 
 For subjects enrolled in Cohort 3, Cohort 4, Cohort 5, and Cohort 6, EQ-5D questionnaire 
(prior to any other assessments/procedures being performed) 
 For subjects enrolled in Cohort 1, Cohort 2, or Cohort 3, neurological assessment including 
MMSE  
 PET-CT for disease assessment:  If the PET-CT is not of high enough resolution, the scan 
must be repeated.  Refer to the imaging charter for detailed instructions. 
 As applicable, bone marrow aspirate/biopsy to confirm response (i.e., for subjects presenting 
with bone marrow involvement prior to therapy or if new abnormalities in the peripheral 
blood counts or blood smear cause clinical suspicion of bone marrow involvement with 
lymphoma after treatment) 
 Physical exam  
 Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature 
 Labs 
 Chemistry Panel  
 CBC with differential 
 β-HCG pregnancy test (serum or urine) on all women of child-bearing potential 
 Anti-axicabtagene ciloleucel antibodies 
 Cytokine levels 
 Lymphocyte subsets  
 Anti-CD19 CAR T cells 
 RCR analysis  


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 For subjects enrolled in Cohort 3, Cohort 4, Cohort 5, and Cohort 6, taper or discontinue 
levetiracetam as clinically indicated.  See Section 6.4 for further details.   
 For subjects assigned to Cohort 3, Cohort 4, Cohort 5, and Cohort 6, lumbar puncture for 
collection of CSF samples at Week 4 (± 3 days) 
 Adverse/Serious Adverse Event reporting (refer to Section 9 for safety reporting guidelines) 
 Concomitant medications documentation  
If a subject is admitted to the hospital during the 7-day observation period, discharged, and is 
subsequently re-admitted to the hospital with any axicabtagene ciloleucel related adverse 
event(s), the following labs will be collected on the day of hospital re-admission and then weekly 
through and including on the day of discharge: 
 PBMCs (anti-CD19 CAR T cells)  
 Cytokines  
At any time during the post treatment assessment period, if a subject progresses and is either not 
eligible for re-treatment or chooses not to pursue re-treatment, the subject will proceed directly 
to the Month 3 visit and be followed for survival, subsequent therapy and disease outcomes in 
the long term follow-up period.  A PBMC (for anti-CD19 CAR T cells) and serum sample (for 
cytokine evaluation) should be collected at the time of progression, prior to starting any 
subsequent anti-cancer therapy. 
 
  
7.13.9. 
Long-term Follow-up Period 
All enrolled subjects will be followed in the long term follow-up period for survival and disease 
status, if applicable.  Subjects will begin the long term follow-up period after they have 
completed the Month 3 visit of the post treatment assessment period (whether they have 
responded to treatment or went straight to the Month 3 visit due to disease progression)  
 Every 3 months (± 2 weeks) through Month 18 
 Every 6 months (± 1 month) between Month 24 - Month 60 
 Beginning with year 6, Month 72 (± 3 months), subjects will return to the clinic 1 time 
annually up to 15 years.   
The following procedures will be completed for subjects who are enrolled and receive 
axicabtagene ciloleucel at the time points outlined in the SOA: 
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 For subjects enrolled in Cohort 3, Cohort 4, Cohort 5, and Cohort 6, EQ-5D questionnaire 
(prior to any other assessments/procedures being performed) 
 Physical exam 
 PET-CT/ Disease assessment through 24 months or until disease progression, whichever 
occurs first. If subject’s disease has not progressed by Month 24, disease assessments will 
continue to be performed per institutional standard of care.  
 Survival status 
 Labs  
 CBC with differential  
 Anti-axicabtagene ciloleucel antibodies (refer to Section 7.11) 
 Lymphocyte subsets  
 Anti-CD19 CART-cell levels 
 RCR analysis  
 Subsequent therapy for the treatment of NHL  
 Refer to Sections 9.2 and 9.4 for targeted adverse/serious adverse event reporting 
 Neurological, hematological, infections, autoimmune disorders, and secondary malignancies  
 Targeted concomitant medication documentation (for 24 months or until disease progression, 
whichever occurs first) 
 Gammaglobulins, immunosuppressive drugs, anti-infectives, and vaccinations 
Subjects may be contacted by telephone to confirm survival status and report targeted 
concomitant medication use. 
If a subject progresses in the long-term follow-up (LTFU) phase, the subject will continue to be 
followed for survival status and subsequent therapy for the treatment of NHL.  A PBMC sample 
(for anti-CD19 CAR T cells) and serum (for cytokine evaluation) should be collected at the time 
of progression, prior to starting any subsequent anti-cancer therapy.  
 
 
The following procedures/assessments will be completed for subjects who are enrolled, but do 
not receive axicabtagene ciloleucel, at the time points outlined in the SOA: 
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 Subsequent therapy for the treatment of NHL 
 Survival status 
 Disease assessment per standard of care 
 Adverse/Serious Adverse Event reporting and concomitant medication documentation until 
30 days after last procedure (e.g., leukapheresis, conditioning chemotherapy).  
Should the subject fail to return to the clinic for a scheduled protocol specific visit, sites will 
need to make 2 attempts by a combination of telephone and mail 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 the subject will be considered lost to follow-up and no 
additional contact will be required. 
7.13.10. 
Retreatment  
Subjects who achieve a partial response (PR) or CR will have an option to receive a second 
course of conditioning chemotherapy and axicabtagene ciloleucel under the following 
conditions: 
 Subject had a PR or CR  
 Subjects disease subsequently progress 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
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  Subjects who are retreated will 
follow the same treatment schedule and procedural requirements per the initial treatment.  
Subjects enrolled in Phase 2 will receive the same axicabtagene ciloleucel regimen as the 
original target dose.  Subjects enrolled in Phase 1 will receive the axicabtagene ciloleucel 
regimen selected for Phase 2 if they are retreated.  
 
 
   
 
 
 
 
 
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Axicabtagene ciloleucel; KTE-C19 
Clinical Protocol: KTE-Cl9-101 
Table 11. 
Schedule of Assessments 
Procedures 
Screening 
Enrollment/ 
Leukapheresis 
Within 28 
Within approx. 5 
Day 
days of 
days of eligibility 
enrollment 
confirmation 
Medical history 
X 
ECOG Perfonnance Status 
X 
EQ-SD Questionnaire (Cohort 3,4 
X 
and 5 only) 
Neurological assessment including 
Mini Mental Status Exam (MMSE)5 
X 
ECG 
X 
ECHO 
X 
Archival/Fresh tumor1 
X 
Brain MRI 
X 
PET-CT/ disease assessment 2 
X 
Physical exam 
X 
Vital signs (BP, HR, 0 2 sat, temp) 
X 
X 
Weight (plus Height at screening) 
X 
X 
Pregnancy test ( serum or urine) 
X 
Lwnbar Puncture6 
X 
Blood draw for Chemistry panel 
X 
X 
Blood draw for CBC w/differential 
X 
X 
Blood draw for C-reactive protein 
X 
(CRP) 
Blood draw for Anti-axicabtagene 
ciloleucel antibodies 3 
X 
Blood draw for Lymphocyte subsets 
X 
Blood draw for Cytokines 7, 11 
X 
CONFIDENTIAL 
Debulking 
Conditioning Chemotherapy 
Therapy 
Pe.-iod 
(Coho11 S) 
Afte1· 
enrollment 
and at least 
-5 
-4 
-3 
-2 
-1 
14 days prio1· 
to Day-5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xu 
Page 80 of 118 
Kite Phanna, Inc. 
Final 
IP 
Post Treatment Follow-up 
Administration 
(each visit calculated from Day 0) 
Pe.-iod12 
Week 
Week 
Week 
Month 
Month 
2 
3 
4 
2 
3 
0 
1 - 7 
(±2 
(±2 
(± 3 
(± 1 
(± 1 
days) 
days) 
days) 
week) 
week) 
X 
X 
X 
QOD S 
X 
X 
between Day 7 & 
Day 14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QOD II 
X 
X 
11 February 2019 


Axicabtagene ciloleucel; KTE-C19 
Clinical Protocol: KTE-Cl9-101 
Kite Phanna, Inc. 
Final 
Procedures 
Screening 
Enrollment/ 
Debulking 
Conditioning Chemotherapy 
IP 
Post Treatment Follow-up 
Leukapheresis 
Therapy 
Pe.-iod 
Administration 
(each visit calculated from Day 0) 
(Coho11 S) 
Pe.-iod12 
Afte1· 
Week 
Week 
Week 
Month 
Month 
Within 28 
Within approx. 5 
enrollment 
Day 
days of 
days of eligibility 
and at least 
-5 
-4 
-3 
-2 
-1 
0 
1 - 7 
2 
3 
4 
2 
3 
(±2 
(±2 
(± 3 
(± 1 
(± 1 
enrollment 
confirmation 
14 days prio1· 
to Day-5 
days) 
days) 
days) 
week) 
week) 
Blood draw for Anti-CD19 CART 
Day 
cells7,U 
X 
X 
110,21°, 
X 
X 
X 
X 
3, 7, 10 
Blood draw for RCR analysis 
4 
X 
X 
Leukapberesis 
X 
Debulking Therapy (Coho11 5 only) 
X 
Fludarabine/Cyclophosphamide 
X 
X 
X 
Prophylactic Steroid13 (Cohort 6 
x•3 
xu 
only) 
Axicabtagene ciloleucel infusion IV 
X 
Tocilizumab8 
Day2 
Levetiracetam9 
Starting on Day 0 
Adverse events/ Concomitant 
medication 
X 
X 
1. 
Archival/Fresh tumor sample: Either FFPE tumor block or up to 20 unstallled slides. For sub3ects enrolled Ill Cohort 4 Cohort 5, and Cohort 6, a block or 30 unstallled slides. 
Archived and fresh tumor samples (if applicable) will be submitted to central laboratory after 
eligibility has been confirmed and prior to start of conditioning chemotherapy. Post treatment fresh tumor samples (if applicable) will be collected/submitted anytime between 
Day 7 and Day 14. See Section 7. 11 and 7 .12 and central laboratory manual for details 
2. 
PET-CT (Neck-Chest-Abdomen-Pelvis)/disease assessment PET-CT pe1fo1med follow-ing last line of therapy (>28 days from enrolliuent) may be used for confomation of 
eligibility. If PET-CT pe1fo1med > 28 days prior to the initiation of conditioning chemotherapy or if subject receives any anti-cancer therapy between screening and 
conditioning chemotherapy, baseline scans must be repeated. Screening PET-CT should be completed as close to enrolhuent as possible. As applicable, bone ma1Tow 
aspirate/biopsy will be performed to confom response (i.e., for subjects presenting with bone ma1Tow involvement prior to therapy or if new abno,malities in the peripheral 
blood counts or blood smear cause clinical suspicion of bone ma1Tow involvement with lymphoma after treatment). Bone mrurnw samples may also be collected and 
analyzed centrally for subjects who develop toxicities post axicabtagene ciloleucel. See Section 7 .10 and Section 7 .12 
-
3. 
Blood draw for Anti-axicabtagene ciloleucel antibodies: Baseline antibody sample to be collected prior to start ofleukapheresis. Post axicabtagene ciloleucel antibody sample 
to be collected at Week 4 and Month 3 visits. See Section 7 .11 for further details 
4. 
Blood draw for RCR: on Day 0 prior to administration of axicabtagene ciloleucel and at Month 3, 6 and 12; then collect yearly for up to 15 yeru·s. Yearly sruuples will only be 
analyzed if positive at Month 3, 6, or 12. 
5. 
MMSE and Cytokines: prior to axicabtagene ciloleucel infusion on Day 0, then on Day 1 and then every other day during the 7 day post infusion monitoring period for 
Cohort 1, Coho,t 2, and Coho,t 3. MMSE will not be required for Coho,t 4, Cohort 5, and Cohort 6. 
6. 
Lumbar Puncture: subjects with symptoms of CNS malignancy ( e.g., new onset severe headaches, neck stiffness, or focal neurological fllldings) will have lumbar puncture 
pe1fo1med at screening to assess cerebral spinal fluid for possible CNS involvement. Subjects with new onset Grade :::: 2 neurologic symptolllS post axicabtagene ciloleucel 
infusion will have lumber ptlllcttu·e performed to assess cerebral spinal fluid. 
CONFIDENTIAL 
Page81 ofll8 
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Axicabtagene ciloleucel; KTE-C19 
 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
 
Final 
CONFIDENTIAL 
 
Page 82 of 118 
 
11 February 2019 
  For subjects enrolled in 
Cohort 3,Cohort 4, Cohort 5, and Cohort 6, lumbar punctures for collection of CSF samples will be performed at the following time points: after eligibility is confirmed and 
prior to start of conditioning chemotherapy, post axicabtagene ciloleucel infusion on Day 5 (±3 days), and at the Week 4 visit (±3 days).   
7. 
If a subject is 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 anti-CD19 CAR T cells and cytokines will be collected on day of hospital re-admission and then weekly through and including the 
day of discharge. Blood samples for anti-CD19 CAR T cells and cytokines should also be collected at the time of disease progression prior to starting any subsequent 
anticancer therapy. 
8. 
For subjects enrolled in Cohort 3, administer tocilizumab at a dose of 8 mg/kg IV over 1 hour (not to exceed 800mg) on Day 2.  See Sections 6.3.4 for further details.  
9. 
For subjects enrolled in Cohorts 3, 4, 5, and 6, administer levetiracetam at a dose of 750 mg (PO or IV) BID starting on Day 0.  See Sections 6.3.4 and 6.4.1 for further 
details. 
10. For subjects enrolled in Cohorts 4 and 5, blood draw for Anti-CD19 CAR T cells will be collected on Day 3, Day 7, Day 10. For subjects enrolled in Cohort 6, blood draw 
for anti-CD19 CAR T cells will be collected on Day 1, Day 2, Day 3, Day 7, and Day 10. 
11. Blood draw for cytokines: prior to axicabtagene ciloleucel infusion on Day 0, then on Day 1, and then every other day during the 7 day post infusion monitoring period. For 
subjects enrolled in Cohort 5, additional cytokine sample after debulking therapy from Day -5 prior to conditioning chemotherapy. For subjects enrolled in 
Cohort 6, additional cytokine sample will be drawn on Day 2. 
12. Refer to Appendix B for requirements by country regulatory agencies. 
13. For subjects enrolled in Cohort 6, administer dexamethasone 
  
CCI
CCI


Axicabtagene ciloleucel; KTE-C19 
Clinical Protocol: KTE-Cl9-101 
Table 12. 
Schedule of Assessments (Long-term Follow-up Period) 
Procedure 
Long Term Follow-up Pe1iod 
(Each \oisit calculated from Day 0) 
Visit Frequency 
Month 
Month 
Month 
Month 
Month 
Month 
Month 
Month 
Month 
6 
9 
12 
15 
18 
24 
30 
36 
42 
EQ-5D Questionnaire (Cohorts 3, 4, 
X 
5, and 6 only) 
Physical exam1 
X 
X 
X 
X 
X 
X 
PET-CT/disease assessment2 
X 
X 
X 
X 
X 
X 
x2 
x2 
x2 
Survival Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood draw for CBC w/differential 3 
X 
X 
X 
X 
X 
X 
Blood draw for Anti-axicabtagene 
X 
X 
X 
ciloleucel antibodies 
4 
Blood draw for Lymphocyte subsets 
X 
X 
X 
X 
X 
X 
3 
Blood draw for anti-CD19 CART 
X 
X 
X 
cells3 
Blood draw for RCR analysis 5 
X 
X 
X 
X 
Targeted AE/SAEs 6 
X 
X 
X 
X 
X 
X 
Targeted concomitant medication 7 
X 
X 
X 
X 
X 
X 
Subsequent therapy for NHL 8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
l . 
Physical exams will continue through Month 24 
Kite Phanna, Inc. 
Final 
Month 
Month 
Month 
Month 72 and 
48 
54 
60 
Annually Thereafter 
x2 
x2 
x2 
x2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2. 
PET-CTs/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 pe1fo1med per standard of care. 
3. 
Subjects w-ill continue to provide samples for CBC w/diffs, lymphocyte subsets and anti-CD19 CART cells through Month 24 
4. 
Anti-axicabtagene ciloleucel antibody samples: refer to Section 7. 11 
5. 
RCR samples: collect and measmed at Month 3, 6 and 12, then collect yearly for up to 15 years. Yearly samples w-ill only be analyzed if positive at Month 3, 6, or 12. 
6. 
Targeted AEs/SAEs will be collected for 24 months or until disease progression (whichever occtu·s first) 
7. 
Targeted concomitant medications will be collected for 24 months or until disease progression (whichever occtu·s first) 
8. 
Subsequent therapy administered after axicabtagene ciloleucel infusion for a subjects' disease such as non-study specified chemotherapy, immunotherapy, targeted agents, as 
well as stem cell transplant and radiation therapy must be collected until subject completes the long teim follow up period, is considei·ed lost to follow up, withdraws consent, 
or dies. Subjects may be contacted by telephone to collect info,mation about subsequent thei·apy for NHL and to assess stu'Vival status. 
CONFIDENTIAL 
Page 83 of 118 
11 February 2019 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 84 of 118 
 
11 February 2019 
 
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 but continue 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 investigational product, study treatment or other 
protocol required therapies and must 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 or undergo procedures and the subject does not wish to 
continue further study follow-up.  Subject data collected up to withdrawal of consent will be 
retained and included in the analysis of the study, and where permitted by local regulations, 
publically available data (death records) can be included after withdrawal of consent.  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 also 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 or 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: 
 Adverse Event 
 Subject request 
 Product not available 
 Lost to Follow-up 
 Death 
 Decision by sponsor 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
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11 February 2019 
 
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 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 86 of 118 
 
11 February 2019 
 
9. 
SAFETY REPORTING 
9.1. 
Adverse Events 
An adverse event 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 adverse events observed by the investigator or reported by 
the subject are recorded in the subject’s medical record.  
The definition of adverse events 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.  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 adverse event. 
Interventions for pretreatment conditions (such as elective cosmetic surgery) or medical 
procedures that were planned before study participation are not considered adverse events.  
Hospitalization for study treatment infusions or precautionary measures per institutional 
policy are not considered adverse events. 
The term “disease progression” as assessed by measurement of malignant lesions on 
radiographs or other methods should not be reported as adverse events.  Death due to disease 
progression in the absence of signs and symptoms should be reported as the primary tumor 
type (e.g., B-Cell Lymphoma).  
For situations when an adverse event or serious adverse event is due to the disease under 
investigation report the signs and symptoms.  Worsening of signs and symptoms of the 
malignancy under study should also be reported as adverse events in the appropriate section 
of the CRF.  
The investigators clinical judgment is used to determine whether a subject is to be removed 
from treatment due to an adverse event.  In the event a subject requests to withdraw from 
protocol required therapies or the study due to an adverse event, 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 adverse events observed by the investigator 
or reported by the subject that occur from enrollment (ie, commencement of leukapheresis) 
through 3 months after treatment with axicabtagene ciloleucel infusion or until the initiation 
of another anti-cancer therapy, whichever occurs first.   After 3 months, targeted adverse 
events including (eg, neurological, hematological, infections, autoimmune disorders, and 
secondary malignancies) will be monitored and reported for 24 months after treatment with 
axicabtagene ciloleucel or until disease progression, whichever occurs first. 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 87 of 118 
 
11 February 2019 
 
For subjects who are enrolled, but do not receive axicabtagene ciloleucel, the adverse event 
reporting period ends 30 days after the last study-specific procedure (eg, leukapheresis, 
conditioning chemotherapy).  
The investigator must address the below for adverse events:  
 Adverse event diagnosis or syndrome (if not known, signs or symptoms) 
 Dates of onset and resolution 
 Severity 
 Assessment of relatedness to investigational product, conditioning chemotherapy or study 
procedures 
 Action taken 
Adverse event grading scale used will be the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. A copy of the grading scale can be downloaded from 
the CTEP home page (http://ctep.cancer.gov). Cytokine Release Syndrome events will also 
be reported using the grading scale outlined in Section 6.4.  
In reviewing adverse events, investigators must assess whether the adverse event is possibly 
related to 1) the investigational product (axicabtagene ciloleucel), 2) conditioning 
chemotherapy, or 3) any protocol-required study procedure.  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 
adverse event.  Additional relevant data with respect to describing the adverse event will be 
collected in the CRFs. 
The investigator is expected to follow reported adverse events until stabilization or 
resolution.  If a subject begins a new anticancer therapy, the adverse event reporting period 
for non-serious adverse events 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. 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 88 of 118 
 
11 February 2019 
 
An abnormal laboratory test result must be reported as an adverse event if it is a change from 
baseline and meets any of the following criteria: 
 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 
 Clinically significant in the investigator’s judgment  
9.3. 
Definition of Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the following 
serious criteria: 
 Fatal 
 Life threatening (places the subject at immediate risk of death) 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Congenital anomaly/birth defect 
 Other medically important serious event 
An adverse event 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 a serious adverse event. Examples of such events include movement from routine 
care in the hospital to the intensive care unit (ICU) 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 a serious adverse event with the criterion of 
“other medically important serious event.”  
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of an 
adverse event 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 adverse event recorded on the 
electronic CRF. 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 89 of 118 
 
11 February 2019 
 
9.4. 
Reporting of Serious Adverse Events  
The investigator is responsible for reporting all serious adverse events observed by the 
investigator or reported by the subject that occur after signing of the consent through 3 
months after the axicabtagene ciloleucel infusion or until the initiation of another anti-
cancer therapy, whichever occurs first.  After 3 months, only serious targeted adverse 
events (e.g., neurological, hematological, infections, autoimmune disorders, and secondary 
malignancies) observed by the investigator or reported by the subject will be reported for 
24 months after axicabtagene ciloleucel infusion or until disease progression, whichever 
occurs first.   For subjects who screen fail or are enrolled but do not receive axicabtagene 
ciloleucel, the reporting period for serious adverse events ends 30 days after the last 
procedure (e.g., screen procedure, leukapheresis, conditioning chemotherapy).   
Serious events that the investigator assesses as related to axicabtagene ciloleucel should be 
reported regardless of the study period. 
All SAEs must be submitted via email to 
 within 24 hours following 
the investigator’s knowledge of the event and using a SAE Report Form.  
Subsequently, all serious adverse events will be reported to the health authorities per local 
reporting guidelines. 
Progression of the malignancy during the study should not be reported as a serious adverse 
event. Adverse events associated with disease progression may be reported as serious adverse 
events.  If the malignancy has a fatal outcome within 3 months of the last day of the 
conditioning therapy or axicabtagene ciloleucel, then the event leading to death must be 
recorded as a serious adverse event with CTCAE Grade 5. 
Death must be reported if it occurs during the serious adverse event 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 the axicabtagene ciloleucel infusion, regardless of 
attribution to treatment, requires expedited reporting within 24 hours.  Any death occurring 
greater than 3 months after the axicabtagene ciloleucel infusion 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 adverse event reporting period that are 
attributed by the investigator solely to progression of underlying lymphoma should be 
recorded as serious adverse events (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.  The term “unexplained death” should be captured if the cause of death is not 
known.  However, every effort should be made to capture the established cause of death, 
which may become available later on (eg, after autopsy). Deaths during the post-study 
survival follow-up due to underlying cancer should be recorded only on the Survival Status 
CRF.  
PPD


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
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11 February 2019 
 
9.6. 
Diagnosis versus Signs and Symptoms 
For adverse events, 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 signs 
and symptoms will be captured on the CRF 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. 
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%) through at least 
6 months after conditioning chemotherapy dosing or axicabtagene ciloleucel dosing, 
whichever is longer. Male subjects are recommended not to father a child for at least 
6 months after completing conditioning chemotherapy dosing or axicabtagene ciloleucel 
dosing, whichever is longer.  
If a pregnancy occurs in a female subject enrolled into the study, or a female partner of a 
male subject, within 6 months of completing the conditioning chemotherapy or 
axicabtagene ciloleucel dosing (whichever is longer), the pregnancy must be reported to 
the key sponsor contact.  Information regarding the pregnancy and/or the outcome may be 
requested by the key sponsor.  
The pregnancy should be reported to the key sponsor contact within 24 hours of the 
investigator’s knowledge of the pregnancy event.  
If a lactation case occurs while the female subject is taking protocol required therapies report 
the lactation case to the key sponsor contact. 
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of protocol required therapies through 6 months. 
Any lactation case should be reported to the key sponsor contact within 24 hours of the 
investigator’s knowledge of the event. 
9.8. 
Hospitalization and Prolonged Hospitalization 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event as described in Section 9.4.   


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
Page 91 of 118 
 
11 February 2019 
 
The following hospitalization scenarios are not considered to be serious adverse events: 
 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 
9.9. 
Abnormal Vital Sign Values 
Not all vital sign abnormalities qualify as an adverse event.  A vital sign result must be 
reported as an adverse event 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 whether an isolated vital sign abnormality should 
be classified as an adverse event.  However, if a clinically significant vital sign abnormality 
is a sign of a disease or syndrome (eg, high blood pressure), only the diagnosis 
(ie, hypertension) should be recorded on the CRF. 
9.10. 
Safety Review Team and Dose-limiting Toxicity 
Phase 1 Study 
The SRT will be specifically chartered to review safety data during Phase 1 of the study and 
make recommendations on further study conduct in Phase 1 and progression to Phase 2 based 
on the incidence of axicabtagene ciloleucel DLT and review of serious adverse events.    
Dose-limiting toxicity is defined as the following axicabtagene ciloleucel-related events with 
onset within the first 30 days following axicabtagene ciloleucel infusion: 
 Grade 4 neutropenia lasting longer than 21 days from the day of cell transfer 
 Grade 4 thrombocytopenia lasting longer than 35 days from the day of cell transfer 
 Any axicabtagene ciloleucel-related adverse event requiring intubation, including 
Grade 4 confusion requiring intubation for airway protection is considered to be a DLT. 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
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11 February 2019 
 
 All other Grade 3 toxicities lasting more than 3 days and all Grade 4 toxicities, with the 
exception of the following conditions which are not considered DLTs: 
 Aphasia/dysphasia or confusion/cognitive disturbance which resolves to Grade 1 or less 
within 2 weeks and to baseline within 4 weeks 
 Fever Grade 3   
 Myelosuppression (includes bleeding in the setting of platelet count less than 50 x109/L 
and documented bacterial infections in the setting of neutropenia), defined as 
lymphopenia, decreased hemoglobin, neutropenia and thrombocytopenia unless 
neutropenia and thrombocytopenia meet the DLT definition described above 
 Immediate hypersensitivity reactions occurring within 2 hours of cell infusion (related to 
cell infusion) that are reversible to a Grade 2 or less within 24 hours of cell 
administration with standard therapy 
 Hypogammaglobulinemia Grade 3 or 4 
As noted in Section 6.4 CRS will be graded according to a revised grading system (Lee et al, 
2014).  Adverse events attributed to CRS will be mapped to the overall CRS grading 
assessment for the determination of DLT.   
During Phase 1, approximately 6 to 24 subjects with DLBCL, PMBCL, or TFL will be 
enrolled to evaluate the safety of axicabtagene ciloleucel regimens.   
Subjects in each cohort will be evaluated for DLTs within the first 30 days following the 
completion of their respective axicabtagene ciloleucel infusion.  The analysis of DLTs will 
be based on the DLT evaluable set as defined in Section 10.5 .  The SRT will make 
recommendations based on the incidence of DLT and overall safety profile of the 
axicabtagene ciloleucel regimen.  If the subject incidence of DLT is ≤ 1 of 6 subjects, Cohort 
B1 may be explored or the study may proceed to Phase 2 of the trial.  This decision will be 
based on overall benefit/risk and available biomarker data.  
However, if 2 of the 6 enrolled subjects present with a protocol defined DLT during Phase 1, 
the SRT may recommend enrolling 2 additional sets of 3 subjects (up to 12 subjects in total) 
at the same dose that was administered in the first 6 subjects.  In this scenario, progression to 
an additional cohort or to Phase 2 of the study will proceed if ≤ 2 of the first 9 or if ≤ 3 of the 
12 subjects present with a DLT.  
If the subject incidence of DLT is > 2/6, > 3/9, or > 4/12 subjects, other axicabtagene 
ciloleucel regimens may be explored in an additional 6 to 12 subjects (Figure 3).  The same 
DLT rules apply as above. 


Axicabtagene ciloleucel; KTE-C19 
Kite Pharma, Inc. 
Clinical Protocol: KTE-C19-101 
Final  
CONFIDENTIAL 
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9.11. 
Data Safety Monitoring Board 
Phase 2 Pivotal Study 
 
 
  The DSMB will review safety and efficacy data and be 
chartered to make trial conduct recommendations based on an analysis of risk vs. benefit. 
Phase 2 Safety Management Study 
The DSMB will also meet to review safety data when 20 subjects in Cohort 3, Cohort 4, 
Cohort 5, and Cohort 6 have been treated with axicabtagene ciloleucel and have had the 
opportunity to be followed for 30 days, respectively.  The DSMB may meet more often as 
needed. In addition, Kite Pharma or delegate will submit SAEs or suspected unexpected 
serious adverse reactions (SUSARs) to the DSMB chair for risk benefit analysis.  The DSMB 
Chair will review reported SAEs at least monthly and SUSARs as soon as received.   
9.12. 
Criteria to Pause Enrollment 
Phase 2 Pivotal Study 
As part of its oversight of the study, the DSMB also will assess criteria to pause enrollment 
after 10, 20, 30, and 50 subjects in the Phase 2 pivotal portion of the study have been treated 
with axicabtagene ciloleucel and have had the opportunity to be followed for 30 days.  
Enrollment will be paused if any of the following criteria is met: 
1) Subject incidence of Grade 5 axicabtagene ciloleucel-related adverse events within 
30 days is > 10%. 
or 
2) Subject incidence of the following Grade 4 axicabtagene ciloleucel-related adverse events 
lasting more than 7 days is > 33%: 
 Neurologic toxicities 
 CRS (per Lee 2014 criteria) (Lee et al, 2014) 
 Other non-hematological serious adverse event 
 Infection (treatment-related) 
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10. 
STATISTICAL CONSIDERATIONS 
The primary objective of the Phase 1 Study is to evaluate the safety of axicabtagene 
ciloleucel regimens.  The primary objective of the pivotal Phase 2 portion is to evaluate the 
efficacy of axicabtagene ciloleucel, as measured by ORR in subjects with DLBCL, PMBCL, 
and TFL.  Secondary objectives will include assessing the safety and tolerability of 
axicabtagene ciloleucel and additional efficacy endpoints.  Inferential testing will only be 
performed for efficacy for Phase 2 pivotal study Cohort 1 and Cohort 2.  For the Phase 2 
safety management study, Cohort 3, Cohort 4, Cohort 5, and Cohort 6, the primary objective 
is to assess the impact of prophylactic regimens, earlier interventions, debulking therapy, or 
prophylactic steroids on the rate and severity of CRS and neurologic toxicities. 
10.1. 
Hypothesis 
Phase 2 pivotal study Cohort 1 and Cohort 2:  This study is designed to differentiate between 
a treatment that has a true response rate of 20% or less and a treatment with a true response 
rate of 40% or more.  The hypothesis is that the ORR to axicabtagene ciloleucel in Cohort 1 
and Cohort 2 is significantly greater than 20%. 
Phase 2 safety management study Cohort 3, Cohort 4, Cohort 5, and Cohort 6:  No 
hypothesis will be tested in Cohort 3, Cohort 4, Cohort 5, and Cohort 6, which will be used 
to assess the impact of prophylactic regimens, earlier interventions, debulking therapy, or 
prophylactic steroids on the rate and severity of CRS and neurologic toxicities. 
10.2. 
Study Endpoints 
10.2.1. 
Primary 
Phase 1 study:  Incidence of adverse events defined as DLT. 
Phase 2 pivotal study:  ORR, defined as the incidence of either a complete response or a 
partial response by the revised IWG Response Criteria for Malignant Lymphoma (Cheson et 
al, 2007) as determined by the study investigators.  All subjects who do not meet the criteria 
for an objective response by the analysis data cutoff date will be considered non-responders.  
Phase 2 safety management study:  incidence and severity of CRS and neurologic toxicities. 
10.2.2. 
Secondary 
Duration of response (DOR): Among subjects who experience an objective response, DOR 
is defined as the date of their first objective response (which is subsequently confirmed) to 
disease progression per the revised IWG Response Criteria for Malignant Lymphoma 
(Cheson et al, 2007) or death regardless of cause. Subjects not meeting the criteria for 
progression or death by the analysis data cutoff date will be censored at their last evaluable 
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ORR among subjects in Phase 1 will be summarized. 
ORR per Independent Radiological Review Committee (IRRC) (Phase 2):  ORR per IRRC 
is defined as the incidence of either a complete response or a partial response by the revised 
IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) as determined by the 
IRRC.  All subjects that do not meet the criteria for an objective response by the analysis data 
cutoff date will be considered non-responders.   
Progression-free Survival (PFS): PFS is defined as the time from the axicabtagene ciloleucel 
infusion date to the date of disease progression per the revised IWG Response Criteria for 
Malignant Lymphoma (Cheson et al, 2007) or death from any cause.  Subjects not meeting 
the criteria for progression by the analysis data cutoff date will be censored at their last 
evaluable disease assessment date.   
OS:  OS is defined as the time from axicabtagene ciloleucel infusion to the date of death.  
Subjects who have not died by the analysis data cutoff date will be censored at their last 
contact date. 
Incidence of adverse events and clinical significant changes in safety lab values. 
Incidence of anti-axicabtagene ciloleucel antibodies, levels of anti-CD19 CAR T cells in 
blood, and levels of cytokines in serum will be summarized. 
Additional Phase 2 Safety management study secondary endpoints include the following: 
 ORR for subjects treated in the safety management study Cohort 3, Cohort 4, Cohort 5, 
and Cohort 6 
 Changes over time in the EQ-5D scale score and EQ-5D VAS score for subjects treated 
in Cohort 3, Cohort 4, Cohort 5 and Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
10.3. 
Sample Size Considerations 
The anticipated enrollment in this study is approximately 268 to 286 subjects. 
Phase 1 Study:  Six to 24 subjects will be enrolled into each cohort in Phase 1 of this study. 
If the study proceeds to Phase 2 pivotal study, approximately 72 subjects will be enrolled into 
Cohort 1, and approximately 20 subjects will be enrolled into Cohort 2.  
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In the Phase 2 safety management study, approximately 40 subjects will be enrolled into 
Cohort 3, approximately 40 subjects will be enrolled and dosed into Cohort 4, approximately 
50 subjects will be enrolled and dosed into Cohort 5, and approximately 40 subjects will be 
enrolled and dosed into Cohort 6. 
ORR and all analyses based on the objective response (objective response, duration of 
response, progression-free survival) in the Phase 1 and Phase 2 portions of the study will be 
based on a mITT population consisting of all subjects who receive the target dose of 
axicabtagene ciloleucel.   
 
  For Cohort 3, Cohort 4, Cohort 5, and Cohort 6, the primary objective will be to 
assess the impact of prophylactic regimens, earlier interventions, debulking therapy, or 
prophylactic steroids on the rate and severity of CRS and neurologic toxicities.  ORR with 
axicabtagene ciloleucel treatment in subjects with relapsed or refractory DLBCL, PMBCL, 
TFL, or HGBCL in Cohort 3, Cohort 4, Cohort 5, and Cohort 6 will be a secondary 
endpoint, and the analysis will be descriptive.  
10.3.1. 
Phase 2 Pivotal Study, Cohort 1, and Cohort 2 
This study uses a single arm design to test for an improvement in response rate 
 
.  For the test 
of efficacy this study has ≥ 90% power to distinguish between an active therapy with a 40% 
true response rate from a therapy with a response rate of 20% or less with a 1-sided alpha 
level of 0.025.   
 
 
 
  
Within Cohort 1,
 1 primary analyses will be performed.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 The primary analysis of Cohort 1 will occur after 72 subjects in the mITT set have had 
the opportunity to be assessed for response 6 months after the axicabtagene ciloleucel 
infusion.  The nominal alpha level for the assessment of efficacy at the primary analysis 
is 0.011. 
 
   
For Cohorts 1 and 2 combined, 1 primary analysis will be performed when 72 subjects in the 
mITT set in Cohort 1 and 20 subjects in the mITT set in Cohort 2 have had the opportunity to 
be assessed for response 6 months after the axicabtagene ciloleucel infusion.  This testing 
will be performed at a 1-sided alpha level of 0.0075.  Descriptive confidence intervals about 
the ORRs within Cohorts 1 and 2 will be presented with the inferential analysis of Cohorts 1 
and 2 combined. 
As indicated above, inferential testing of Cohort 1 will occur when 72 subjects in the mITT 
set in Cohort 1 have had the opportunity to be followed for 6 months after the axicabtagene 
ciloleucel infusion.  The efficacy data from any additional subjects (beyond 72) enrolled into 
Cohort 1 will be analyzed descriptively.  Similarly, inferential testing of Cohorts 1 and 2 will 
occur when 72 subjects in the mITT set of Cohort 1 and 20 subjects in the mITT set of 
Cohort 2 have had the opportunity to be followed for 6 months following the axicabtagene 
ciloleucel infusion.  The efficacy data from any additional subjects (beyond 92) enrolled into 
Cohorts 1 and 2 will be analyzed descriptively.   
The derivation of the alpha levels for the test of Cohort 1 and the overall study population 
were originally obtained under the assumption of 40 subjects enrolled into Cohort 2.  These 
original derivations are retained in this protocol amendment as they result in a more 
conservative alpha level for the test of Cohort 1.   
This procedure preserves the designated alpha level (1-sided) of 0.025 and has ≥ 90% power.  
 
 
10.3.2. 
Phase 2 Safety Management Study  
The primary objective of Phase 2 safety management study Cohort 3, Cohort 4, Cohort 5, 
and Cohort 6 is to assess the impact of prophylactic regimens, earlier interventions, 
debulking therapy, or prophylactic steroids on the rate and severity of CRS and neurologic 
toxicities.  The assessment of ORR is a secondary objective, and the analysis will be 
descriptive.  
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10.4. 
Statistical Assumptions 
Phase 1 Study 
The primary endpoint for the Phase 1 portion of the study is the incidence of DLT. 
Phase 2 Pivotal Study 
Cohorts 1 and 2 of this trial will enroll subjects with chemo-refractory lymphoma, as 
evidenced by failure to achieve even a transient or partial response to prior biologic and 
combination chemotherapy or by early recurrence after ASCT. 
 
 
 
 
 
 
   
Phase 2 Safety Management Study 
Analyses of the safety and efficacy endpoints will be descriptive, with no formal statistical 
testing being performed.  Subject incidence rates of treatment-emergent CRS, neurologic 
toxicities, axicabtagene ciloleucel-related adverse events, and ORRs will be summarized by 
cohort.  DOR, PFS, and OS will also be summarized by cohort.  
10.5. 
Analysis Subsets   
10.5.1. 
Phase 1 Study 
Depending on the dosing cohort and results of the Phase 1 portion of the study, axicabtagene 
ciloleucel may be: 
 administered as a single infusion at a target dose of 2 x 106 anti-CD19 CAR T cells/kg 
(± 20%).  For subjects weighing greater than 100 kg, a maximum flat dose of 2 x 108 
anti-CD19 CAR T cells will be administered. A minimum dose of 1 x 106 anti-CD19 
CAR T cells/kg may be administered; or 
 administered as a single infusion at a target dose of 1 x 106 anti-CD19 CAR T cells/kg 
(± 20%) in the Phase 2 portion of the study. In this case, for subjects weighing greater 
than 
 anti-CD19 CAR T cells will be 
administered. A 
 anti-CD19 CAR T cells/kg may be 
administered. 
The DLT evaluable set (Phase 1 only), defined for each dosing cohort in Phase 1, will 
include subjects treated in the Phase 1 dosing cohort who:   
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 received the target and were followed for at least 30 days after the anti-CD19 CAR T cell 
infusion; or  
 received a dose of anti-CD19 CAR T cells lower than the target for that cohort and 
experienced a DLT during the 30 day post-infusion period.   
If needed, more subjects will be enrolled to achieve 6 DLT evaluable subjects at the target 
dose for each cohort.  
Safety set:  the safety set is defined as all subjects treated with any dose of axicabtagene 
ciloleucel. 
10.5.2. 
Phase 2 Study   
In the Phase 2 portion of the study (including the Phase 2 pivotal study and SMS), subjects 
are to be dosed at a target of 2 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 greater than 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 1 x 106 anti-CD19 CAR T cells/kg 
up to 2 x 106 anti-CD19 CAR T cells/kg or, if the subject weighs more than 100 kg, the 
subject receives 2 x 108 anti-CD19 CAR T cells.  
Modified Intent-to-Treat Set:  the mITT set will consist of all subjects enrolled and treated 
with axicabtagene ciloleucel at a dose of at least 1 x 106 anti-CD19 CAR T cells/kg.   
This analysis set will be used for all analyses of objective response and endpoints based on 
objective response (objective response, duration of response, progression-free survival) for 
both the Phase 1 and Phase 2 portions of the study (including both pivotal and SMS). 
Safety analysis set:  the safety analysis set is defined as all subjects treated with any dose of 
axicabtagene ciloleucel. 
Full Analysis set (FAS):  the full analysis set will consist of all enrolled subjects and will be 
used for the summary of subject disposition, sensitivity analyses of ORR and DOR, and 
subject listings of deaths. 
10.6. 
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 Phase 2 portion of 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 analysis plan, DSMB charter, 
and Trial Integrity Document. 


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10.7. 
Interim Analysis 
10.7.1. 
Interim Analysis and Early Stopping Rules 
Phase 1 Study 
The SRT will be chartered to review safety during Phase 1 of the study only and make 
recommendations on further study conduct in Phase 1 and progression to Phase 2.   
Phase 2 Pivotal Study 
An independent DSMB will be formed to review accumulating safety and efficacy data  
 
   
The DSMB will also monitor criteria to pause enrollment (see Section 9.12). 
Phase 2 Safety Management Study 
The DSMB will review safety data when 20 subjects treated in Cohort 3, Cohort 4, Cohort 5, 
and Cohort 6 have had the opportunity to be followed for 30 days, respectively.   
10.7.2. 
Safety Interim Analysis 
The DSMB will review AE and SAE information on a regular basis throughout subject 
treatment in Phase 2 of the study.  The DSMB may request additional safety data or to 
modify the study conduct.  The sponsor may request additional reviews by the DSMB if 
safety concerns are identified. Data submitted to the DSMB may be monitored or 
unmonitored to facilitate timely DSMB review.   
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.8. 
Planned Method of Analysis 
Phase 1 Study 
Descriptive analysis of the Phase 1 portion of the study may occur at any time. 
Phase 2 Pivotal Study  
The primary efficacy analyses of Cohort 1 will be performed when 72 subjects in the mITT 
set of Cohort 1 have had the opportunity to be evaluated for response 6 months after the 
axicabtagene ciloleucel infusion.  The primary analysis of Cohorts 1 and 2 combined will be 
performed when 72 subjects in the mITT set of Cohort 1 and 20 subjects in the mITT set of 
Cohort 2 have had the opportunity to be evaluated for response at 6 months after the target 
axicabtagene ciloleucel infusion.  Additional analyses may occur after the primary analysis.  
These additional analyses will be descriptive and will occur after inferential testing has been 
performed.  The final analysis will occur when all subjects have completed the study.  
The primary endpoint of ORR for all analyses (
 primary) will be based 
on investigator review of disease assessments in the mITT set.  For Cohorts 1 and 2, 
sensitivity analyses of ORR based on central radiologic review of disease assessments will be 
performed. 
Analyses of efficacy endpoints will be summarized by study phase, for Cohort 1 alone, for 
Cohort 1 and Cohort 2 combined, and for Cohort 3 alone.  Analyses of safety endpoints will 
be evaluated by study phase, cohort, Cohort 1 and 2 combined.  
Phase 2 Safety Management Study 
The primary analysis of Cohort 3, Cohort 4, Cohort 5, and Cohort 6 will occur after all 
treated subjects in each cohort have had the opportunity to be followed for 6 months, 
respectively.  The ORR in Cohort 3, Cohort 4, Cohort 5, and Cohort 6 will be based on 
investigator review of disease assessment in the mITT set.  No central radiologic review of 
disease assessment will be performed for these cohorts. 
Descriptive analyses of the Phase 2 SMS Cohort 3, Cohort 4, Cohort 5, and Cohort 6 may 
occur at any time. 
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10.8.1. 
Objective Response Rate 
The incidence of objective response and exact 2-sided 95% confidence intervals will be 
generated.  For the Phase 2 pivotal study, Cohort 1 and Cohort 2, an exact binomial test will 
be used to compare the observed response rate to a response rate of 20%. 
10.8.2. 
Duration of Response 
Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for duration 
of response. Estimates of the proportion of subjects in response at 3-month intervals from the 
first response will be provided. The competing-risk analysis method (Pepe 1991; Fine and 
Gray 1999) may be used to estimate the cumulative incidence of relapse.  The cumulative 
incidence of relapse in the presence of non-disease related mortality (the competing risk) 
may be estimated along with 2-sided 95% confidence intervals at 3-month intervals.   
10.8.3. 
Progression-free Survival 
Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for 
progression-free survival time.  Estimates of the proportion of subjects alive and progression-
free at 3-month intervals will be provided. 
10.8.4. 
Overall Survival 
Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for OS.  
Estimates of the proportion of subjects alive at 3-month intervals will be provided. 
10.8.5. 
Safety 
Subject incidence rates of adverse events including all, serious, fatal, CTCAE version 4 
Grade 3 or higher and treatment related AEs reported throughout the conduct of the study 
will be tabulated by preferred term and system organ class.  Changes in laboratory values and 
 will be summarized with descriptive statistics.  
 
 
For Cohort 3, Cohort 4, Cohort 5, and Cohort 6, the incidences and severity of CRS and 
neurologic toxicities may be compared to the rates in Cohort 1 and Cohort 2 combined with a 
binomial test.   
Tables and/or narratives of deaths through the long term follow-up and treatment related 
SAEs will be provided. 
10.8.6. 
Long-term Data Analysis 
All subjects will be followed for survival for up to approximately 15 years after the last 
subject receives axicabtagene ciloleucel.  No formal hypothesis testing will be performed 
based on data obtained after the cutoff for the primary analysis.  Descriptive estimates of key 
efficacy and safety analyses may be updated to assess the overall treatment profile. 
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11. 
REGULATORY OBLIGATIONS  
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 sites respective IRB/IEC for approval. Once 
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 are to submit site specific and study serious 
adverse events (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 contained at all material submitted to the key sponsor contact. 
The following rules are to be applied. 
 Subjects will be identified by a unique identification number 
 Date of birth or year of birth/age at time of enrollment will be reported according with 
local laws and regulations 
For reporting of serious adverse events, subjects will be identified by their respective subject 
identification number, initials and data of birth or year of birth (as per their local reporting 
requirements for both initials and date of birth) 
Per federal regulations and International Conference on Harmonisation/Good Clinical 
Practice (ICH/GCP) guidelines, investigators and institutions are required to permit 
authorization to the sponsor, contract research organization (CRO), 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 clinical study report will be signed by the coordinating investigator.  The coordinating 
investigator will be identified by Kite Pharma under the following criteria: 
 A recognized expert in the disease setting 
 Provided significant contributions to the design or analysis of study data 
 Participate 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 investigators 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 of the trial completion or 
early termination and provide the CRO with a copy of the correspondence. 
Kite Pharma reserves the unilateral right, at is sole discretion, to determine whether to 
manufacture axicabtagene ciloleucel T cells and provide them to sites and subjects after the 
completion of the study and before treatment becomes commercially available. 


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13. 
STUDY DOCUMENTATION AND ARCHIVE 
The investigator will maintain a list of qualified staff to whom study responsibilities have 
been delegated.  These 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, radiology and 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, use of the 
CRFs as source documentation as a routine practice is not recommended. 
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, regulatory authorities and IRB/IECs. The 
filing system will include at minimum: 
 Subject content including ICFs and subject identification 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 Pharma and the investigator. Should storage no longer be 
available to archive source documents or must be moved to an alternative location, the 
research staff should notify the key sponsor contact prior to the 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 assuring that subject confidentially is respected. 
The monitor is responsible for source document verification of CRF data at regular intervals 
during the study. Protocol adherence, 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 medications 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-C19-101 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:  
 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 re appropriately investigated or 
resolved 
When a large, multicenter group has conducted the work, the group should identify the 
individual who accepts 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 
Pharma for review and approval. The study contract between the institution, principal 
investigation and Kite Pharma or its delegate will outline the requirements for publication 
review. 


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16. 
COMPENSATION 
Kite Pharma 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. 
REFERENCES 
Ardeshna KM, Kakouros N, Qian W, Powell MG, Saini N, D'Sa S, et al. Conventional 
second-line salvage chemotherapy regimens are not warranted in patients with malignant 
lymphomas who have progressive disease after first-line salvage therapy regimens. Br J 
Haematol. 2005;130(3):363-72. 
Better M, Pugach O, Lu L, Somerville R, Kassim S, Kochenderfer J, et al. Rapid cell 
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18. 
APPENDICES 
Appendix A 
Revised IWG Response Criteria for Malignant Lymphoma  (Cheson et al, 
2007) 
Appendix B 
Monitoring of subjects after IP administration per country regulatory agencies: 


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Appendix A 
Revised IWG Response Criteria for Malignant Lymphoma  
(Cheson et al, 2007) 
Complete Remission (CR):  CR requires all of the following:  
 Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy.  
 Typically FDG-avid lymphoma (large cell, mantle cell and follicular lymphomas are all 
typically FDG-avid):  in subjects with no pretreatment PET scan or when the PET scan 
was positive before therapy, a post-treatment residual mass of any size is permitted as 
long as it is PET negative.   
 Variably FDG-avid lymphomas/FDG avidity unknown:  in subjects without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, all lymph nodes and 
nodal masses must have regressed to normal size (≤ 1.5 cm in greatest diameter if > 
1.5 cm before therapy).  Previously involved nodes that were 1.1 to 1.5 cm in their long 
axis and more than 1 cm in their short axis before treatment must have decreased to ≤ 
1.0 cm in their short axis after treatment.   
 The spleen and/or liver, if considered to be enlarged before therapy on basis of physical 
exam or CT scan, must should be normal size on CT scan and not be palpable on physical 
examination and nodules thought to represent lymphoma must no longer be present.   
 A bone marrow aspirate and biopsy is performed only when the patient had bone marrow 
involvement with lymphoma prior to therapy or if new abnormalities in the peripheral 
blood counts or blood smear cause clinical suspicion of bone marrow involvement with 
lymphoma after treatment.  The bone marrow aspirate and biopsy must show no evidence 
of disease by morphology or if indeterminate by morphology it must be negative by 
immunohistochemistry.  The biopsy core sample must be a minimum of 20 mm in length.  
Partial Remission (PR): PR requires all of the following: 
 ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest 
dominant nodes or nodal masses.  Dominant nodes or nodal masses should be clearly 
measurable in at least 2 perpendicular dimensions, should be from different regions of the 
body if possible and should include mediastinal and retroperitoneal nodes if possible.   
 No increase in size of nodes, liver or spleen and no new sites of disease.   
 If multiple splenic and hepatic nodules are present, they must regress by ≥ 50% in the 
SPD.  There must be a > 50% decrease in the greatest transverse diameter for single 
nodules.    


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 Bone marrow is irrelevant for determination of a PR.  If patient has persistent bone 
marrow involvement and otherwise meets criteria for CR the patient will be considered a 
PR. 
 Typically FDG-avid lymphoma:  for subjects with no pretreatment PET scan or if the 
PET scan was positive before therapy, the post-treatment PET scan should be positive in 
at least one previously involved site.  Note: in subjects with follicular lymphoma or 
mantle-cell lymphoma, a PET scan is only indicated in subjects with one or at most two 
residual masses that have regressed by 50% on CT scan. 
Stable Disease (SD):  
 Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.  
PET should be positive in typically FDG-avid lymphomas. 
Progressive Disease:  
Defined by at least one of the following:   
 ≥ 50% increase from nadir in the sum of the products of at least two lymph nodes, or if a 
single node is involved at least a 50% increase in the product of the diameters of this one 
node.   
 Appearance of a new lesion greater than 1.5 cm in any axis even if other lesions are 
decreasing in size 
 Greater than or equal to a 50% increase in size of splenic or hepatic nodules  
 At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis.  
 Lesions should be PET positive in typically FDG-avid lymphomas unless the lesion is too 
small to be detected by PET (< 1.5 cm in its long axis by CT)


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Appendix B 
Monitoring of subjects after IP administration per country regulatory 
agencies: 
Germany: 
The post-infusion monitoring of subjects, described in Section 7.13.7.2 in this protocol, will be 
extended by monitoring on Day 8, Day 9, and Day 10, according to procedures outlined in 
Table 11, column “IP administration period, 1-7”. 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 7.4), blood draw for chemistry panel 
with CRP, blood draw for CBC w/differential (see Section 7.11), and neurological assessment. 
Any observed toxicity will be managed according to Section 6.4 of this protocol.  
France: 
The post-infusion monitoring of subjects in this protocol will be extended by monitoring on 
Day 8, Day 9, and Day 10, according to procedures outlined in Table 11, column “IP 
administration period, 1-7.” The L'Agence nationale de sécurité du médicament et des 
produits de santé (ANSM) recommends a 10-day hospitalization after infusion of any CAR 
T-cell product.   
The daily monitoring will include vital signs (see Section 6.4), blood draw for chemistry 
panel with CRP, blood draw for CBC w/differential (see Section 7.11), and neurological 
assessment. Any observed toxicity will be evaluated according to Section 6.4 of this 
protocol. 

SAP_001.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Sponsor: 
Kite Pharma, Inc. 
2400 Broadway 
Santa Monica, CA 90404 
United States of America 
 
 
Product Name: 
Axicabtagene ciloleucel 
 
 
Protocol: 
A Phase 1/2 Multicenter Study Evaluating the Safety and 
Efficacy of KTE-C19 in Subjects with Refractory Aggressive 
Non-Hodgkin Lymphoma (ZUMA-1) 
 
 
Version Number: 
Version 3.0 
 
 
Release Date: 
08 July 2019 
 
 
Replaces Previous 
Version(s): 
Version 2.0; dated 28 August 2016 
 
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 site 
research staff 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.  Questions regarding how this document should be used or the conduct of 
the clinical trial should be directed to the key sponsor contacts. 
Kite 
A GIL EAu Compal'ly 


KTE-C19 
Kite Pharma, Inc. 
Statistical Analysis Plan 
 
KTE-C19-101 (ZUMA-1) 
CONFIDENTIAL 
Page 2 
08 July 2019 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .............................................................................................................................. 1 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 4 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 4 
LIST OF ABBREVIATIONS ........................................................................................................................................ 5 
1. 
INTRODUCTION ................................................................................................................................................ 7 
2. 
OBJECTIVES ....................................................................................................................................................... 8 
3. 
STUDY OVERVIEW ........................................................................................................................................... 9 
3.1. 
Study Design ............................................................................................................................................ 9 
3.2. 
Hypothesis .............................................................................................................................................. 12 
3.3. 
Sample Size Considerations ................................................................................................................... 12 
3.3.1. 
Phase 2 Pivotal Study, Cohorts 1 and 2 ................................................................................ 14 
3.3.2. 
Phase 2 SMS, Cohorts 3, 4, 5 and 6 ..................................................................................... 15 
3.4. 
Statistical Assumptions .......................................................................................................................... 17 
4. 
STUDY ENDPOINTS AND COVARIATES .................................................................................................... 19 
4.1. 
Endpoints ............................................................................................................................................... 19 
4.1.1. 
Primary ................................................................................................................................. 19 
4.1.2. 
Secondary (all Phases, unless noted) .................................................................................... 19 
 
 
4.2. 
Covariates ............................................................................................................................................... 20 
5. 
DEFINITIONS .................................................................................................................................................... 24 
5.1. 
General ................................................................................................................................................... 24 
5.2. 
Safety ..................................................................................................................................................... 25 
5.3. 
Efficacy .................................................................................................................................................. 26 
6. 
ANALYSIS SETS............................................................................................................................................... 28 
6.1. 
Modified Intent-to-Treat (mITT) (defined for Phase 2) ......................................................................... 28 
6.2. 
Safety Analysis Set ................................................................................................................................ 28 
6.3. 
Full Analysis Set (FAS) ......................................................................................................................... 28 
6.4. 
mITT Re-treatment Analysis Set (defined for Phase 2) ......................................................................... 28 
6.5. 
Safety Re-treatment Analysis Set ........................................................................................................... 28 
6.6. 
Subgroup Analysis Sets .......................................................................................................................... 28 
6.7. 
Interim Analysis Sets ............................................................................................................................. 29 
7. 
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES ................................................................... 30 
7.1. 
Phase 1 – Safety Interim Analyses ......................................................................................................... 30 
7.2. 
Phase 2 – Interim Safety and Efficacy Analyses .................................................................................... 31 
7.3. 
Access to Aggregate and Subject Level Data and Individual Subject Treatment Assignments ............. 32 
8. 
DATA SCREENING AND ACCEPTANCE...................................................................................................... 33 
8.1. 
General Principles .................................................................................................................................. 33 
8.2. 
Electronic Transfer and Archival of Data .............................................................................................. 33 
8.3. 
Handling of Missing and Incomplete Data ............................................................................................. 33 
8.3.1. 
Efficacy ................................................................................................................................ 33 
8.3.2. 
Safety.................................................................................................................................... 33 
CCI-


KTE-Cl9 
Kite Phan na, Inc. 
Statistical Analysis Plan 
KTE-Cl9-101 (ZUMA-I) 
8.4. 
Detection ofBias .................................................................................................................................... 34 
8.5. 
Outliers ................................................................................................................................................... 34 
8.6. 
Distributional Characteristics ................................................................................................................. 34 
8. 7. 
Validation and Configw-ation Management ........................................................................................... 34 
9. 
STATISTICAL METHODS OF ANALYSIS .................................................................................................... 35 
9.1. 
General Principles .................................................................................................................................. 35 
9.2. 
Subject Accountability ........................................................................................................................... 35 
9.3. 
Important Protocol Deviations ............................................................................................................... 36 
9 .4. 
Demographic and Baseline Characteristics ............................................................................................ 36 
9.5. 
Efficacy Analyses ................................................................................................................................... 37 
9.6. 
I 
9.9. 
9.10. 
9.5.1. 
Objective Response and Best Response ............................................................................... 38 
9.5.2. 
DOR ..................................................................................................................................... 41 
9.5.3. 
PFS ....................................................................................................................................... 41 
9.5.4. 
os ......................................................................................................................................... 42 
9.5.9. 
Scores ................................................................................................................................... 42 
1111 
Safety Analyses ...................................................................................................................................... 43 
9.6.1. 
Adverse Events ..................................................................................................................... 43 
-
9.6.3. 
9.6.4. 
9.6.5. 
9.6.6. 
La orato1y Test Resu ts ........................................................................................................ 44 
Anti-axicabtagene Ciloleucel Antibodies ............................................................................. 45 
Replication Competent Retrovirus (RCR) ............................................................................ 45 
Ex osure to Stud Treatment and Product Characteristics .................................................. 45 
CAR T cells Measured in Peripheral Blood ........................................................................................... 46 
B-cell Aplasia ......................................................................................................................................... 46 
10. CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ............................................................................. 47 
11. REFERENCES ................................................................................................................................................... 48 
12. APPENDICES .................................................................................................................................................... 50 
13. HISTORY OF REVISIONS ............................................................................................................................... 63 
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Appendix 2. 
Appendix 3. 
Appendix 4. 
Appendix 5. 
CONFIDENTIAL 
Sow-ce and Disposition of Non-Clinical Database Data ......................................................... 52 
Conventions for Clinical Data That Require Imputation for Pa1t ial or Missing Dates ........... 53 
Sample Adverse Event Table Layouts .................................................................................... 54 
Derivation of Time to Event Endpoints and Last Date Known to Be Alive ........................... 58 
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LIST OF IN-TEXT TABLES 
Table 1. 
Planned and Target Doses of Axicabtagene Ciloleucel .......................................................... 13 
Table 2. 
Literature Review of Responses in Refractory NHL (SD or PD to Last Line of 
Therapy) ................................................................................................................................. 17 
Table 3. 
SCHOLAR-1:  Response Rate to Chemotherapy after Chemorefractory Disease 
{Crump 2017} ........................................................................................................................ 18 
Table 4. 
Imputation Rules for Partial or Missing Start Dates ............................................................... 53 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Phase 1 Dosing Cohorts and Regimens .................................................................................. 10 
Figure 2. 
Phase 2 Study Design Schema................................................................................................ 16 
Figure 3. 
Phase 1 DLT Evaluation Scheme ........................................................................................... 31 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADaM 
Analysis data model 
AE 
Adverse event 
ASCT 
Autologous stem cell transplant 
CAR 
Chimeric antigen receptor 
CIF 
Cumulative incidence  
CR 
Complete response 
CRS 
Cytokine release syndrome 
CTCAE 
Common Terminology Criteria for Adverse Event 
DLBCL 
Diffuse large B cell lymphoma 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
DORR 
Duration of response to retreatment 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
EQ-5D 
European quality of life-5 dimensions 
FAS 
Full analysis set 
HGBCL 
High grade B-cell lymphoma 
HLGT 
High-level group term 
IRRC 
Independent Radiology Review Committee 
mITT 
Modified intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MST 
MedDRA search terms 
NE 
Not evaluable 
ORR 
Objective response rate 
OS 
Overall survival 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PFS 
Progression-free survival 
PMBCL 
Primary mediastinal B cell lymphoma 
PR 
Partial response 
RCR 
Replication-competent retrovirus 
SAE 
Serious adverse event 
SCT 
Stem cell transplant 
SD 
Stable disease 
SDTM 
Study data tabulation model  
SMQ 
Standardized MedDRA query  
SMS 
Safety management study 


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Abbreviation 
Definition 
SOC 
System organ class 
SPD 
Sum of the product of the diameter 
TEAE 
Treatment-emergent adverse event 
TFL 
Transformed follicular lymphoma 
TLS 
Tumor lysis syndrome 
VAS 
Visual analogue scale 
 


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1. 
INTRODUCTION  
This statistical analysis plan provides the pre-specification and details for the statistical analyses 
outlined within protocol KTE-C19-101 entitled “A Phase 1-2 Multi-Center Study Evaluating the 
Safety and Efficacy of KTE-C19 in Subjects with Refractory Aggressive Non-Hodgkin 
Lymphoma (NHL)”.  The scope of this document is to provide details on the planned interim, 
primary, and final analyses. 


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2. 
OBJECTIVES 
The primary objective of Phase 1 is to evaluate the safety of axicabtagene ciloleucel regimens. 
The primary objective of Phase 2 pivotal study is to evaluate the efficacy of axicabtagene 
ciloleucel, as measured by objective response rate (ORR) in subjects with diffuse large B-cell 
lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed 
follicular lymphoma (TFL). Secondary objectives will include assessing the safety and 
tolerability of axicabtagene ciloleucel and additional efficacy endpoints. 
The primary objective of the Phase 2 safety management study is to assess the impact of 
prophylactic regimens, earlier interventions, debulking therapy, or prophylactic steroid use on 
the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities. The key 
secondary objectives include assessment of efficacy, levels of anti-CD19 chimeric antigen 
receptor (CAR) T cells, cytokines in blood/serum, and the change in European Quality of Life-5 
Dimensions (EQ-5D) scores from baseline to Month 6. 


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3. 
STUDY OVERVIEW 
3.1. 
Study Design 
Study KTE-C19-101 is a Phase 1-2 multicenter, open-label study evaluating the safety and 
efficacy of axicabtagene ciloleucel in subjects with refractory NHL. Study KTE-C19-101 will be 
separated into 3 distinct parts designated as Phase 1 study, Phase 2 pivotal study (Cohort 1 and 
Cohort 2), and Phase 2 safety management study (SMS) (Cohort 3, Cohort 4, Cohort 5 and 
Cohort 6).  
Each subject will proceed through the following study periods: 
• Screening  
• Enrollment/Leukapheresis  
• Bridging therapy (if applicable, for Phase 2 SMS) or debulking therapy (if applicable, Phase 
2 SMS, Cohort 5) 
• Conditioning chemotherapy  
• Investigational product treatment  
• Post-treatment assessment  
• Long-term follow-up 
Further details on study procedures may be found in the study protocol.   
Phase 1 Study 
During Phase 1, approximately 6-24 subjects with DLBCL, PMBCL, or TFL will be enrolled to 
evaluate the safety of axicabtagene ciloleucel regimens.  If the initial regimen is determined to be 
safe, a higher dose of conditioning chemotherapy may be investigated.  If the regimen is 
determined to not be safe, reduced doses of conditioning chemotherapy and/or axicabtagene 
ciloleucel may be explored.  A safety review team (SRT), internal to the study sponsor, will 
review the safety data and make recommendations on further study conduct of Phase 1 and 
progression to Phase 2 as depicted in Figure 1 and outlined in Figure 3. 


KTE-Cl9 
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Figure 1. 
Phase 1 Dosing Cohorts and Regimens 
Yes• 
*May be explored. see Protocol Section 9.6 
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Phase 2 Pivotal Study 
In Phase 2 pivotal study, subjects will enroll into 2 separate Cohorts designated as Cohort 1 and 
Cohort 2. 
• Cohort 1 will enroll adult subjects with refractory DLBCL. 
• Cohort 2 will enroll adult subjects with refractory PMBCL and TFL. TFL is defined as 
subjects who received prior chemotherapy for follicular lymphoma. 
Phase 2 Safety Management Study 
In the Phase 2 SMS, subjects will enroll sequentially into 3 separate Cohorts designated as 
Cohort 3, Cohort 4, Cohort 5 and Cohort 6. 
• Cohort 3 will enroll adult subjects with relapsed or refractory transplant ineligible DLBCL, 
PMBCL, or TFL. 
• Cohort 4 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, or 
HGBCL after two systemic lines of therapy. 
• Cohort 5 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, or 
HGBCL after two systemic lines of therapy. 
• Cohort 6 will enroll adult subjects with relapsed or refractory DLBCL, PMBCL, TFL, or 
HGBCL after 2 systemic lines of therapy. 
The DSMB will review safety and efficacy data two times during the Phase 2 pivotal portion of 
this study, when 20 and 50 subjects in Cohort 1 have been treated with the target dose of 
axicabtagene ciloleucel and have had the opportunity to complete the 3 month disease 
assessment. The DSMB will review Cohorts 3, 4, 5 and 6 safety data when 20 subjects in each 
Cohort have had the opportunity to be followed for 30 days.  The DSMB will also review 
enrollment pausing criteria after 10, 20, 30, and 50 subjects in the Phase 2 pivotal portion of the 
study have been dosed with axicabtagene ciloleucel and have had the opportunity to be followed 
for 30 days.    
The DSMB will be chartered to make trial conduct recommendations based on an analysis of risk 
vs benefit.  The DSMB may meet more often as needed. 
The primary analyses will be conducted when 72 subjects in the mITT- set of the Phase 2 pivotal 
Cohort 1 and 20 subjects in the mITT set of Cohort 2 have completed the 6 month disease 
response assessment, are lost to follow-up, withdraw from the study, or die, whichever occurs 
first (see details in Section 3.3) 


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The primary analysis of efficacy endpoints will be based on investigator review of disease 
assessments and evaluated per the revised futemational Working Group Criteria for Malignant 
Lymphoma {Cheson 2007}, hencefoith referred to throughout this document as "fuvestigator 
read- {Cheson 2007}". Secondary efficacy analyses will be based on central radiologic review 
of disease assessments per {Cheson 2007}; these assessments will be refened to throu out this 
document as "Central read -
Cheson 2007 ". 
3.2. 
Hypothesis 
Phase 2 pivotal study Coho1i 1 and Coho1i 2: This study is designed to differentiate between a 
treatment that has a trne response rate of 20% or less and a treatment with a trne response rate of 
40% or more. The hypothesis is that the ORR to axicabtagene ciloleucel in Coho1i 1 and 
Coho1i 2 is significantly greater than 20%. 
Phase 2 SMS Coho1i 3, Coho1i 4, Coho1i 5 and Coho1i 6: No hypothesis will be tested in Coho1i 
3, Coho1i 4, Coho1i 5 and Coho1i 6, which will be used to assess the impact of prophylactic 
regimens, earlier interventions, debulking therapy, or prophylactic steroid use on the rate and 
severity of CRS and neurologic toxicities. 
3.3. 
Sample Size Considerations 
The anticipated enrollment in this study is approximately 268 to 286 subjects. 
Six to 24 subjects will be enrolled into Phase 1 of this study. 
If the study proceeds to Phase 2, approximately 72 subjects will be enrolled into Cohort 1 and 
approximately 20 subjects will be enrolled into Coho1i 2. 
fu the Phase 2 SMS, approximately 40 subjects will be enrolled into Coho1i 3, approximately 40 
subjects will be enrolled and dosed into Coho1i 4, approximately 50 subjects will be enrolled and 
dosed into Cohort 5, and approximately 40 subjects will be enrolled and dosed into Cohort 6. 
As indicated in Section 3 .1, axicabtagene ciloleucel may be dosed at doses ranging from 1 x 106 
to 2 x 106 mg/kg. The target dose of axicabtagene ciloleucel for each Cohort is provided in 
Table 1. 
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Table 1. 
Planned and Target Doses of Axicabtagene Ciloleucel 
Cohort 
Regimen and Planned Dose of Axicabtagene 
Ciloleucel 
Target Dose of Axicabtagene Ciloleucel 
A1 
500 mg/m2 cyclophosphamide x 3 days 
30 mg/m2 fludarabine x 3 days 
2 x 106 anti-CD19 CAR T cells/kg 
• 
2 x 106 (+/- 20%) (1.6 x 106 up to and 
including 2.4 x 106) anti-CD19 CAR T 
cells/kg 
• 
For subjects weighing > 100 kg, a 
maximum flat dose of 2 x 108 anti-CD19 
CAR T cells 
Phase 2 (all 
Cohorts) 
500 mg/m2 cyclophosphamide x 3 days 
30 mg/m2 fludarabine x 3 days 
2 x 106 anti-CD19 CAR T cells/kg 
• 
1 x 106 to 2 x 106 anti-CD19 CAR T 
cells/kg 
• 
For subjects weighing > 100 kg, a 
maximum flat dose of 2 x 108 anti-CD19 
CAR T cells 
 
Efficacy analyses will be based on a modified intent to treat (mITT) population consisting of all 
subjects enrolled in the Phase 2 portion of the study who receive the target dose of axicabtagene 
ciloleucel. 
Safety analyses will be based on all subjects dosed with axicabtagene ciloleucel. 
DLT analyses will be based on the DLT evaluable set, defined in Section 6.6. 
CCI


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Primary analyses of Phase 2 Coho1t 1, Cohorts 1 and 2 combined, Cohort 3, Coho1t 4, Coho1t 5 
and Coho1t 6 are specified separately. If subject accmal and treatment is such that the primary 
analysis of Phase 2 Cohort 1 occurs at the same time as the primaiy analysis of Coho1ts 1 and 2, 
then one clinical study repo1t (CSR) will be written that includes both the primaiy analysis of 
Coho1t 1 and the primai·y analysis of Coho1ts 1 and 2 combined. Othe1wise, the primary analysis 
CSR will be written when the first primai·y analysis occurs. The CSR will be ainended or a CSR 
addendum will be written to summarize the results of the primary analysis of Coho1ts 3, 4, 5 and 
6, respectively. 
3.3.1. 
Phase 2 Pivotal Study, Cohorts 1 and 2 
to test for an im rovement in response rate-
. For the test of efficac~
s 
:::: 90% power to distinguish between an active therapy with a 40% hue response rate from a 
therapy with a response rate of 20% or less with a I-sided alpha of 0.025. 
Within Coho1t 1 
1 primary analyses will be perfo1med. 
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have had the oppo1tunity to be assessed for response 6 months after the axicabtagene 
ciloleucel infusion. 
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primaiy analysis is 0.011. 
Within Coho1is 1 and 2 combined, 1 primaiy analysis will be perfo1med when 72 subjects in the 
mITT set of Coho1i 1 and 20 subjects in the mITT set in Coho1i 2 have had the oppo1iunity to be 
assessed for response at 6 months after the axicabtagene ciloleucel infusion. This testing will be 
peifonned at a I-sided alpha level of 0.0075. Confidence intervals about the ORRs within 
Coho1is 1 and 2 will be presented with the inferential analysis of the overall study population. 
As indicated above, inferential testing of Cohort 1 will occur when 72 subjects in the mITT set in 
Coho1i 1 have had the oppo1iunity to be followed for 6 months after the axicabtagene ciloleucel 
infusion. The efficacy data from any additional subjects (beyond 72) enrolled into Coho1i 1 will 
be analyzed descriptively and included in analyses of all secondary endpoints. Similai·ly, 
inferential testing of Coho1is 1 and 2 will occur when 72 subjects in the mITT set of Coho1i 1 
and 20 subjects in the mITT set of Coho1i 2 have had the opportunity to be followed for 
6 months following the axicabtagene ciloleucel infusion. The efficacy data from any additional 
subjects (beyond 92) enrolled into Coho1is 1 and 2 will be analyzed descriptively. fu the event 
that 72 subjects in the mITT set in Coho1i 1 and 20 subjects in the mITT set in Coho1i 2 ai·e 
accrned at the same time, the primary analysis of Coho1i 1 and the primary analysis of Coho1is 1 
and 2 combined will be perfo1med at the same time. 
The derivation of the alpha levels for the test of Coho1i 1 and Coho1is 1 and 2 combined were 
originally obtained under the assumption of 40 subjects enrolled into Coho1i 2. These original 
derivations are retained in this protocol amendment as they result in a more conservative alpha 
level for the test of Cohort 1. 
ated I-sided al ha level of 0.025 and has:::: 90% 
3.3.2. 
Phase 2 SMS, Cohorts 3, 4, 5 and 6 
The primary objective of Phase 2 safety management study Coho1i 3, Coho1i 4, Coho1i 5, and 
Coho1i 6 is to assess the impact of prophylactic regimens, eai·lier inte1ventions, debulking 
therapy, or prophylactic steroids on the rate and severity of CRS and neurologic toxicities. The 
assessment of ORR is a secondaiy objective, and the analysis will be descriptive. 
The planned primary analyses of Coho1is 3, 4, 5 and 6 will occur after all subjects treated with 
axicabtagene ciloleucel in each of these Coho1is have had the opportunity to be followed for 6 
months after the axicabtagene ciloleucel infusion. 
A schema of the Phase 2 study design is provided in Figure 2. 
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3.4. 
Statistical Assumptions 
Kite Phanna, Inc. 
Phase 1 and Coho11s 1 and 2 of this trial will emoll patients with chemo-refracto1y lymphoma, as 
evidenced by failure to achieve even a transient or pa1t ial response to prior biologic and 
combination chemotherapy or by early recmTence after ASCT. 
This study assumes that the underlying response rate (in the absence of treatment with 
investigational therapy) in Coho1ts 1 and 2 is 20% and that an improvement in the response rate 
to 40% provides clinically meaningful benefit. 
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4. 
STUDY ENDPOINTS AND COVARIATES   
4.1. 
Endpoints 
4.1.1. 
Primary 
• Phase 1: the incidence of adverse events (AEs) defined as DLTs 
• Phase 2 pivotal study (Cohorts 1 and 2): ORR (Investigator read – {Cheson 2007}  
• Phase 2 SMS (Cohorts 3, 4, 5 and 6): the rate and severity of CRS and neurologic toxicities 
4.1.2. 
Secondary (all Phases, unless noted)  
• ORR (Investigator read – {Cheson 2007}) for subjects in Phase 1 and Phase 2 SMS (Cohorts 
3, 4, 5 and 6) 
• Duration of response (DOR) (Investigator read – {Cheson 2007}) 
• Progression-free survival (PFS) (Investigator read – {Cheson 2007}) 
• Overall survival (OS) 
• ORR (CR + PR) (Central read – {Cheson 2007}) in Phase 2 pivotal study 
• DOR (Central read – {Cheson 2007}) in Phase 2 pivotal study 
• Best objective response (Central read – {Cheson 2007}) in Phase 2 pivotal study 
• PFS (Central read – {Cheson 2007}) in Phase 2 pivotal study 
• The incidence of AEs, including identified and potential risks for axicabtagene ciloleucel 
• The incidence of significant laboratory abnormalities 
• The incidence and persistence of anti- axicabtagene ciloleucel antibodies and anti-product 
impurity antibodies 
• Levels and persistence of anti-CD19 CAR T cells in blood samples 
• Levels and persistence of cytokines in blood samples 
• The subject incidence of replication competent retrovirus (RCR) detected in blood samples 
• Changes over time in the EQ-5D scale score and EQ-5D VAS score in Phase 2 SMS 
(Cohorts 3, 4, 5 and 6) 


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Covariates 
Kite Phanna, Inc. 
The following baseline covariates may be used to examine efficacy in subgroups or covariate 
analyses: 
• 
Race 
• 
Sex 
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Age at baseline(< 65, 
65) 
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The following baseline covariates may be used to examine safety in subgroups or covariate 
analyses: 
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65) 
• 
Sex (male, female) 
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5_ 
DEFINITIONS 
5.1. 
General 
Kite Phanna, Inc. 
Study enrollment: Study enrollment occurs at the commencement of leukapheresis. 
Study day 0: Study day O is defined as the day the subject received the first axicabtagene 
ciloleucel infusion. The day prior to study day O will be study day -1 . The day of enrollment 
and any days after enrollment and before study day -1 will be sequential and negative 
integer-valued. 
Baseline: The baseline value is defined as the last value measured prior to conditioning 
chemotherapy. For subjects in phase 2 SMS ( e.g. Coho1t 5), if conditioning chemotherapy was 
not administered per protocol, the baseline value is defined as the last value measured prior to 
axicabtagene ciloleucel infusion. 
Study therapy: Study therapy is defined as conditioning chemotherapy or axicabtagene 
ciloleucel. 
On-study: Time from enrollment to the last date of contact 
End of study: This will occur after all subjects have been followed for 15 years post 
axicabtagene ciloleucel infusion, have withdrawn consent, been lost to follow-up, experienced an 
AE that precluded further follow up, or have died. 
Refractory Subgroup at baseline: Refractory subgroups are defined below. A subject may 
meet the criteria for multiple refractory subgroups. In this event, any subject who meets the 
criteria for relapse post ASCT will be categorized as such. If a subject meets more than one 
refractory subgroup other than relapse post ASCT, the refracto1y subgroup defined by the 
subject's last line of therapy prior to study entry will be used to categorize the subject into a 
refractory subgroup. Note that bridging or debulking therapies should not be included for 
defining the Relapsed/Refractory subgroups . 
• 
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Bulky disease: bulky disease is defined as the presence of a single lesion with largest diameter 
10 cm or larger or mediastinlllll wider than 1/3 of the chest on a chest x-ray. The presence of 
bulky disease will be determined by the investigator when baseline disease extent is evaluated. 
Actual follow-up time: Actual follow-up time among all subjects ti·eated with axicabtagene 
ciloleucel is calculated as the time from the first dose of axicabtagene ciloleucel to the date of 
death, last date known to be alive, lost to follow-up, or full withdrawal of consent, whichever is 
later. 
Potential follow-up time: Potential follow-up time is defined as the time from the axicabtagene 
ciloleucel infusion to the data cutoff date for the analysis. 
5.2. 
Safety 
Treatment-emergent adverse event (TEAE): Any AE with onset on or after the first dose of 
conditioning chemotherapy. For subjects taking reti·eatment of axicabtagene ciloleucel, TEAEs 
during retreatment period may be summarized separately. 
Deaths: All deaths that occur after study enrollment up through the end of study will be 
summarized. Deaths that occur from axicabtagene ciloleucel infusion up through 30 days after 
the infusion will also be summarized. For subjects taking retreatment of axicabtagene ciloleucel, 
deaths occuned during reu-eatment period may also be summarized separately. 
AEs of interest: Adverse events of special interest for axicabtagene ciloleucel ti·eatment include 
identified risks (CRS, neurologic toxicity, infections, cytopenias, hypogammaglobulinemia) and 
potential risks (seconda1y malignancies, tumor lysis syndrome, bone maITow failure, graft-
versus-host-disease, replication competent reu-ovirus, immunogenicity). 
Neurologic toxicity (neurotoxicity): Neurotoxicity AEs are identified with a search sti·ategy 
based on known neurologic toxicities associated with anti-CD19 immunotherapy {Topp 2015}. 
The search su-ategy focuses on cenu-al nervous system toxicity, without regard to relatedness, 
temporal relationshipor concomitant conditions ( eg CRS). Events are identified with a search list 
ofMedDRA preferred tenns. Additionally, the MedDRA system organ classes (SOCs) of 
Psychiati·ic Disorders and Nervous System Disorders will be reviewed for additional events; 
these events will then be evaluated for potential inclusion as neurologic AEs. 
CRS: CRS is identified via collection of the syndrome on a case repo1i specifically designed to 
collect CRS. Specific symptolllS of the CRS collected on the AEs log are coded using Medicinal 
Dictionaiy for Regulato1y Activities (MedDRA) and ai·e linked to the con esponding CRS 
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episode. Individual symptoms of CRS will be graded per Common Tenninology Criteria for 
Adverse Events (CTCAE) v4.03, and CRS syndrome severity is graded according to a 
modification of the grading system proposed by Lee and colleagues {Lee 2014}. In the modified 
grading scale, neurologic AEs are not repo1ied as paii of the CRS syndrome and will be repo1ied 
sepai·ately and summarized sepai·ately. 
Immunogenicity (anti-axicabtagene ciloleucel antibody): Immunogenicity ai·e identified by the 
development of antibodies against CAR expressing cells by flow cytometiy. In addition, a 
manual review of the AE tenns indicative of autoimmunity, inclusive of infusion-related events 
and anaphylactic reactions among subjects who test positive for anti-axicabtagene ciloleucel 
antibodies, will be performed. 
For other AEs of special interest, specific adverse events may be mapped to these categories 
using dictionary coded event te1m and standardized Med.DRA queries (SMQs) or other search 
strategies. Specific definitions of these events and the coded te1ms to which they conespond will 
be provided in the Program Safety Analysis Plan. 
Duration of an AE of special interest: Duration of an AE of special interest is defined as the time 
from the earliest onset date of the AEs in the event class of interest through the resolution date of 
the last AEs in the event class, regardless of the gaps of the days between multiple events, i.e., 
the resolution date of the last AE in the event class - the staii date of the first AE in the event 
class + 1. The duration may only be calculated on subjects for whom all AEs in the event class 
have been resolved by the data cutoff date. 
5.3. 
Efficacy 
ORR: propo1iion of subjects with either a CR or PR while on study. All subjects who do not 
meet the criteria for objective response by the analysis data cutoff date will be considered 
non-responders. The derivation of this endpoint will only include response assessments obtained 
prior to any other additional therapy ( e.g. SCT or retreatment with axicabtagene ciloleucel). 
Response may be defined per Investigator read - { Cheson 2007} or Centi·al Read - { Cheson 
2007}. 
DOR: DOR is defined only for subjects who experience an objective response and is the time 
from the first objective response to disease progression or death from any cause. Response and 
progression may be defined per Investigator read - { Cheson 2007} or Central Read - { Cheson 
2007}. Subjects not meeting the criteria for progression or death from any cause by the analysis 
data cutoff date will be censored at their last evaluable disease assessment date. DOR will be 
derived using disease assessments obtained on study prior to initiation of new anticancer therapy 
( excludin SCT . Disease assessments obtained after SCT will be used in the derivation of 
DOR. 
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Kite Phanna, Inc. 
PFS: PFS is defined as the time from axicabtagene ciloleucel infusion date to the date of disease 
progression or death from any cause. Progression may be defined per Investigator read -
{Cheson 2007} or Central Read - {Cheson 2007}. Subjects not meeting the criteria for 
progression by the analysis data cutoff date will be censored at their last evaluable disease 
assessment date. PFS will be derived using disease assessments obtained on study prior to 
initiation of new anti-cancer thera 
excludin SC . Disease assessments after SCT will be 
used in the derivation of PFS. 
-
OS: OS is defined as the time from axicabtagene ciloleucel infusion to the date of death from 
any cause. Subjects who have not died by the analysis data cutoff date will be censored at their 
last date known to be alive prior to the data cutoff date with the exception that subjects known to 
be alive or detennined to have died after the data cutoff date for each anal sis will be censored at 
the data cutoff date. 
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6. 
ANALYSIS SETS 
The following analysis sets are defined for each study Phase separately. 
6.1. 
Modified Intent-to-Treat (mITT) (defined for Phase 2) 
The mITT analysis set will consist of all subjects treated with at least 1.0 x 106 anti-CD19 
CAR T cells/kg.  The mITT analysis set will be used for efficacy analyses of Phase 2. 
6.2. 
Safety Analysis Set 
The safety analysis set is defined as all subjects treated with any dose of axicabtagene ciloleucel. 
For interim analyses, the safety set will be focused only on those subjects who have had the 
opportunity to be followed for one month after the axicabtagene ciloleucel infusion. 
6.3. 
Full Analysis Set (FAS) 
The FAS will consist of all enrolled patients and will be used for the summary of subject 
disposition, sensitivity analyses of ORR and DOR, and subject listings of deaths. 
6.4. 
mITT Re-treatment Analysis Set (defined for Phase 2) 
The mITT Re-treatment Analysis Set will consist of the set of all subjects who undergo 
re-treatment with axicabtagene ciloleucel at a dose of at least 1.0 x 106 anti-CD19 
CAR T cells/kg.  This set will be used for all re-treatment efficacy analyses. 
6.5. 
Safety Re-treatment Analysis Set 
The Safety Re-treatment Analysis Set will consist of all subjects who undergo re-treatment with 
axicabtagene ciloleucel. 
For interim analyses, the Safety Re-treatment set will be focused only on those subjects who 
have had the opportunity to be followed for one month after the re-treatment axicabtagene 
ciloleucel infusion. 
6.6. 
Subgroup Analysis Sets 
Subgroup analyses of selected efficacy and safety endpoints may be performed for the baseline 
covariates defined in Section 4.2.   


KTE-Cl9 
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6.7. 
Interim Analysis Sets 
Kite Phanna, Inc. 
The DLT evaluable Set(s) (Phase 1 only), defined for each dosing Coho1i in Phase 1, will 
include subjects treated in the Phase 1 dosing Coho1i who: 
• 
Received the target and were followed for at least 30 days after the axicabtagene ciloleucel 
infusion; or 
• 
Received a dose of anti-CD19 CART cells (axicabtagene ciloleucel) lower than the target for 
that Coho1i and experienced a DLT during the 30 day post-infusion period. 
If needed, more subjects will be emolled to achieve 6 DLT evaluable subjects at the target dose 
for each Coho1i. 
Phase2 SMS 
The SMS Interim Analysis Sets will consist of the first 20 subjects treated in Phase 2 Coho1i 3, 
Coho1i 4, Coho1i 5 and Coho1i 6 respectively who have had the oppo11unity to be followed for 30 
days after the axicabtagene ciloleucel infusion. 
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7. 
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES 
The SRT will review the safety data during Phase 1 of the study and make a recommendation to 
progress the study from Phase 1 to Phase 2 based on the incidence of DLT and review of serious 
adverse events (SAEs).   
The DSMB will meet 2 times during the Phase 2 Cohort 1 of the study.  The DSMB will review 
safety and efficacy data and will be chartered to make trial conduct recommendations based on 
the risk versus benefit of treatment with axicabtagene ciloleucel. The DSMB will also meet to 
review safety data after 20 subjects in Phase 2 Cohorts 3, 4, 5 and 6 have been dosed with 
axicabtagene ciloleucel and have had the opportunity to be followed for 30 days, respectively. 
Additionally, as part of its oversight of the study, the DSMB will also assess criteria to pause 
enrollment after 10, 20, 30, and 50 subjects in the Phase 2 pivotal portion have been treated with 
axicabtagene ciloleucel and have had the opportunity to be followed for 30 days.  Enrollment 
will be paused if any of the following criteria are met: 
1) subject incidence of grade 5 axicabtagene ciloleucel related AEs within 30 days is > 10% 
OR 
2) subject incidence of the following grade 4 axicabtagene ciloleucel-related AEs lasting more 
than 7 days is > 33%: 
• Neurotoxicity 
• CRS (per Lee 2014 criteria) 
• Other non-hematologic SAE 
• Infection (treatment-related) 
These DSMB reviews will be based on SAE reports. 
The DSMB may meet more often as needed. 
7.1. 
Phase 1 – Safety Interim Analyses   
The SRT will evaluate the incidence of DLTs and SAEs after 6 subjects, 9 subjects 
(if applicable), and 12 subjects (if applicable) have met the criteria for the DLT evaluable set.  
The SRT may recommend progression to the Phase 2 portion of the trial according to the schema 
in Figure 3. 


KTE-Cl9 
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Figure 3. 
Kite Phanna, Inc. 
Phase 1 DLT Evaluation Scheme 
Meet criteria for the DLT 
evaluable set 
------------------------------.. 
r----------------
1 I 
I 
5 1 with DLT 
I 
I 
I i 
Proceed to next 
Cohort or Phase 2 
as depicted in 
Figure 1 
n=6 
(DLBCL/PMBCL/TFL) 
----------, 
,--
1 
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s 2 of 9 with DLT 
s 3 of 12 with DLT 
Proceed to next 
Cohort or Phase 2 as 
depicted ,n Figure 1 
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2·3 with DLT 
Enroll 3 to 6 
additional 
subjects 
*or proceed to Phase 2 w-ith the dose previously tested in the NCI study, as depicted in Figure I. 
7.2. 
Phase 2 - Interim Safety and Efficacy Analyses 
An independent DSMB will be chaii ered to make recommendations on stud 
Phase 2 01i ion of the stud . Details ma be found in the DSMB Chaiier. 
--. 
I 
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> 3 with DLT 
Evaluate a lower 
doseofKTE-C19or 
cond1t1ornng 
chemotherapy• 
Safety analyses will present data from both study Phases and all Cohol1s. 
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interim analyses are for safety and will be conducted when 20 subjects in 
~
, Coho1i 4, Cohort 5 and Coho1i 6 have been treated with axicabtagene 
ciloleucel and have had the oppo1iunity to be followed for 30 days, respectively. 
After the planned primaiy analysis of Coho1i 1 and the planned primaiy analysis of the Cohorts 1 
and 2 combined, additional efficacy and safety analyses of Coho1is 1 and 2 may be perfo1med to 
suppo1i regulatory interaction or publications. These analyses will be descriptive. Additional 
descriptive analyses of Coho1is 3, 4, 5 and 6 data may also be conducted after the primaiy 
analyses of these Coho1is have been completed. 
7.3. 
Access to Aggregate and Subject Level Data and Individual Subject 
Treatment Assignments 
This study is open-label. Subjects, the study sponsor, and investigators will be awai·e that each 
subject is planned to be treated with axicabtagene ciloleucel. Data handling procedures designed 
to maintain the trial credibility and validity in this open-label single aim study ai·e described in 
the Trial futegrity Document. 
An independent statistician will perfo1m the interim safety and efficacy analyses for the Phase 2 
po1iion of the study and provide these repo1is to the DSMB. Members of the DSMB and 
independent statistician will not have any direct contact with study center personnel or subjects. 
The DSMB will communicate recommendations to Kite Phaima in accordance with the DSMB 
cha1ier. 
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8. 
DATA SCREENING AND ACCEPTANCE 
8.1. 
General Principles 
The database will be subject to the edit checks outlined in the Data Management Plan and 
additional manual data reviews defined by the study team.  Data inconsistencies will be reviewed 
and resolved before the database snapshot for the primary analyses and the final database lock.  
For interim analyses, snapshots may include data that has not passed all data cleaning procedures 
at the time the data are extracted for snapshot.   
8.2. 
Electronic Transfer and Archival of Data 
The Medidata Rave system will be used to collect the data in this study.  Raw data extracted 
from Medidata Rave will be archived prior to further dataset creation, maintenance, and analysis.  
Raw data, SDTM data, and ADaM datasets will be archived for all planned analyses.  Any 
additional unplanned analyses that occur after the primary analyses and prior to the final analysis 
will also be archived.  Key data external to the clinical study database (see below) will be 
included in the relevant SDTM and ADAM modules when the external data are available.  For 
the SRT analyses, raw data may be archived and used in data review. 
Data from the central pathology laboratory (including tumor pathology, tumor genetic, and 
molecular characteristics), the product manufacturing (total T cells, CAR T cells [transduction 
ratio], duration of manufacturing time), central laboratory assessment of subject serum samples 
(including CAR T cell levels in the peripheral blood, antibody assays, RCR testing), and central 
radiology review will be generated from contract laboratories and Kite Pharma.  These data will 
be transferred to Kite and held in a peripheral directory and not built into the clinical trial 
database.  At the time analyses require these data, they may be merged with the SDTM and 
ADAM datasets. 
The source and disposition of all data sources obtained from imaging vendors or laboratories is 
described in Appendix 2. 
8.3. 
Handling of Missing and Incomplete Data 
8.3.1. 
Efficacy 
The method for handling missing data is described in the definition for each efficacy endpoint.  
Every effort will be made to obtain complete dates for deaths.  In the event of a partial or missing 
death date and the corresponding censoring date for survival, the algorithm in Appendix 3 will be 
used. 
8.3.2. 
Safety 
Partial AE start dates will be imputed.  If dates are missing or incomplete for AE start dates, the 
algorithm defined in Appendix 3 will be used.  Completely missing death dates or death dates 
with only a year reported will not be imputed.   


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8.4. 
Detection of Bias 
A listing of subjects with important protocol deviations will be generated.  The deviations 
included in this list will include, but not be limited to, violations of eligibility criteria and use of 
exclusionary medication during the study.  Lack of protocol compliance will be evaluated by 
summarizing the subject incidence of important protocol deviations.  High rates of important 
protocol deviations may indicate bias. 
Endpoints derived from investigator assessment of radiologic scans and disease assessments may 
be subject to bias; the concordance between investigator and central review of radiologic scans 
and disease assessments will be summarized. 
8.5. 
Outliers 
Descriptive statistics will be used to identify potential outliers in any key variables analyzed.  
Suspected outliers will be included in all analyses unless there is sufficient scientific justification 
to exclude them. 
8.6. 
Distributional Characteristics 
The primary analysis of the primary endpoint is an exact binomial test used to compare the 
observed response rate in the Phase 2 Cohort 1 and Cohort 1 and 2 combined to a response rate 
of 20%.  This test assumes only the independence of the individual subject responses.  The 
validity of the assumption of a 20% historical response rate is described in Section 3.4. 
An exact 95% confidence interval will be generated about the response rate.  The 
Clopper-Pearson method will be used to generate this interval.  While the Clopper-Pearson 
interval provides adequate coverage probability, it is commonly wider than necessary {Brown 
2002}, leading to overly conservative estimates of the lower bound of ORR.  Sensitivity analyses 
will be conducted in which the interval is calculated with different methods (Section 9.5.1). 
8.7. 
Validation and Configuration Management 
Programs for the development of the SDTM and ADAM datasets and the generation of the 
tables, figures, and listings will be developed and maintained 
 Standard 
Operating Procedures (SOPs) and Kite SOPs if applicable. The software and version used to 
generate analyses will be indicated in the archived documentation. 
CCI


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9_ 
STATISTICAL METHODS OF ANALYSIS 
9.1. 
General Principles 
Kite Phanna, Inc. 
The goal of the primaiy statistical analysis is to compare the observed response rate in Phase 2 
Coho1i 1 and in Coho1is 1 and 2 combined per investigator read - { Cheson 2007} to a historical 
control rate of20% with an exact binomial test. Hypothesis testing will be one-sided, and all 
95% confidence intervals will be 2- sided. At the time of planned analyses, 95% confidence 
intervals for the response rate in each study Cohort will be presented. 
The timing of the interim and primary analyses will be based on subject accmal and disease 
assessment milestones. The primary analysis clinical stud re 01i CSR will be written at the 
rimai anal sis of Phase 2 Coho1is 1 and 2 combined. 
Additionally, the CSR will be amended with the primaiy analyses of Phase 2 SMS Coho1i 3, 
Coho1i 4, Coho1i 5 and Coho1i 6, and may be amended with additional subject safety and 
survival follow up after the planned primai·y analysis. 
from all subjects treated will be included in the prima1y analysis. 
Analyses of the Phase 1 and Phase 2 po1i ions of the study will be presented separately. Within 
the Phase 1 summaries, each dose Coho1i will be presented separately. For data presented over 
time, assessments may be grouped into "windows" based on the actual assessment times. 
9.2. 
Subject Accountability 
The number of subjects screened, emolled, leukapheresed, treated with conditioning 
chemotherapy, treated with axicabtagene ciloleucel, and re-treated with axicabtagene ciloleucel 
will be summarized. The reasons for discontinuing treatment and discontinuing study will be 
summarized. 
Summaries of actual and potential follow up time will be provided. 
The number of subjects emolled by countiy and site will be smnmai·ized. 
The number of subjects in each analysis set will be provided. 
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9.3. 
Important Protocol Deviations 
The clinical study team will define important protocol deviation categories and review all 
potential important protocol deviations at minimum, prior to the database snapshot for the 
primary efficacy analysis.  Important protocol deviations will be categorized by deviation type 
(e.g. entry/eligibility, use of excluded medication).  The subject incidence of important protocol 
deviations will be summarized overall and by deviation category. 
9.4. 
Demographic and Baseline Characteristics 
Summary statistics and frequencies for the following demographic and baseline characteristics 
will be tabulated: 
• ECOG performance status at baseline 
• Sex (male, female) 
• Height 
• Weight 
• Age at baseline (< 65, ≥ 65) 
• Ethnicity 
• Race:  white, black, Asian, other (categories may be collapsed or expanded based on accrual) 
• Country 
• Disease type (DLBCL, PMBCL, TFL, HGBCL) 
• Disease subtype (DLBCL associated with chronic inflammation, EBV + DLBCL, T cell / 
histiocyte rich large B cell lymphoma, primary cutaneous DLBCL (leg type), DLBCL not 
otherwise specified, primary mediastinal (thymic) large B cell lymphoma, transformation of 
follicular lymphoma to DLBCL, other) 
• Number of prior chemotherapy regimens 
• Response to last chemotherapy regimen (among subjects who are not relapsed post ASCT) 
• Refractory subgroup 
• Prior autologous stem cell transplant (ASCT) 
• Prior anti-CD20 treatment 


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• Prior anthracycline treatment 
• Prior platinum treatment 
• Tumor burden, as measured by the SPD of selected nodes or lesions at baseline 
• Morphologic characteristics (centroblastic, immunoblastic, anaplastic, other) 
• CD19 expression in tumors at baseline 
• Molecular subgroup (germinal center B cell-like (GBC), activated B-cell like (ABC)) 
• BCL-2 alterations / overexpression (Y/N) 
• BCL-6 alterations / overexpression (Y/N) 
• C-MYC alterations / overexpression (Y/N) 
• Double hit (C-MYC alteration/overexpression and either BCL-2 or BCL-6 
alteration/overexpression) status 
• Triple hit (3 of 3 recurrent chromosome translocations) status 
• Disease stage (I, II, III, IV) and extent (presence of B symptoms, splenic involvement, bulky 
disease, extranodal disease) 
• International prognostics index (IPI) risk category 
• History of bone marrow involvement 
9.5. 
Efficacy Analyses 
Efficacy analyses will be conducted on the mITT analysis set.  For the primary analysis, the 
investigator assessment of disease status per {Cheson 2007} will be used.  Sensitivity analyses 
will be conducted that use the central radiology review of disease assessments per {Cheson 
2007}.  The investigator and central radiology reviewer will provide the determination of disease 
status (CR, PR, SD, PD, NE) at each time point.  SAS programs developed by Kite Pharma and 
 will derive the best overall response, DOR, and PFS based on these assessments. 
The primary efficacy analysis will be presented in the following analysis populations: 
• mITT set 
 
 
 
 
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I 
I 
Kite Phanna, Inc. 
For subjects re-treated with axicabtagene ciloleucel, disease assessments obtained prior to 
retreatment but not disease assessment obtained after retreatment will be included in the primaiy 
smnmai·ies of objective and best response, DOR, PFS, and sUilllllai·ies of change in tumor 
burden. For such subjects, disease assessments obtained after re-treatment will be included in 
the summaries of objective and best response to retreatment with axicabtagene ciloleucel and 
DOR after re-treatment with axicabtagene ciloleucel. The subject's OS time will be derived 
from the last date known alive regardless of re-treatment time. 
9.5.1. 
9.5.1.1. 
Objective Response and Best Response 
Primary Analyses of Objective Response 
The subject incidence of objective response will be calculated. An exact binomial test will be 
used to compai·e the observed response rate to the hypothesized historical control rate of 20%. 
The subject incidence of best response (CR, PR, SD, PD, NE, ND) will be calculated. 
Confidence intervals will be provided about the ORR, calculated with the following methods: 
• 
Clopper-Peai·son (an exact interval) 
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The primary analysis of objective response and best response will include subjects from the 
Phase 2 pivotal po1i ion and will be conducted for subjects by Coho1i and for Coho1is 1 and 2 
combined. Analyses of Coho1i 2 alone and individual Coho1is 3, 4, 5 and 6 in the Phase 2 SMS 
will be descriptive. The exact binomial test will not be presented for Coho1is 3, 4, 5 and 6. 
Sensitivity analyses of objective response will be conducted in the FAS set. 
The number and percent of subjects who initially attain a paii ial response and subsequently attain 
a complete response will be Sllffilnai·ized. 
9.5.1.2. 
Analyses of Objective Response and Best Response per Central Read 
The analyses of objective response and best response specified above will be repeated for 
objective response and best response per central read - { Cheson 2007}. 
The concordance of objective response and best objective response per investigator read -
{Cheson 2007} and central read- {Cheson 2007} will be evaluated. A Sllffilnaiy table of 
concordance, concordance rate, a kappa statistic, and a 2-sided 95% confidence interval about 
the kappa statistic will be provided. 
Fmi her analyses between the investigator and central reads may be described in a supplemental 
SAP. -
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Analyses of Objective Response - Phase 1 
Kite Phanna, Inc. 
Analyses of objective response in Phase 1 may occur at any time during Phase 1. The pmpose of 
these analyses may include publications, preliminaiy evaluation of benefit-risk, and to infonn 
decisions on dose. 
At minimum, ORRs and 95% confidence intervals will be generated for each dose Coho1i in 
Phase 1. 
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9.5.2. 
DOR 
Kite Phanna, Inc. 
The Kaplan-Meier approach will be used to estimate DOR. Disease assessments obtained after 
SCT while in study treatment induced remission will be used in the derivation of DOR. The 
number of subjects censored and the reasons for censoring will be summarized. Analyses will be 
generated for DOR per investigator read- {Cheson 2007}, as well as per centrnl read - {Cheson 
2007}. The reverse Kaplan-Meier approach {Schemper 1996} will be used to estimate the 
follow-up time for DOR. 
9.5.3. 
PFS 
Kaplan-Meier plots, estimates and 2-sided 95% confidence intervals will be generated for PFS. 
Disease assessments obtained after SCT while in study ti·eatment induced remission will be used 
in the derivation of PFS. Estimates of the propo1iion of subjects alive and progression-free at 3 
month intervals will be provided. The number of subjects censored and the reasons for censoring 
will be summarized. Analyses will be generated for PFS per investigator read - { Cheson 2007} 
and PFS per central read - {Cheson 2007}. 
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9.5.4. 
OS 
Kite Phanna, Inc. 
The analysis of OS will use the same methods as the analysis of PFS. A graphical sunnnary of 
the time to response, DOR, retreatment, progression, and death times from the time of 
axicabtagene ciloleucel infusion depicted on a horizontal time axis for each patient ("swim lane 
plot") will be provided. 
-
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9.5.9. 
European Quality of Life-5 Dimensions and Visual Analogue Scale Scores 
EQ-5D and VAS scores will be collected and summarized at baseline and post study treatment 
visits for Phase 2 SMS Coho1is 3, 4, 5 and 6. Changes in the EQ-5D-5L and VAS scores from 
baseline at post-study treatment visits will also be summarized with descriptive statistics. 
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9.6. 
Safety Analyses 
Kite Phanna, Inc. 
Safety analyses will be conducted on the safety analysis set. The primary analysis of safety data 
will summarize all TEAEs and laboratory values. Additional summaiy tables will present all 
TEAEs, as well as AEs with onset time categorized by study treatment period ( conditioning 
chemotherapy treatment period, axicabtagene ciloleucel treatment period, primary post-treatment 
follow up period, and secondaiy post-treatment follow up period). For subjects who undergo 
retreatment with axicabtagene ciloleucel, AEs occmTing in the axicabtagene ciloleucel 
re-ti·eatment period may be summarized in an additional separate summaiy that presents only the 
AEs occurring during the reti·eatment period. Sample table layouts ai·e provided in Appendix 3. 
AEs will be coded with the Medical Dictionaiy for Regulato1y Activities (MedDRA) at the time 
of each analysis. The version of the MedDRA may vary over time as the cmTent version in use 
is updated. The severity of AEs will be graded using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Cytokine release 
syndrome (CRS) will be graded using a revised CRS grading scale developed by Lee et al {Lee 
2014} and per CTCAE 4.03. The incidence and severity of CRS will be reported as a syndrome 
with severity per Lee et al. Individual symptoms associated with CRS will be graded per 
CTCAE version 4.03. 
Fatal AEs that ai·e atti-ibuted to disease progression may be included in the death summary with a 
primaiy death reason of 'disease progression' regardless of the coded CTCAE version 4.03 
prefeITed te1m. 
Subjects emolled but not dosed with axicabtagene ciloleucel will be followed for AEs for 
30 days after the last study procedure. AEs reported in these patients will be ai·chived in the 
study database and available in SDTM and ADAM datasets, but will not be tabulated in AE 
sumrnanes. 
Safety summa11es will be presented sepai·ately for each Phase 1 dosing Coho1t and for Phase 2 by 
Coho1t and overall. 
9.6.1. 
Adverse Events 
The subject incidence of the following treatment-emergent AEs will be tabulated for the: 
• 
Summai·y of AEs (any, worst severity, serious, related) 
• 
All AEs 
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• 
All SAEs 
• 
All leukapheresis-related AEs 
• 
All conditioning-chemotherapy-related AEs 
• 
All axicabtagene ciloleucel-related AEs 
• 
All conditioning chemotherapy-related SAEs 
• 
All axicabtagene ciloleucel-related SAEs 
• 
All grade 3 or higher AEs 
• 
All grade 3 or higher conditioning chemotherapy-related AEs 
• 
All grade 3 or higher axicabtagene ciloleucel-related AEs 
• 
Fatal AEs 
• 
AEs of interest, including identified risks and potential risks 
Kite Phanna, Inc. 
Summary statistics for the onset time (Kaplan-Meier estimates) and dmation of AEs of interest 
will be provided. 
The subject incidence of deaths by treatment period will be provided. 
A subject listing of deaths and SAEs (including nanatives) will be provided overall and by 
treatment period. 
A sUIIllnaiy of demographics and baseline chai·acteristics ainong subjects who experience CRS 
and who do not experience CRS may be provided. 
-
9.6.3. 
Laboratory Test Results 
Laboratory results will be graded according to NCI Common Toxicity Criteria (CTCAE version 
4.03). The incidence of worst grade CTCAE toxicities post axicabtagene ciloleucel infusion for 
all analytes will be provided. Laborato1y data collected at baseline and through the axicabtagene 
ciloleucel Treatment Period will be summai·ized. Shifts from baseline to minimum post-baseline 
and / or maximum post-baseline may be presented for select analytes. 
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9.6.4. 
Anti-axicabtagene Ciloleucel Antibodies 
Kite Phanna, Inc. 
The subject incidence of any anti-axicabtagene ciloleucel antibodies and anti-product impmity 
antibodies will be tabulated. For subjects testing positive for antibodies, the persistence of the 
antibody over time will be summarized. 
9.6.5. 
Replication Competent Retrovirus (RCR) 
The subject incidence of replication competent retrovirns (RCR) detected in blood samples will 
be tabulated overall and by assessment time. The persistence ofRCR over time will be 
summarized. 
9.6.6. 
Exposure to Study Treatment and Product Characteristics 
Summary statistics and subject listings will be provided for the following: 
• 
Total BSA-adjusted dose of cyclophosphamide 
• 
Total BSA-adjusted dose of fludarabine 
• 
Weight-adjusted dose of axicabtagene ciloleucel 
• 
Total CAR T cells of the axicabtagene ciloleucel infusion 
• 
Total T cells of the axicabtagene ciloleucel infusion 
• 
Transduction ratio 
• 
Percentages of CD4 and CD8 T cells 
• 
Percentages of T cell memo1y phenotypes 
• 
IFN-gamma production in co-cultures of axicabtagene ciloleucel product and CD19+ target 
cells 
• 
Vector copy number of axicabtagene ciloleucel product 
Separate summaries will be presented for the 2nd administration of conditioning chemotherapy 
for subjects in the Re-treatment Analysis Set. 
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9.9. 
CAR T cells Measured in Peripheral Blood 
Kite Phanna, Inc. 
Summary statistics for the level of CAR T cells in sernm post axicabtagene ciloleucel infusion 
will be provided for CAR T cells measured at intervals outlined in the Schedule of Assessment 
of the protocol. The area under the concentrntion over time curve may be sUilllllarized from day 
0 to day 28. 
9.10. 
B-cell Aplasia 
The subject incidence of B-cell aplasia, and the subject incidence of recovery after B-cell aplasia 
will be provided for each subject based on B cells measured by flow cytometiy prior to 
conditioning chemotherapy, on the day of the axicabtagene ciloleucel infusion, week 4, month 3, 
month 6, month 9, month 12, month 15, month 18, and month 24. The use of IVIG ti·eatment will 
be sUilllllarized. 
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10. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES 
None. 


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11. 
REFERENCES 
Ardeshna KM, Kakouros N, Qian W, Powell MG, Saini N, D'Sa S, et al. Conventional second-
line salvage chemotherapy regimens are not warranted in patients with malignant 
lymphomas who have progressive disease after first-line salvage therapy 
regimens. Br J Haematol 2005;130 (3):363-72. 
Brown LD, Cai TT, DasGupta A. Interval Estimation for a Binomial Proportion. Statistical 
Science 2001;16 (2):101-33. 
Brown LD, Cai TT, DasGupta A. Confidence Intervals for a Binomial Proportion and 
Asymptotic Expansions. The Annals of Statistics 2002;30 (1):160-201. 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of 
Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 
2014;32 (27):3059-68. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007;25 (5):579-86. 
Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in 
refractory diffuse large B-cell lymphoma: results from the international 
SCHOLAR-1 study. Blood 2017;130 (16):1800-8. 
Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. 
Journal of the American Statistical Association 1999;94 (446):496-509. 
Hitz F, Connors JM, Gascoyne RD, Hoskins P, Moccia A, Savage KJ, et al. Outcome of Patients 
with Chemotherapy Refractory and Early Progressive Diffuse Large B Cell 
Lymphoma After R-CHOP Treatment. Blood (ASH Annual Meeting Abstracts, 
Poster Session) 2010;116 (Abstract #1751). 
Josting A, Rueffer U, Franklin J, Sieber M, Diehl V, Engert A. Prognostic factors and treatment 
outcome in primary progressive Hodgkin lymphoma: a report from the German 
Hodgkin Lymphoma Study Group. Blood 2000;96 (4):1280-6. 
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the 
diagnosis and management of cytokine release syndrome. Blood 2014;124 
(2):188-95. 
Matasar MJ, Czuczman MS, Rodriguez MA, Fennessy M, Shea TC, Spitzer G, et al. 
Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or 
refractory intermediate grade B-cell lymphoma. Blood 2013;122 (4):499-506. 


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Moskowitz CH, Bertino JR, Glassman JR, Hedrick EE, Hunte S, Coady-Lyons N, et al. 
Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and 
peripheral-blood progenitor-cell mobilization regimen for transplant-eligible 
patients with non-Hodgkin's lymphoma. J Clin Oncol 1999;17 (12):3776-85. 
Nagle SJ, Woo K, Schuster SJ, Nasta SD, Stadtmauer E, Mick R, et al. Outcomes of patients 
with relapsed/refractory diffuse large B-cell lymphoma with progression of 
lymphoma after autologous stem cell transplantation in the rituximab era. 
American Journal of Hematology 2013;88 (10):890-4. 
Pepe MS, Mori M. Kaplan-Meier, marginal or conditional probability curves in summarizing 
competing risks failure time data? Statistics in Medicine 1993;12 (8):737-51. 
Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, et al. Autologous 
bone marrow transplantation as compared with salvage chemotherapy in relapses 
of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 1995;333 
(23):1540-5. 
Putter H, Fiocco M, Geskus RB. Tutorial in biostatistics: competing risks and multi-state models. 
Statistics in Medicine 2007;26 (11):2389-430. 
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin 
Trials 1996;17 (4):343-6. 
Seshadri T, Kuruvilla J, Crump M, Keating A. Salvage Therapy for Relapsed/Refractory Diffuse 
Large B Cell Lymphoma. Biology of Blood and Marrow Transplantation 2008;14 
(3):259-67. 
Song Y, Chi GY. A method for testing a prespecified subgroup in clinical trials. Stat Med 
2007;26 (19):3535-49. 
Telio D, Fernandes K, Ma C, Tsang R, Keating A, Crump M, et al. Salvage chemotherapy and 
autologous stem cell transplant in primary refractory diffuse large B-cell 
lymphoma: outcomes and prognostic factors. Leukemia & Lymphoma 2012;53 
(5):836-41. 
Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, et al. Safety and activity 
of blinatumomab for adult patients with relapsed or refractory B-precursor acute 
lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet 
Oncology 2015;16 (1):57-66. 
Wang SJ, O'Neill RT, Hung HM. Approaches to evaluation of treatment effect in randomized 
clinical trials with genomic subset. Pharm Stat 2007;6 (3):227-44. 
 


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12. 
APPENDICES 
 
 
Appendix 2. 
Source and Disposition of Non-Clinical Database Data 
Appendix 3. 
Conventions for Clinical Data That Require Imputation for Partial or Missing Dates 
Appendix 4. 
Sample Adverse Event Table Layouts 
Appendix 5. 
Derivation of Time to Event Endpoints and Last Date Known to Be Alive 
 
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Appendix 2. 
Source and Disposition of Non-Clinical Database Data 
Sample Type 
Analysis / Data 
Element 
Testing Lab / 
Source 
Responsible to 
transfer to TCR 
Include in 
Clinical Data 
Submitted to 
FDA 
Analysis Plan 
Product cells 
Total T cells 
Batch record 
Kite/TCR 
Yes 
Primary SAP 
Product cells 
Transduction ratio 
Batch record 
Kite/TCR 
Yes 
Primary SAP 
Product cells 
Total CARCAR T 
cells 
Batch record 
Kite/TCR 
Yes 
Primary SAP 
Product cells 
Total T Cells 
Batch record 
Kite/TCR 
Yes 
Primary SAP 
Product cells 
Days of 
manufacture 
PCT / Batch 
record 
Kite/TCR 
Yes 
Primary SAP 
Product cells 
CD4/CD8 Ratio, 
Memory 
phenotypes 
Kite  
Kite 
No 
Primary SAP and 
supplemental 
translational 
research SAP 
Product cells 
Cytokines (co 
culture) 
Kite 
Kite 
No 
Supplemental 
translational 
research SAP 
Biospecimen 
(post KTE-C19 
infusion 
samples) 
Cell 
differentiation and 
phenotype 
Kite 
Kite 
No 
Supplemental 
translational 
research SAP 
Biospecimen 
Cytokines 
Kite 
Kite 
No 
Supplemental 
translational 
research SAP 
Biospecimen 
CAR PCR 
 
 
Yes 
Primary SAP and 
Supplemental 
translational 
research SAP 
Biospecimen 
Antibody 
 
 
Yes 
Primary SAP 
Biospecimen 
RCR 
 
 
Yes 
Primary SAP 
Tissue blocks 
Pathology 
 
 
Yes 
Primary SAP 
Independent 
Radiology 
Review 
{Cheson 2007} 
 
 
Yes 
Primary SAP 
All data will be archived at 
 Kite Pharma. Data indicated as ‘Yes’ for inclusion in the clinical data submitted to FDA 
will be merged with the clinical data.  Data indicated as ‘No’ for inclusion in the clinical data submitted to FDA will be archived 
at 
 or Kite but may not merged with the clinical data. 
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Appendix 3. 
Conventions for Clinical Data That Require Imputation for Partial or 
Missing Dates 
The following data will be imputed using the following algorithm: 
• AE start dates 
• Deaths (please see exceptions below) 
• Concomitant medication start dates 
• Subsequent anti-cancer therapy start dates 
Table 4. 
Imputation Rules for Partial or Missing Start Dates 
Start Date 
Stop Date 
Complete:  yyyymmdd 
Partial:  yyyymm 
Partial:  yyyy 
Missing 
< day 0 
≥ day 0 
< day 0 
yyyymm 
≥ day 0 
yyyymm 
< day 0 
yyyy 
≥ day 0 
yyyy 
Partial 
yyyymm 
= day 0 
yyyymm 
2 
1 
2 
1 
n/a 
1 
1 
≠ day 0 
yyyymm 
2 
2 
2 
2 
2 
 
Partial 
yyyy 
=day 0 
yyyy 
3 
1 
3 
1 
n/a 
1 
1 
≠ day 0 
yyyy 
3 
3 
3 
3 
3 
 
Missing 
4 
1 
4 
1 
4 
1 
1 
1 = impute the date of day 0 
2 = impute the first of the month 
3 = impute January 1 of the year 
4 = impute January 1 of the stop year 
Note:  if the start date imputation leads to a start date that is after the stop date, then do not impute the start date. 
Imputation rules for partial or missing death dates: 
1) 
If death year and month are available but day is missing: 
• 
If mmyyyy for the last date known to be alive = mmyyyy for death date, set death date to the day after the last date known to 
be alive. 
• 
If mmyyyy for the last date known to be alive < mmyyyy for death date, set death date to the first day of the death month. 
• 
If mmyyyy for last date known to be alive > mmyyyy for death date, data error and do not impute. 
2) 
If both month and day are missing for death date or a death date is completely missing, do not impute and censor the subject 
survival time at the last date known to be alive. 


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Appendix 4. 
Sample Adverse Event Table Layouts   
All treatment emergent adverse events will be summarized in the AE Summary Table format below.  Tables will be generated for 
Phase 1, Phase 2 Cohort 1, Phase 2 Cohort 2, Phase 2 Cohort 1 and 2 combined, Phase 2 Cohort3, Phase 2 Cohort 4, Phase 2 Cohort 5, 
and Phase 2 Cohort 6. 
AE Summary Table Format 
 
(N = ) 
Any TEAE 
X (XX) 
     Worst Grade 1 
 
     Worst Grade 2 
 
     Worst Grade 3 
 
     Worst Grade 4 
 
     Worst Grade 5 
 
     Worst Grade ≥ 3 
 
 
 
Any Serious TEAE 
 
     <Worst Grades as above> 
 
 
 
Any Conditioning Chemotherapy Related TEAE 
 
     <Worst Grades as above> 
 
 
 
Any Serious Conditioning Chemotherapy Related TEAE 
 
     <Worst Grades as above> 
 
 
 
 


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Adverse Event Summary Layout 1:  All AE summaries and AE subgroup analyses will be provided in format 1.  The preferred terms 
will be sorted by descending order of frequency of the All, Any column.  Tables will be generated for Phase 1, Phase 2 Cohort 1, 
Phase 2 Cohort 2, Phase 2 Cohort 1 and 2 combined, Phase 2 Cohort 3, Phase 2 Cohort 4, Phase 2 Cohort 5, and Phase 2 Cohort 6. 
Subject Incidence of <AE Descriptor> Adverse Events in Descending Order of Preferred Term by Worst Severity 
(N = ) 
MedDRA Preferred Term n (%) 
Any 
Worst Grade 
1 
Worst Grade 
2 
Worst Grade 
3 
Worst Grade 
4 
Worst Grade 
5 
Any 
 
 
 
 
 
 
Preferred Term 1 
 
 
 
 
 
 
Preferred Term 2 
 
 
 
 
 
 
 
Adverse Event Summary Layout 2:  All AE summaries and AE subgroup analyses will be provided in format 2.  The preferred terms 
will be sorted by descending order of frequency of the All, Any column.  Tables will be generated for Phase 1, Phase 2 Cohort 1, 
Phase 2 Cohort 2, Phase 2 Cohort 1 and 2 combined, Phase 2 Cohort 3, Phase 2 Cohort 4, Phase 2 Cohort 5, and Phase 2 Cohort 6. 
Subject Incidence of Grade 3 or Higher <AE Descriptor> Adverse Events in Descending Order of Preferred Term by Worst 
Severity 
(N = ) 
MedDRA Preferred Term n (%) 
Any 
Worst Grade 
3 
Worst Grade 
4 
Worst Grade 
5 
Any 
 
 
 
 
Preferred Term 1 
 
 
 
 
Preferred Term 2 
 
 
 
 
 


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Adverse Event Summary Layout 3:  All treatment emergent adverse events will be presented in the format below.  Tables will be 
generated for Phase 1, Phase 2 Cohort 1, Phase 2 Cohort 2, Phase 2 Cohort 1 and 2 combined, Phase 2 Cohort 3, Phase 2 Cohort 4, 
Phase 2 Cohort 5, and Phase 2 Cohort 6. 
Subject Incidence of <AE Descriptor> Adverse events in Descending Order of Preferred Term by System Organ Class and 
Worst Severity 
(N = ) 
 
Any 
Gr 3 
Gr 4 
Gr 5 
 
 
 
 
 
Any <AE Descriptor> Adverse Event n(%) 
 
XX (X) 
XX (X) 
XX (X) 
XX (X) 
System Organ Class 1 
XX (X) 
XX (X) 
XX (X) 
XX (X) 
     Preferred Term 1 
XX (X) 
XX (X) 
XX (X) 
XX (X) 
     Preferred Term 2 
XX (X) 
XX (X) 
XX (X) 
XX (X) 
System Organ Class 2 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 


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Adverse Event Summary Layout 4:  Fatal adverse events will be summarized in the format below.  Tables will be generated for 
Phase 1, Phase 2 Cohort 1, Phase 2 Cohort 2, Phase 2 Cohort 1 and 2 combined, Phase 2 Cohort 3, Phase 2 Cohort 4, Phase 2 Cohort 5, 
and Phase 2 Cohort 6. 
Subject Incidence of Fatal Adverse Events  
(N = ) 
MedDRA Preferred Term n (%) 
 
Any 
 
Preferred Term 1 
 
Preferred Term 2 
 
 


KTE-Cl9 
Statistical Analysis Plan 
KTE-Cl9-101 (ZUMA-I) 
Appendix 5. 
1.DOR 
Kite Phanna, Inc. 
Derivation of Time to Event Endpoints and Last Date Known to Be 
Alive 
DOR is defined only for subjects who experience an objective response and is the time from the 
first objective response to disease progression or death due to any cause. Response and 
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3.PFS 
Kite Phanna, Inc. 
1111 ---
PFS is defined as the time from axicabtagene ciloleucel infosion date to the date of disease 
progression or death from any cause. Progression may be defined per Investigator read -
{Cheson 2007} or Central Read - {Cheson 2007}. Subjects not meeting the criteria for 
progression by the analysis data cutoff date will be censored at their last evaluable disease 
assessment date. PFS will be derived using disease assessments obtained on study prior to 
initiation of new anti-cancer thera 
excludin SC . Disease assessments after SCT will be 
used in the derivation of PFS. 
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4. OS 
Kite Phanna, Inc. 
OS is defined as the time from axicabtagene ciloleucel infusion to the date of death from any 
cause. Subjects who have not died by the analysis data cutoff date will be censored at their last 
date known to be alive prior to the data cutoff date with the exception that subjects known to be 
alive or detennined to have died after the data cutoff date for each analysis will be censored at 
the data cutoff date. 
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13. 
HISTORY OF REVISIONS 
Version 
Date 
Description of Changes 
Original (1.0) 
11MAY2015 
N/A 
2.0 
28AUG2016 
• 
Added Phase 2 Cohort 3 and the corresponding objectives, sample 
size, endpoints, interim analysis and primary analyses of the cohort 
• 
Updated overall study sample size 
• 
Added the definition of Study Day 0 
• 
Updated the timing of primary clinical study report generation 
 
 
 
 
• 
Replaced lymphocyte subsets section with B-cell aplasia 
• 
Removed All Leukapheresed Analysis Set (ALS) 
3.0 
08JUL2019 
• 
Added Cohort 4, Cohort 5 and Cohort 6 to Phase 2 safety management 
study (SMS) and the corresponding objectives, sample size, endpoints, 
interim analysis and primary analyses of each of the cohorts 
• 
Clarified central read of tumor assessment data are collected for Phase 
2 pivotal study only 
• 
Added EQ-5D scale score and VAS score to Phase 2 SMS 
 
 
• 
Updated the section of definitions (including identified and potential 
risks) 
• 
Updated electronic transfer and archival of data 
• 
Updated the list of demographic and baseline characteristics 
 
 
 
 
  
• 
Updated imputation rules for partial or missing start dates 
 
 
 
• 
Made other changes to improve document consistency with the study 
protocol 
 
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